Allenic and cumulenic lipids

0163-7827/$ - see front matter � 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.plipres.2007.07.001

Abbreviations: AADC, aromatic acid decarboxylase; ABA, abscisic acid; a-Allenic-DOPA allenic analog of amino acid L-3,4-dihydoxyphenylalanine (L-DOPA); GABA, c-aminobutyric acid; HepG2, human hepatocellular liver carcinoma cell line; HUVEC, umbilicvein endothelial cells; LM, leucomycin; LOX, lipoxygenase; LPS, lipopolysaccharide; MGC, mammalian gene collection; MTT assay islaboratory test and a standard colorimetric assay for measuring cellular proliferation; NF-kappa B, factor-kappa B; OAT, optically activtriglycerides; Raji cells are a line of EBV-transformed lymphocytes with surface Fc receptors; TNF-alpha, tumor necrosis factor; VDRvitamin D nuclear receptor.

q See Ref. [1] for a previous article giving additional information.* Corresponding author. Tel./fax: +972 2 590 2947.

E-mail address: [email protected] (V.M. Dembitsky).

Progress in Lipid Research 46 (2007) 328–375

www.elsevier.com/locate/plipres

Progress inLipid Research

Review

Allenic and cumulenic lipids q

Valery M. Dembitsky a,*, Takashi Maoka b

a Department of Medicinal Chemistry and Natural Products, School of Pharmacy,

P.O. Box 12065, Hebrew University, Jerusalem 91120, Israelb Research Institute for Production Development, 15 Shimogamo-Morimoto-Cho, Sakyo-Ku, Kyoto 606-0805,

Kyoto Pharmaceutical University, Japan

Received 14 May 2007; received in revised form 13 June 2007; accepted 2 July 2007

Abstract

Nowadays, about 200 natural allenic metabolites, more than 2700 synthetic allenic compounds, and about 1300 cumu-lenic structures are known. The present review describes research on natural as well as some biological active allenic andcumulenic lipids and related compounds isolated from different sources. Intensive searches for new classes of pharmaco-logically potent agents produced by living organisms have resulted in the discovery of dozens of such compounds possess-ing high anticancer, cytotoxic, antibacterial, antiviral, and other activities. Known allenic and cumulenic compounds canbe subdivided on several structural classes: fatty acids, hydrocarbons, terpenes, steroids, carotenoids, marine bromoal-lenes, peptides, aromatic, cumulenic, and miscellaneous compounds. This review emphasizes the role of natural and syn-thetic allenic and cumulenic lipids and other related compounds as an important source of leads for drug discovery.� 2007 Elsevier Ltd. All rights reserved.

Keywords: Fatty acids; Lipids; Triacylglycerides; Hydrocarbons; Allenic; Cumulenic; Anticancer; Antiviral; Antibacterial; Terpenoids;Carotenoids; Steroids; Peptides; Aromatic; Synthetic

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3292. Allenic fatty acids and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

r-alae,

mailto:[email protected]

V.M. Dembitsky, T. Maoka / Progress in Lipid Research 46 (2007) 328–375 329

2.1. Biosynthesis and synthesis of allenic lipophilic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3322.2. Triacylglycerides of plant species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

3. Allenic prostaglandins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3394. Allenic hydrocarbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3405. Allenic steroids and derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3416. Allenic terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3437. Marine bromoallenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3458. Allenic norisoprenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3489. Allenic carotenoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

9.1. Distribution in nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
99
.1.1. Marine and freshwater algal species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

.1.2. Higher plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354

.1.3. Invertebrates and animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
99.2. Functions and biological activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
10. Aromatic and peptide metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35811. Allenic amino acids and derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36012. Allenic alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36013. Cumulenic lipids and related compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36114. Addition to distributions, biosynthetic preparation and synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36315. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

1. Introduction

Fatty acids constitute an abundant class of natural compounds and are major constituents of many com-plex lipids. Fatty acids differ in the number of olefinic bonds, extent of branching, the length of the hydrocar-bon chain, and the number of functional groups. Allenic fatty acids which are one of the most interestinggroups among the naturally occurring lipids, are often neglected in the literature [2,3]. Allenic fatty (carbox-ylic) acids and other liphophilic metabolites contain the [–HC@C@CH–] group, and cumulenic fatty (carbox-ylic) acids and related compounds contain the [–HC@C@C@CH–] group. Both these lipid groups are rare innature [2–4]. Graphic chemical structures both groups are shown in Fig. 1.

Natural occurrence, structures, and biosynthetic pathways have partly been reported in several publications[4–8]. Among naturally occurring allenic fatty acid derivatives are a large group compounds which show cyto-toxic, antibacterial, antiviral and other activities, [2,8,9]. Synthesis of allenes, cumulenes, and acetylenes hasalso been reviewed [8–14].

The chemistry of allenes began from Jacobus Henricus van’t Hoff (awarded the first Nobel Prize in Chem-istry, 1901), who predicted the structures of allenes and cumulenes paper, in 1875 [15]. The first allenic dicar-boxylic acid, named glutinic acid (2,3-pentadienedioic acid) was isolated from leaf resin of Alnus glutinosa(Betulaceae, also called ‘European alder’), in 1908 by Hans [16]. The first allenic carotenoid, named fucoxan-thin was found in extracts of three species of marine brown algae, Fucus, Dictyota and Laminaria, in 1914 byWillstatter and Page [17]. More recently, fucoxanthin was isolated from other algae, invertebrates, plants, andother species [18–24].

The first allenic sesquiterpene named panacene was isolated from mixture of H2O–Et2O–MeOH extract of aperennial shrub Korean ginseng (also called Panax ginseng) in 1915 by Kondo and Tanaka [25]. In 1931, Minre-discovered the sesquiterpene previously named panacene from Panax ginseng and Panax quinquefolius [26].In 1964, Lee and Lee confirmed the presence of sesquiterpene panacene in Panax ginseng [27]. More recently,brominated analog of panacene was isolated from the sea hare Aplysia brasiliana, and it acts as a fish antife-edent [28]. The second allenic fatty acid, named mycomycin, which was produced by a mold-like Actinomyceteand was active against the Bacilli sp. of human tuberculosis was discovered in 1947 by Johnson and Burdon[29]. The structure of mycomycin and its physical, chemical, and tuberculostatic properties were reported soonafter [30–34].

R CH C CH R1 R CH C C CH R1

R1RR1R

Allenes Cumulenes

R R1 R R1

Fig. 1. Graphical display of chemical structures of allenes and cumulenes. R, R1 = H, alkyl, heteroatoms, and etc.

330 V.M. Dembitsky, T. Maoka / Progress in Lipid Research 46 (2007) 328–375

The first cumulenic acids, such as two c-lactones of 4-hydroxy-2,4,6,7,8-decapentaenoic and 4-hydroxy-2,4,5,6,8-decapentaenoic acids were isolated from several Astereae (Asteraceae) [35].

In the past few decades, natural metabolites containing an allene and cumulene groups have been isolatedfrom plants, marine algae, invertebrates, and other organisms. Extensive pharmacological screening per-formed on both terrestrial and aquatic species resulted in the discovery of novel antitumor, antibacterial,and antiviral agents. The purpose of this review is to summarize more than 300 different natural, syntheticallenic and cumulenic products with pharmacological active properties. These allenic compounds are subdi-vided into several structural classes: fatty acids, hydrocarbons, terpenes, steroids, carotenoids, marine bro-moallenes, peptides, aromatic, as well as cumulenic compounds.

2. Allenic fatty acids and derivatives

The structure of glutinic acid (1) was confirmed in 1958 [36], and its absolute configuration was establishedin 1962 [37]. Glutinic acid has been used as a starting substrate for synthesizing natural allenes [38,39], hetero-cyclic prostanoids [40], alkaloids [41], nucleosides [42] and other heterocyclic compounds [43–45].

Mycomycin (2), antibiotic 07F275 (3), and its methyl ester (4), produced by submerged fermentations offungal culture LL-07F275, were isolated and characterized despite their inherent instability. Since 07F275is a C13-containing allenic diyne, it is closely related to mycomycin, but without double bonds [46]. AntibioticLA-1 (5, 9-oxo-2,4,5,7-decatetraenoic acid) was isolated from the culture broth of LM-producing Streptomy-ces kitasatoensis NU-23-1. During fermentation, before LM is produced, LA-1 is transiently accumulated [47].In 1949, nemotinic acid (6, 4-hydroxy-5,6-undecadiene-8,10-diynoic acid), and nemotin (8) were isolated fromcultures of three Basidiomycete species: Poria tenuis, P. corticola, and an unidentified fungus (B-841). Bothcompounds exhibited antibiotic activity against Staphilococcus aureus [48,49]. Nemotinic acid and 4-b-D-xylo-pyranosyloxy-5,6-undecadiene-8,10-diynoic acid (7) were isolated from the cultures of Basidiomycete B-841[50]. Cortinellin (also known as nemotinic acid) has a broad antibiotic spectrum on Gram-positive andGram-negative bacteria, mycobacteria, and fungi (limited concentration at 0.3 cg/mL) [51]. Nemotin and dro-sophilin D (9) are also produced by some Basidiomycete species [52]. Several natural antibiotics, includingnemotinic acid and neomycin, were tested against 60 strains of bacterial viruses by a paper-disk method. Thesecompounds showed good activity against Enterococcus phage (phylum Firmicutes) [53].

1 Glutinic acid

HOOC COOH

CO2H

HH

H

2 Mycomycin

Z E

H

HO

COORH

H

3 Antibiotic 07F275, R = H4 R = Me

5 Antibiotic LA 1

COOHO

RO

COOH

H

H H

6 Nemotinic acid, R = H7 R = Xyl

O

H

O

HH

8 Nemotin

COOH

9 Drosophilin D


Odyssic acid (10, 4-hydroxy-5,6-dodecadiene-8,10-diynoic acid), and its methyl ester (11), odyssin (12),nemotinic acid (6), and its c-lacton (8) have been isolated from the higher fungi belonging to Basidiomycetes[54]. Two years later, odyssic acid, its methyl ester, and odyssin were also found in other unidentified higherfungi [55]. Ten years later, nemotinic acid and nemotin were isolated from the cultured media of Poria suba-cida, P. colorea, and P. mutans, P. subacida also yields Me nemotinate (11). Interestingly, Me nemotinate wasalso derived from the fungus Coprinus flocculosus [56,57]. 3,4-Nonadiene-6,8-diynoic acid (13), its methyl ester(14), and nemotinic acid have been isolated from the fungi Aleurodiscus roseus [58].

The natural C18 allene fatty acid has been isolated from seed oil of Leonotis nepetaefolia, which contains upto 16% laballenic (15, (�)-5,6-octadecadienoic) acid [59]. Lamium purpureum seed oil contains 16% of an acidcharacterized as (�)-octadeca-5,6-trans-16-trienoic (lamenallenic) acid (16). This acid was isolated as its Meester from the transesterification products of L. purpureum oil by countercurrent distribution by using a com-bination of recycling and single withdrawal techniques. Me lamenallenate (17) is strongly levorotatory [60].

Phlomic acid (18, 7,8-eicosadienoic acid or 20:2D7,8 allene) was observed in several genera of the Lamia-ceae, subfamily Lamioideae: hemp nettle (Galeopsis tetrahit), horehound (Marrubium vulgare), Lamium

galeobdolon, L. maculatum, Leonurus cardiaca, L. sibiricus, Moluccella laevis, Panzerina canescens, Phlomis

fruticosa, P. samia, P. tuberose, Physostegia virginiana, Stachys byzantina, and S. palustris. The occurrenceof this fatty acid was correlated with the presence of 20:1 acid, 20:1D9 cis- or 20:1n � 11. Phlomic acid wasapparently produced by chain elongation of the major seed oil fatty acid, laballenic acid, or 18:2D5,6 allene(16) [61]. The 2-(1,2-tetra-decadienyl)-cyclopropane-carboxylic acid (19) and laballenic acid were isolated fromLeonotis nepetaefolia seed oil [62]. A triene allenic fatty acid (20) and methyl ester (21) were shown to occur asa sex pheromone in the male dried bean beetle Acanthoscelides obtectus (Coleoptera, Bruchidae) [63]. The neu-tral lipids of both Phlomis species had a significant number of the same basic components. In fact, the seeds ofboth species contain monohydroxyacyldiacyl glycerides, but those of P. oreophilla had monoepoxyacyl- andmonooxoacyldiacyl glycerides, which were absent in seeds of P. regellii. Lipids of P. oreophilla seeds had ahigh linoleic acid content and those of P. regellii seeds had a high oleic acid content [64].

Two rare bromoallenic aliphatic fatty acids (12E,15S,18S)-15-hydroxy-18-bromo-12,16,17-octadecatrienoicacid (22) and (13Z,15R,18R)-15-hydroxy-18-bromo-13,16,17-octadecatrienoic acid (23) have been isolatedfrom several lichen species: Acarospora gobiensis, Cladonia furcata, Lecanora fructulosa, Leptogium saturni-num, Peltigera canina, Rhizoplaca peltata, Xanthoparmelia camtschadalis, Xanthoparmelia tinctina, and Xanth-

oria elegans [65,66]. The distribution of these isolated allenic fatty acids is shown in Table 1.

12 Odyssin

O

O

H H

HO

COORH H

10 Odyssic acid, R = H11 R = Me

H

COOR

13 R = H14 R = Me

20 R = H, R1 = n-Bu21 R = R1 = Me

COOR

R1

18 Phlomic acid

H

H

COOH

16 Lamenallenic acid, R = H17 R = Me

COORH

H

COOHH

H

15 Laballenic acid

COOH19


Marasin allenic diacetylene (24, 3,4-nonadiene-6,8-diyn-1-ol), an unstable antibiotic, was isolated from theculture medium of Marasmius ramealis as a highly unsaturated, optically active, straight-chain alcohol [67].Marasin belongs to the category of compounds that contain acetylene-allene bonds. Common to these sub-stances, besides their antibiotic action and instability, is their alkali-catalyzed isomerization. This is accompa-nied by changes in ultraviolet and infrared spectra. Marasin was active in vitro against numerous bacteriaincluding Mycobacterium tuberculosis. Marasin, allenic alcohols (25–29), as well as two m-dioxane derivatives(30, 31), were isolated from five basidiomycete fungi (Cortinellus berkeleyanus, Odontia bicolor, Flammula sapi-

nea, Daedalea juniperina, and the unidentified fungus B285) [68]. The sea coral Plexaura homomalla containsprostaglandins of the A and E series. It has been proposed that a key step in the pathway of biosynthesisinvolves the 8(R)-lipoxygenase metabolites of arachidonic acid. The 8-hydroxy-5,9,11,14–20:4, 8-hydroper-oxy-5,9,11,14–20:4, (5Z,8R,11Z,14Z)-8,9-epoxy-5,9,11,14-eicosatetra-enoic acid (32), and prostaglandins wereisolated, but an allenic intermediate (33) has not been discovered [69–71].

31

H

OOH

O

O

30

H

H H

OH26

H

H H

OHR

27 R = H28 R = OH

H

H H

OH29

OH

R

24 Marasin, R = H25 R = Me

HOOCO

32

33

3

3

HOOC

H

H

Br

HOOC

OH

H

Br

H

HOOC

OH22 n = 8

23 n = 7

n

n

2.1. Biosynthesis and synthesis of allenic lipophilic compounds

Biosynthesis of the allene (�)-marasin in Marasmius ramealis was recently reported [72]. [1-14C]-E-Dehy-dromatricaria methyl ester and dimethyl [1-14C]-deca-4,6,8-triyne-1,10-dioate were incorporated into theallene (�)-marasin in M. ramealis without scrambling of the 14C label. These levels of incorporations (0.8%and 4.9%, respectively) strongly suggest that the above esters, or their close relatives, can be converted directly

Table 1Occurrence of bromoallenic acids in lichen species from Tian Shan mountains [65]a

Lichen species 22 23

Acarospora gobiensis 2.8 0.7Cladonia furcata ND 1.9Lecanora fructulosa 3.2 NDLeptogium saturninum 2.5 NDPeltigera canina ND 1.8Rhizoplaca peltata 5.7 NDXanthoparmelia camtschadalis ND 3.6Xanthoparmelia tinctina ND 0.7Xanthoria elegans 1.5 ND

a mg/100 g of dry wet; ND, not detected.


into (�)-marasin in M. ramealis, and that the diyne-allene moiety in the latter compound arises by rearrange-ment, under enzymic control, of an alkyltriyne moiety. Biosynthesis of marasin takes place via four steps asshown in Scheme 1.

Novel allenic analogs (E)- and (Z)-(34–41) of ABA were synthesized and tested for ABA activity [73].The allene functional group was introduced by base-catalyzed isomerization of an enyne to an enallene con-jugated to a ketone, or by reduction of a 2-butyne-1,4-diol to an allenic alcohol. A 3:1 mixture of (E)-(34)and (Z)-(36) strongly inhibited growth of axenic duckweed (Lemna gibba), consequently causing a 50%reduction in frond number at 60 lg/L over a period of 7 days in continuous light. Racemic (24–37, and38–41) ABA compounds caused the same inhibition at 130 lg/L. This mixture caused the production of tur-ion-like structures, an effect previously known to be induced only by short photoperiods or by certain con-centrations of ABA. a-Allenic acids (42–49) were obtained by oxidation of the corresponding alcohols byPseudomonas aeruginosa (ATCC 17504) [74,75]. P. aeruginosa is a Gram-negative, aerobic rod belongingto the bacterial family Pseudomonadaceae. High yields (approx. 60–87%) were obtained, with partial reso-lution of racemic mixtures via preferential oxidation of one isomer. An enantiomeric excess was alsoobtained with a-secondary and b-allenic alcohols. Substituents close to the allenic function decrease theponderal yield. Allenic acids (32, 34, 36 and 37) were also obtained via oxidation of a-allenic alcohols byyeast alcohol dehydrogenase [76] (Scheme 2).

MeCOOMe

Dehydromatricaria ester

(ii) + (iii) + ester hydrolysis

10 9

1

1

910HOOC

COOH

(i) + (iv) + rearrangement

HCH2OH9

1

E

Marasin

Scheme 1. Apparent pathway from dehydromatricaria ester to marasin via dicarboxylic acid: (i) reduction of the C1 ester group to analcohol; (ii) saturation of the C2@C3 double bond; (iii) oxidation of the terminal C10 methyl group, which yields a hydroxymethyl group,then a carboxyl group; (iv) decarboxylation of the acid formed in (iii) produces a C9 compound (marasin).


O

OH

ROOC

E/Z

24 E, R = H25 E, R = Me

H

R

OE/Z

28 R = COOMe, E29 R = COOMe, Z

26 Z, R = H27 Z, R = Me

30 R = AcO, E31 R = AcO, Z

R

R COOH

H

COOH

H32 R = Me33 R = H

34

COOH

MeH

H

35

COOH

H

36

COOH

R

38 R = H39 R = Me

H H

COOH

37

The lipase from Candida rugosa was used for preparing optically active primary allenic alcohol derivatives(50–56) with axial chirality from a racemic mixture. Under optimized conditions (temperature and mediumused) (+)-S-(50, 51, 55, 56) and (�)-R-(52–54) were isolated in excellent yield and with high optical purity.The resolution was carried out on a multigram scale in water/n-hexane at 4 �C [77]. Allenecarboxylic acidderivatives, e.g. (57–55) were synthesized. At 10–200 mg/kg, the allenecarboxylic acids were anti-inflamma-tory, and at 1–250 mg/kg, they were hypolipidemic [78]. Palladium-catalyzed transformation of readily avail-able mixed unsaturated allenic aldehydes (63, 64) occurred, with a good yields of 50% and 82%, respectively[79].

H Me

H

RO

H

H

Me

RO

S

R

H

H

HOR

50 R = H51 R = Ac

53 R = H54 R = Ac

52

SH Me

Me

H

O

O

R

55 R = C11H23

56 R = Ph

H

COOEt

Me

MeO

R1

COOHH

R

R2

R1

COOH

R

57 R = MeS, R1 = Me, R2 = H 58 R = Cl, R1 = H, R2 = Me 59 R = cyclohexyl, R1 = R2 = H

60 R = Cl, R1 = H61 R = F, R1 = Me

62

Pseudo-C2-symmetric chiral phosphorus ylides have been designed and synthesized for the enantioselectivepreparation of allenic esters. Allenic carboxylic esters (65, 66) were obtained in good yields and with highenantiomeric excess (Scheme 3) [80]. Carboxylic allenic acids (67–70) have been synthesized as potent antitu-mor and antiulcer agents [81]. Compound (70) suppresses or eradicates Helicobacter pylori, thus preventing

H

CHO

HHOa

O O

O

Hb

63

Ph

CHO

PhHOa

O O

O

Phb

64

Scheme 2. Synthesis of unsaturated allenic aldehydes: (a) BuLi, tetrahydrofuran (THF)–hexane �20 �C, then COCl2, toluene, �20 �C,then silyl enol ether, MeLi, tetramethylethylenediamine, THF, �40 �C; (b) Pd(PPh3)4, THF, 60 �C.

PhROOC

65 R = Et, 81% ee66 R = t-Bu, 92% ee

P

Ph

Ph

Ph

O

O

R

+ Br- 1. NaHMDS, 25

oC, THF

2.

OPh -78

oC

Scheme 3. Synthesis allenic carboxylic acid esters (NaHMDS, sodium bis(trimethylsilyl)amide).


recurrence of peptic ulcer, and also (70) dose-dependently inhibited water immersion stress-induced ulcerformation in rats. Synthesis of other allenic compounds were reviewed in some books and other publications[6–8,10–14].

Me

Ph OEt

O

Me COOEt

67

Me

Ph

R

OEt

O

68 R = Me69 R = Ph

70

2.2. Triacylglycerides of plant species

Laballenic acid was present in seeds of both species, mostly as a free acid. The epoxy acids of P. oreophillaconsisted of 9,10-epoxystearic, vernolic, coronaric, and 15,16-epoxyoctadec-9,12-dienoic acids [64]. In the tria-cylglycerols of seeds of three species of the family Labiatae (Phlomis regelii, P. oreophilla, and Lavandula

spica), the saturated acids were distributed either in the sn-1 or in the sn-1 and sn-3 positions. The distributionof C18:1 was characteristic for each oil; C18:2 was esterified primarily in the sn-2 position, with some in sn-1 ofthe two terminals; C18:3 in two of the species preferentially occupied sn-3, and sn-1 occupied the other. In P.

regelii, laballenic acid esterified the 3 position of the triacylglycerols, with preference shown for the two ter-minals. Phosphorylation of sn-1,2- and sn-2,3-diacylglycerols was not accompanied by the formation of appre-ciable amounts of secondary products [82].


The advantages and disadvantages of HPLC investigations of triglycerides of seed oil from plants of theLamiaceae family: Ballota nigra, Dracocephalum thymiflorum, Leonurus cardiaca, Mentha piperita, Ocimum

basilicum, Origanum majorana, Phlomis tuberose, Salvia aethiopis, S. tesquicola, Stachys palustris, and S. recta

were reported [83]. Special attention was paid to triglycerides formed from laballenic acid. Four main types oftriacylglycerides (71–75) with laballenic acid have been isolated from seed oil of the Lamiaceae family. Theseed oil of Sebastiana commersoniana (Euphorbiaceae) was rich in triacylglycerides. Linolenic acid was themain fatty acid [82]. A unique triacylglyceride (74) was noted, where one a-carbon of the glyceride backbonewas esterified with 8-hydroxy-5,6-octadienoic acid, in the second position with trans-2-cis-4-decadienoic acid(also known as stillingic acid), and in the third position with a-linolenic acid [84].

The optically active lipid isolated from the seed oil of the Chinese tallow tree, Sapium sebiferum, previ-ously considered to be a triglyceride containing 2,4-decadienoic acid esterified with one of the primaryhydroxyls of glycerol, was shown to be tetraester triglyceride. The other primary hydroxyl of glycerol is ester-ified to 8-hydroxyoctanoic acid, and its x-hydroxyl group, which in turn, is esterified to decanoic acid. Intriacylglycerol the predominant common fatty acids are linoleic and linolenic acids. The 8-C hydroxy acidwas 8-hydroxy-5,6-octadienoic acid (see structure 75). The optical activity observed in compounds with 8-hydroxy-5,6-octadienoic acid probably resulted from the allene function rather than an asymmetric b-C ofglycerol [85]. The highly OAT of the seed oil of Sebastiana ligustrina were isolated and characterized [86].As with the similar, known triglycerides from Sapium sebiferum, the optically active 8-hydroxy-5,6-octadie-noic acid was esterified to glycerol and to 2,4-decadienoic acid. The other two acyl moieties in the triglycer-ides of both these species are common fatty acids, principally 16:0, 18:1, 18:2, and 18:3, which occur in pairsranging in degree of unsaturation from 16:0, 18:1 to 18:3, 18:3. Analysis of lipids of parts of the related spe-cies Stillingia sylvatica and S. texana revealed no allene or carbonyl conjugation, and thus by implication, noOAT. A substance having IR absorptions characteristic of allenes and carbonyl, conjugated dienes, but dif-ferent from OAT, was found in the stems of S. texana. The seeds of S. sebiferum are known to contain OAT,but it was not found in fresh leaves [86].

O

O

HO

O O

O

OH

H

7

ZE

4

75

5

5O

O

H

H(CH2)8Me

O

O O

(CH2)6Me

(CH2)4Me

O

5O

O

H

H(CH2)8Me

O

O O

(CH2)6Me

(CH2)4Me

O

129

9

5

O

O

H

H(CH2)8Me

O

O O

(CH2)4Me

(CH2)3Me

O

O

O

H

H(CH2)8Me

O

O O

(CH2)6Me

(CH2)3Me

O

71

72

73

74

α-ketol

RR

O OH

Z

13

76 9,11,12,14-Octadecataetraenoic acid

77 12,13(S)-oxido-9Z,11,15Z-octadecatrienoic acid

Linolenic acid

7-iso-Jasmonic acid

Reductaseβ-oxidation

O

COOH

O

(CH2)7COOHα- and γ-ketolsand racemic OPDA

Spontaneous hydrolysis

Allene oxide cyclase

Allene oxide synthase

+ H2O2

+ H+

HO2C5

5

HO2C

OOH

Z Z

EZ

HO2C

H

5

H

13(S)-Hydroperoxylinolenic acid

5

HO2C

O

Lipoxygenase

13-Hydroxy-9,11-octadecatrienoic acid

Z EHO2C

OH

5

- H2O

HO2CO+

HOOH

+

5 78

Fig. 2. The proposed mechanism involves the formation of reactive intermediate cations and allenic acid when used in oxidation oflinolenic acid. The lipoxygenase-catalyzed formation of the linolenic acid hydroperoxide includes the enzymatic conversion of the alleneoxide (12,13S)-epoxyoctadecatrienoic acid to enantiomeric 12-oxo-(10,15Z)-phytodienoic acid (OPDA) and later to jasmonic acid as wellas its chemical decomposition to a- and c-ketol and racemic OPDA.


The composition of glycerides was detected for seed oils of Anethum graveolens, Carum carvi, Corian-

drum sativum, Cuminum cyminum, Foeniculum vulgare, Pertroselinum sativum, Piminella anisum, Asclepias

syriaca, A. incarnata, Vincetoxicum nigrum, and Leucas cephalotes. Of these, the rarely occurring fattyacids are petroselinic, vaccenic, and laballenic acids [87,88]. Seed oil from Leonotis nepetaefolia contains16% of laballenic acid [59]; the oil of Leucas urticaefolia seeds contains 24% of 5,6-octadecadienoic(laballenic acid) [89], and Leucas cephalotes was found to be a new seed oil rich in labellenic acid up


to 28 wt.% [90]. The kernel oil of Chinese tallow (Sapium sebiferum) seed contains tetraester triglyceridescomposed of trans-2,cis-4-decadienoic acid joined in an estolide linkage to 8-hydroxy-5,6-octadienoic acid[91].

Earlier investigations showed that a particular isoform of LOX localized on lipid bodies plays a role ininitiating the mobilization of triacylglycerols during seed germination [92]. Physiological functions of LOXswithin whole cotyledons of cucumber (Cucumis sativus) were analyzed by measuring the endogenousamounts of LOX-derived products. As the dominant metabolite of the LOX pathway in this tissue,lipid-body LOX-derived esterified (13S)-hydroperoxy linoleic acid accumulated to about 14 lM/g freshweight, which represented about 6% of the total amount of linoleic acid in cotyledons. This LOX productwas not only reduced to its hydroxy derivative, leading to degradation by b-oxidation, but alternatively, itwas metabolized by fatty acid hydroperoxide lyase, leading to the formation of hexanal as well. Further-more, the activities of the LOX form metabolizing linolenic acid, were detected by measuring the accumu-lation of volatile aldehydes, ketones, and carboxylic acids [93]. Allene oxides are unstable epoxides that havebeen implicated as intermediates in the biotransformation of hydroperoxy-ecosatetraenoic acids and relatedhydroperoxides to ketols and cyclopentenones. However, direct proof of the structure of the putative alleneoxide intermediates has been hampered by their extreme instability under the conditions of their biosynthe-sis (Fig. 2).

The isolation and structural elucidation of allene oxides prepared from the (13S)-hydroperoxides of lin-oleic and linolenic acids have been described [92]. 12,13(S)-Oxido-9Z,11-octa-decadienoic acid was derivedfrom linoleic acid, and 12,13(S)-oxido-9Z,11,15Z-octadecatrienoic acid (77) was derived from linolenic acid(Fig. 2). Analysis of the breakdown products formed upon exposure to H2O led to identification of thehydrolysis and cyclization products previously characterized as enzymic derivatives of the (13S)-hydroper-oxides in flaxseed. 12,13(S)-Oxido-9Z,11-octadecadienoic and 12,13(S)-oxido-9Z,11,15Z-octadecatrienoic(77) acid were formed via reactive intermediate cations (78) and allenic fatty acid (76). An intermediate cat-ion (78) is unstable and produced allenic acid (76). This allenic fatty acid, with internal hydroperoxide, pro-duced allene oxide (77). Allene oxide (77) is also a reactive intermediate with an unusual structure,characterized by an epoxide ring with an exocyclic carbon–carbon double bond. Allene oxide cyclaseand/or spontaneous hydrolysis acts to form well-known jasmonic acid, a- and c-ketols, and racemic 12-oxo-(10,15Z)-phytodienoic acids, respectively [94–96]. Moreover, allene oxide cyclase catalyzes the stereo-

3

OH

O

O

O

3

COOMe

OH

O

COOHMe

Me

O

3

Me

MeCOOH

O

O

3

COOMe

O

OH OH

3

COOMe

Me

Me

O

OCOOMe

Me

Me COOMe

Me

Me

O

Me

MeCOOH

79

80

81

82

83

84

85

86

87

Fig. 3. Oxidation of allenic acids underwent via allene oxides and formed a-hydroxyketones and lactones.


specific cyclization of an unstable allene oxide to (9S,13S)-12-oxo-(10,15Z)-phytodienoic cacid, the ultimateprecursor of jasmonic acid [93].

Allenic carboxylic acids (79, 80) have been converted to functionalized lactones and a-ketols by oxidation–cyclization promoted by dimethyldioxirane. These transformations can be rationalized by the involvement ofallene oxide (81, 82) and spirodioxide intermediates (83, 84). When products were formed directly from alleneoxides, keto lactones are formed. The corresponding spirodioxide intermediates produced lactones (87) withappropriately situated a-hydroxyketone moieties (85, 86) (Fig. 3). Use of prepared solutions of the oxidantgenerally proceed via spirodioxides, whereas in situ reactions normally yielded products derived from theallene oxides [97]. Oxidation and epoxidation of allenic acids and other allenes have recently been reviewed[98].

3. Allenic prostaglandins

The term prostaglandin derives from the prostate gland. Prostaglandins were first discovered and iso-lated from human semen in 1935 by the Swedish physiologist Ulf Von Euler [99]. Prostaglandins playactive roles in stimulating human muscle contraction and in regulating the cardiovascular and nervous sys-tems. Structurally, they are unsaturated carboxylic acids, consisting of a 20-carbon skeleton that also con-tains a five-member ring; they are biochemically synthesized from arachidonic acid [100,101]. Allenicprostaglandins have not been isolated from natural sources, but some bioactive analogs of natural pros-taglandins have been synthesized and used in pharmaceutical science and clinics. Bronchodilator (88), aPGF2 analog, was prepared [102]; this prostaglandin (89) had 0.05–0.2 times the activity of PGF2a inan antifertility assay in hamsters [103]. Allenic prostaglandins (90) and (91) have physiological activitiessimilar to natural prostaglandins, e.g., as ovarian cycle regulators, broncho dilators, antihypertensives,and sedatives [104].

Prostaglandin-E analogues inhibit gastric acid secretion [105,106]. Enprostil (92), a synthetic analogue ofprostaglandin E2, is effective in treating patients with duodenal or gastric ulcers. Four allenic isomers, whichare prostanoids, are structurally related to PGE2. Enprostil also exhibited a potent agonist effect at FP and TPreceptors in the rat colon and guinea pig aorta (�logEC50 values = 7.34 and 6.54) [107]. The unnatural allenicR- and S-isomers of (92) were much less potent than (92), with the latter being virtually inactive. The (92) andthe natural R- and S-isomers, therefore, were EP3, FP, and TP agonists, being most potent at the EP3 recep-tor. The preferred configurations for these receptors appear to be the R form, and to a lesser extent, the S formof the natural allenic isomer [99]. In a MTT assay, concentrations of enprostil (>10 lM) had cytotoxitic effectson HT-29 cells [108]. Furthermore, enprostil (1 lM) suppressed IL-8 production in HT-29 cells, SW620 andCaCo2 were stimulated with interleukin-1-beta (IL-1-b) or LPS, but did not suppress this response when cellswere stimulated with TNF-a. The obtained results suggest that enprostil affects a point in the pathwaybetween the IL-1 receptor or the LPS receptor and nuclear NF-kappa B, without affecting the pathwaybetween the TNF receptor and NF-kappa B, with the latter factor being required for IL-8 gene transcription[108].

Enprostil and the somatostatin analogue SMS 201 995 affected the growth of a clonal variant of thehuman gastric adenocarcinoma cell line (MKN45) [109]. For example, Enprostil reduced postprandialserum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45in vitro. It also inhibited growth of colonic cancer cells PROb and REGb [110]. Moreover, Enprostilhas been shown to exert both antisecretory and mucoprotective effects [111]. Another prostaglandin, fen-prostalene (93, also known as Bovilene), could induce abortion during mid-pregnancy in bitches, and thesubsequent estrus may occur early with a low conception rate [104]. It has a known inhibitory effect onprostaglandin synthesis in newborn pigs [105,106]. Prostalene (94) solution may be used under the FederalFood, Drug, and Cosmetic Act for controlling estrus in mares [107,108]. Prostalene (at 1 mg) produced anincreased pregnancy rate after both foal heat and second postpartum estrus breedings in the mare [109].Other pharmacological and toxicological properties of prostalene were reviewed [110]. The prostacyclinanalogs, carbacyclin (95) and isocarbacyclin (96), were found to be potent antiplatelet agents in a ratthrombocytopenia model [111].


COOH

O

HO OH

88

COOH

HO

HOOH89

COOH

HO

OAc 90

COOH

O

HO91

R

93 Fenprostalene

OH

HO

OHPhO

H

H

MeOO

92 Enprostil

O

HO

OHPhO

H

H

MeOO

96 Isocarbacyclin

95 Carbacyclin

OHOH

MeO2C

H

CO2Na

OH OH

94 Prostalene

OH

HOH

H

MeOO

OH

4. Allenic hydrocarbons

Allenic hydrocarbons (97, 98, 100, 102, 106–109), previously unknown as a molecular class, have recentlybeen found in some Australian melolonthine scarab beetles: Antitrogus consanguineus, Dermolepida albohir-

tum, Lepidiota crinita, L. negatoria, and L. picticollis [112]. Syntheses of nonracemic allenes of known predom-inating chirality were acquired using both organotin chemistry and sulfonylhydrazine intermediates, andcomparisons then demonstrated that the natural allenes were predominantly (R)-configured. Distribution ofallenic hydrocarbons in scarab beetles are shown in Table 2. Previously, three allenic hydrocarbons only,9,10-tricosadiene (99), 9,10-pentacosadiene (101), and 9,10-heptacosadiene (103) were isolated from the sameAustralian melolonthine scarab beetles [113].

Table 2Distribution of D9,10-alkadienes in Canebeetle species [112]

Scarab species D9,10-Alkadienes

A. consanguineus 102, 103,a 104, 107

L. negatoria 103a

L. crinita 108, 109a

L. picticollis 101a

D. albohirtum 101a

a Major allene in each species.


Examination of the chemistry of a number of Australian insect species provided examples of unusual struc-tures and encouraged researchers to determine their absolute stereochemistry by stereocontrolled synthesesand chromatographic comparisons. Inter alia, studies with the fruit-spotting bug (Amblypelta nitida), certainparasitic wasps (Biosteres sp.), the aposematic shield bug (Cantao parentum), and various species of scarabgrubs were summarized. Determination of enantiomeric excesses (ee’s) for component allenes, epoxides, lac-tones, and spiroacetals was also reported [114].

n

106 n = 6107 n = 8108 n =11109 n =13

n 99 n = 1 100 n = 2101 n = 3102 n = 4

H

H

97

98

10

103 n = 5104 n = 7105 n = 9

5. Allenic steroids and derivatives

It has been established that the Hawaiian sponge Callyspongia diffusa contains 24-keto-cholesterol and anew allenic sterol, 24-ethyl-D5,24(28),28-cholestatrien-3b-ol (110) [115]. Isolated compounds specificallyinhibited the conversion of stigmast-5-en-3b-ol to stigmasta-5,24(28)-dien-3b-ol and/or to 24,28-epoxy-stig-mast-5-en-3b-ol in Bombyx mori larvae [116]. The (110) held the larvae in the second instar for >20 days whenadministered alone or with the dietary sterols. Synthetic cholesta-5,23,24-trien-3b-ol (111) inhibited insectgrowth and development, but did not act via inhibition of sterol dealkylation [117]. A series of allenicderivatives of cholesterol (112–115) was synthesized from pregnenolone [118]. These compounds carry anallenic function at C20 or C22 and were devised with the aim of inhibiting C22 hydroxylation of ecdysonebiosynthesis by a suicide-substrate mechanism. The four compounds synthesized could efficiently inhibitthe synthesis of ecdysone in the prothoracic glands of Locusta. It also was shown that all allenic steroidsinduced a decrease in the synthesis of ecdysone [119]. Three steroidal compounds (116–118) with allenic sidechains substituted for phosphonyl-linked groups were synthesized and tested for their effects on Leishmania

donovani and L. mexicana mexicana culture growth [120]. The compounds inhibited organism proliferationat concentrations in 5–10 lg/mL. Interestingly, the same two di-Et phosphonosteroid compounds (117 and118) that inhibited Leishmania proliferation were also the most active against P. carinii, as detected by thepotent effect they had in reducing cellular ATP content. The most potent inhibitors of this group of com-pounds were characterized by two ethyl groups at the phosphate function. Leishmania organisms treated with(117) exhibited reduced growth after transfer into inhibitor-free medium. Because there are currently no axenicmethods available for the continuous subcultivation of Pneumocystis carinii, the effects of these drugs on thisorganism were evaluated by two alternative screening methods.


111

HO

H

HH

H

110

HO

H

HH

H

115 R =

114 R =

113 R =

112

OH

H

OH

OH

H

OH

OH

HO

R

HO

The effects of conjugated allenic 3-oxo-5,10-secosteroids, (4R)-5,10-secoestra-4,5-diene-3,10,17-trione (119)and of (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione (120) on epididymal D4-5a-reductase and 3a-hydroxy steroid dehydrogenase were reported [121]. Assessment by IC50 values showed that D4-5a-reductasewas inhibited approx. 50- and 250-fold more effectively than 3a-hydroxy steroid dehydrogenase by (119) and(120), respectively. It also shown that compound (120) inhibited androgen biosynthesis in the mature rat (0.8–8 mg/kg/day for 7 days, i.p.) [122].

118

H

H H

O

PH

OEtO

OEt

H

116 R = H117 R = Et

H

H H

MeO

PH

ORO

OR

C

O

O

H H

HAc

C

O

O

H H

HO

119

120

123 C22 = S124 C22 = R

22

E

Z

OH

HOH

H

CH

H

OH

E

Z

121 C22 = S122 C22 = R

22

OH

HOH

H C

OH

OH

Dihydroxyvitamin D3

OH

HOH

H

OH


The steroid hormone 1a,25-dihydroxyvitamin D3 [(3b,5Z,7E)-9,10-secocholesta-5,7,10(19)-trienetriol], inwhich allenic functionality has been incorporated into the side chain (121–124), has been synthesized [123].The hormonal form of vitamin D, 1a,25-dihydroxyvitamin D3, generates many biological actions by interac-tions with its VDR. The presence of a carbon-25 hydroxyl group is necessary for optimizing binding to theVDR. To examine the effect of spatial orientation of the 25-hydroxyl, researchers recently observed two pairsof 22,23-allene side chain analogs [124]. The 22R orientation in analogs HR (52%) and LA (154%) resulted inhigher affinity binding than the 22S orientation of analogs (121 and 123) HQ (21%) and LB (3.5%;1,25D = 100%).

Limited trypsin proteolysis revealed that 22R analogs (122 and 124) induced VDR conformationalchanges better suited to protect VDR from digestion than 22S analogs. 22R analogs were also able toinduce gene transcription at 10–100-fold lower concentrations than 1,25D; however, 22S analogs were lesseffective. Analog LA was at least 10-fold more potent than 1,25D at inducing differentiation, whereas theother analogs were less potent. None of the analogs were as potent as 1,25D in promoting in vivo intes-tinal calcium absorption or bone calcium mobilization. LA was the most potent of the analogs butrequired 20–30-fold higher doses than 1,25D. The 25-hydroxyl orientation, combined with the 16,17-enefunctionality of analog LA, enhances its ability to interact with VDR and induce biological activity. Allen-ic sulfone (125), an analog of dehydroepiandrosterone sulfatide, a potent, natural inhibitor of glucose-6-phosphate dehydrogenase, was obtained from propargylic sulfone (126) by tautomerizing the electrophilicallene (125) [125].

126

H

O

HH

O2S

C13H27

H

O

HH

O2S

H

125

C13H27

6. Allenic terpenoids

Vernonallenolide (127), 4b-hydroxy-4,5-dihydro-vernonallenolide (128), and an epoxide of vernonalleno-lide (129) have been isolated from seven Vernonia species, mainly from northern Brazil [126]. The aerial partsof Vernonia cotoneaster from India afforded vernonallenolide (127), 4b-hydroxy-4,5-dihydrovernonallenolide(128) [127]. Three Vernonia species, namely, V. compactiflora, V. cotoneaster, and V. chalybaea, also containvernonallenolide [128,129]. Acalycixeniolides C (130), D (131), E (132), and four new diterpenoids of the xeni-cane class have been isolated from the gorgonian Acalycigorgia inermis. Isolated compounds exhibited cyto-toxicity against a human leukemia cell line [130]. Novel compounds, acalycixeniolide C, D, and E, isolatedfrom Acalycigorgia inermis, inhibit the growth of leukemia, and were thus used for the treatment of cancer[131]. Acalycixenolide E (132), from Acalycigorgia inermis, exhibits potent anti-angiogenic activity bothin vitro and in vivo. Compound (132) inhibits the bFGF-induced proliferation of HUVEC in a dose-dependentmanner, along with the basic fibroblast growth factor-induced migration, invasion, and tube formation ofHUVECs. Moreover, (132) potently inhibits the in vivo neovascularization of the chorioallantoic membranesof growing chick embryos [132].


A bioactive metabolite, ginamallene (133), was isolated from four species of Acalycigorgia and was shownto be a xenicin-type norditerpene having terminal allene functionality [133]. Acalycixeniolide B 0 (134), C 0

(135), and the previously reported ginamallene have been isolated from a gorgonian of the genus Acalycigorgia

as inhibitors of cell division of fertilized sea urchin eggs [134,135]. Twelve fungal strains from marine habi-tates, predominantly from the North Sea, were studied in a chemical screening program with respect to theirsecondary metabolite production. The strain WDMH46 (Paraspheaoshaeria sp.) produced several secondarymetabolites with an allene moiety, named lupallenes (136–142), which were isolated, and their structures elu-cidated by Diana Wolff (University of Gottingen, Germany) [136].

129

C

O

OAc

O

OAc

O

128

C

O

OAc

O

OAc

Me OH

127 Vernonallenolide

C

O

OAc

H

O

OAc

132 Acalycixeniolide E

O

H

HO

AcO

131 Acalycixeniolide D

O

O

H

HO

130 Acalycixeniolide C

O

O

H

HO

H

O

OAc

AcO

H

H

133 Ginamallene

O

R

O

134 Acalycixeniolide B', R = OAc 135 Acalycixeniolide C', R = H

Table 3Distribution of major lupallens in the strain WDMH46 (Paraspheaoshaeria sp., Ref. [136])

Metabolite Occurrence, % of total

136 17.9137 18.9138 17.6139 9.3140 29.3


Lupallene A (138), C (137), and E (139) have shown antimicrobial activity against Candida albicans,
Stapphylococcus aureus, Bacillus subtilis, and Escherichia coli. Distribution of the major allenic metabolitesin the strain WDMH46 (Paraspheaoshaeria sp.) are shown in Table 3. Metabolites not indicated in Table3 are considered as minor compounds. A new unusual diterpene, irciniketene (143, 7-cis-14,15-didehyd-roretinal), was isolated from the marine sponge Ircinia selaginea collected from the sea around Baihai(Guangxi Province, China) [137]. In this structure, a ketene function is connected with a long conjugatedsystem via an allene unit. Irciniketene showed a moderate inhibition toward MGC and HepG2 tumor celllines.
OH

OHO

OH136 Lupallene A C-7 S137 Lupallene B C-7 R

7

OH

RO

OH

OH

HO

138 Lupallene C, R = Ac139 Lupallene E, R = H

OH

OAcO

OH

140 Lupallene D

OH

HOO

OH

141 Lupallene F1, R142 Lupallene F2, S

143 Irciniketene

C

C

C

O

MeZ

7. Marine bromoallenes

Although the debrominated sesquiterpene panacene was isolated from the plants Panax ginseng and P.

quinquefolius [22–27], more recently, brominated analog of panacene (144) was isolated from the marine gas-tropod mollusc Aplysia brasiliana [28]. Simple bromoallene (145) was isolated from the red alga Laurencia


obtusa [138]. Two halogenated C15 acetogenins, itomanallenes A (146) and B (147), with a terminal bromoal-lene moiety, have been isolated from the red alga Laurencia intricata collected in Okinawan waters. The alco-hol corresponding to itomanallene B seems to be a plausible precursor of itomanallene A, which has anunusual 2,10-dioxabicyclo[7.3.0]dodecene skeleton [139]. Laurallene (148) and isolaullene (149), both bro-moallenes, were isolated from Laurencia nipponica [140,141]. Kumausallene (150) is a natural product isolatedfrom the red algae Laurencia nipponica. It contains a 2,6-dioxabicyclo[3.3.0]octane ring system in its core[142,143]. Kumausallene and 1-epi-kumausallene (151), obtained from red algae of the genus Laurencia, weresynthesized [144]. Kumausallene and pannosallene (152) produced major metabolites by the Japanese marinered alga Laurencia nipponica Yamada (Rhodomelaceae, Ceramiales) [145].

Okamurallene (153), a halogenated C15 metabolite, was isolated from some red algal species belongingto the genus Laurencia [146]. The red alga Laurencia okamurai yielded four nonterpenoid C-15 bromoal-lenes (154–156) as minor components, together with laurinterol and debromolaurinterol as major compo-nents [147]. The structures of okamurallene and three metabolites (157–159) were isolated from the redalga Laurencia intricata [148]. The 12-membered O-bridged cyclic ether obtusallene derivatives (160–164)were present in extract of the red seaweed Laurencia obtusa from Kas in the Turkish Mediterranean[149], 10-bromoobtusallene (134) was detected from the same alga [150]. New polyhalogenated (165–169), 12-membered, O-bridged cyclic C15-ethers, having in common oxygenation at C(6) and a bromoal-lene side chain at C(4) [where C(1) is the bromoallene-chain terminus], were isolated from the red seaweedLaurencia obtusa from the Turkish Mediterranean Sea [151]. Two new natural brominated allenes, termednipponallene 1 (170) and neonipponallene 2 (172), were isolated from the red alga Laurencia nipponica,collected near the Russian shore of the Sea of Japan (Troitsa Bay) [152]. Laurallene (171), brominatedcyclic ether extracted from Laurencia nipponica [140,153], was also found in other algal species of thegenus Laurencia.

R

147 Itomanallene B

146 Itomanallene A

Br

H H

O

AcO

O

O

Br

H

Br

145 Bromoallene

H

HBr

H

144 Panacene

O

OH

BrH

H

H

H

S

S

148 Laurallene

O

O

H

H

H

H

Br

Br

149 Isolaurallene

O

O

Br H

H

H

H

Br

152 Pannosallene

S

O

O

H

H

Br

HH

H H

Br

R/S

150 Kumausallene, R151 1-epi-Kumausallene, S

O

OH

H

H

H

Br

Br

H


A bromoallene metabolite, termed aplysiallene (173), was isolated from the Japanese sea hare, Aplysia

kurodai, (Gastropoda), as an Na,K-ATPase inhibitor. The known metabolites, laurinterol and debromo-laurinterol, isolated from this sponge, were also evaluated for their Na, K-ATPase inhibitory activity[154]. A C-15 nonterpenoid (174) was detected in the red alga Laurencia okamurai [155]. From a singlecollection of the red alga Laurencia implicata, three new unusual secondary metabolites (175–177) wereisolated [156]. Other findings include (a) two C-15 bromoallenes (178, 179); (b) a 12-membered O-bridgedcyclic ether obtained from extract of Laurencia obtusa from Kas in the Turkish Mediterranean, and (c)kasallene (180), a highly oxygenated bromoallene, which has been isolated from the red alga L. obtusa

[157].

O

OH

HH

Br

H

Br

OS

155 Isookamurallene

154 Deoxyokamurallene

ZSO

OH

HH

Br

H

Br

156

O

O

H

Br

BrO

153 Okamurallene

O

OH

HH

Br

H

Br

OH

HS S

159O

O

Br

H

HO

Br

H

H

H

H

Br

H

O

O

Br

Br

157

164 Obtusallene IV

162 Obtusallene III, R = H163 Peracetylobtusallene III, R = Ac

OCl

H

H

O

Br

H

Br

H

R

ORO

H

H

O

OROR

H

Br

H

160 Obtusallene I, R = H, R1 = Cl161 10-Bromoobtusallene, R,R1 = Br

RO

R1

Cl

H

H

Br

H

O

R

O

OH

HH

Br

H

Br

H

Cl

HO

S

158

Br H

S

168 Obtusallene VIII, R = H169 Obtusallene IX, R = Ac

O

H

H

O

OR

Br

H

Br

H

Br

S

H

Br

O

H

R

O

Cl

O

167 Obtusallene VII

O

H

H

OBr

H

Br

HCl

BrOH

H

165 Obtusallene V, R = Br166 Obtusallene VI, R = H

S

172 Neonipponallene 2

O

Br

H

OAc OAc

H

Br

H

H

170 Nipponallene 1, R171 Laurallene, S

R

O

O

Br

HH

H

H

H

Br

HR/S

RO

O H

H

Br

HH

H

H

R

173 Aplysiallene, R = Me174 R = Br

180 Kasallene

O

OH

OHO

OH

Br179

OO

H

H

Cl

Br

Br

178

177

O

OH

HBr

BrAcO

Br

176

175

O

OH

HBr

Br

H

OBr

OO

H

H Br

O

O

H

H

HO

HO OH

Br

8. Allenic norisoprenoids

Natural norisoprenoids (181–189), structurally derived from carotenoids, are widely distributed inplants, algae, and insects, and because of their often low flavor thresholds, many of them are highly



potent aroma compounds and, thus, of great interest for the flavor and fragrance industries [158–160].Norisoprenoids as degradation carotenoid products [160], represent preferable cleavage of 6,7,7,8,8,9,and 9,10 bonds lead to flavor components with 9,10,11, and 13 carbon atoms, respectively. In theintact plant, carotenoid degradation is likely to be affected by oxygenase systems and by photo-oxy-genations and other nonenzymatic oxidations [161]. The sensory-active C9-, C10-, C11-, and C13-nori-soprenoids naturally emerge from the oxidative cleavage of tetra-terpenoid precursor carotenoids[159,162].

Nonselective fissions of the polyene chain induced by abiotic factors such as heat or light, result in abroad spectrum of oxidized breakdown products [163,164]. A smaller range of products, which often dis-play biological activities, was released by enzymatic cleavage reactions. In the last few years, enzymescatalyzing the centrical or excentrical fission of specific carotenoids in vivo have been isolated and char-acterized from plants [165]. Recently, chemical, photochemical, and oxidase-coupled degradation ofcarotenoids to norisoprenoids have been reported [158,166]. The brownish secretion emitted upon distur-bances by the grasshopper, Romalea microptera, produced four allenic norisoprenoids (181–184) [167],which are produced by degradation of related allenic carotenoids [158]. An allenic ketodiol (185) withthe natural stereochemistry observed in samples isolated from the defensive secretions of a large flightlessgrasshopper was synthesized from b-ionone by a sequence of reactions involving photosensitized oxygen-ation and photo-stereomutation [168]. Biosynthesis of fucoxanthin and neoxanthin may involve the samereactions [158,169].

Twenty-four norisoprenoids, including grasshopper ketone, which are either free volatile components ofjuices of Vitis vinifera cv. Chardonnay, Semillon, and Sauvignon Blanc, or were liberated by glycosidaseenzyme, or acid hydrolysis of extracts of these juices, have been identified [170]. The hypothetical 7-oxomeg-astigmane precursors, grasshopper ketone and megastigm-5-en-7-yne-3,9-diol, as well as the related allene, 9-hydroxymegastigma-4,6,7-trien-3-one (183), have been observed for the first time, co-occurring with damasce-none, 3-hydroxy-b-damascone 3-oxo-b-damascone, and 3-oxo-a-damascone. Hydrolytic studies have shownthat megastigm-5-en-7-yne-3,9-diol is a precursor of damascenone and 3-hydroxy-b-damascone during wineconservation.

Allenic norisoprenoid glycoside, icariside B1 (186) was observed in some plant species: Epimedium grandi-florum var. thunbergianum [171], Epimedium diphyllum [172], Vitis vinifera cv. Riesling leaves [173], Nepeta cad-

mea [174], in leaves of Glochidion obovatum [175], Ebenus cretica [176], in the fruit of anise (Pimpinella anisum)[177], in the aerial parts of three species of Erigeron: E. annuus, E. philadelphicus, and E. sumatrensis [178], inthe leaves of Cryptostegia grandiflora [179], Peucedanum japonicum [180], Taraxacum obovatum [181], in theaerial parts of Crepidiastrum lanceolatum [182], Evodia austrosinensis [183], and in leaves of Laurus nobilis

[184].Two glycosides citroside A (187) and B (188), were isolated from the methanol extract of leaves of Citrus

unshiu [185]. On the basis of spectral and chemical evidence, the structures of the new glycosides were detectedas (5-dehydroxygrasshopper ketone-5-yl) 5-b-D-glucopyranoside (187) and a (5-dehydroxy-allenic ketodiol-5-yl) 5-b-D-glucopyranoside (188), from the methanol extracts of coriander (fruit of Coriandrum sativum) [186],and celery seed (fruit of Apium graveolens) [187]. Citroside A was also isolated from the barks of Prunus ssiori

and P. padus [188], the leaves of Hydrangea macrophylla var. thunbergii [189], lulo leaves (Solanum quitoense)[190], the aerial parts of Phlomis grandiflora var. grandiflora [191], a leaf extract of Eriobotrya japonica [192],the aerial parts of Phlomis spinidens [193], the leaves of Melaleuca quinquenervia [194], the leaves of Lasianthus

wallichii [195], the aerial portion of Erythroxylum cambodianum [196], and from the aerial parts of Tribulus

parvispinus [197]. Citroside B was also isolated from the leaves of Solanum quitoense [198]. A potent antiulcer-ogenic compound, cassioside: (3R)-4-[(2 0R,4 0S)-2 0-hydroxy-4 0-(b-D-apiofuranosyl-(1! 6)-b-D-glucopyrano-syl)-2 0,6 0,6 0-trimethylcyclo-hexylidene]-3-buten-2-one (189), was isolated from a hot water extract ofCinnamomi Cortex (the dried stem bark of Cinnamomun cassia) [199], and from the juices of grapes and otherfruits [200]. The allenic epoxycyclohexanes (190, 191) were isolated from the culture medium of Eutypa lata

[201,202].


OH

OH

O

H

190

OH

OH

O

H

191

O

HO

HO

OH

HO

O OH

H

O

HO O

H

O

O

OH

OH

OH

OH186 Icariside B1

187 Citroside A, R188 Citroside B, S

R/S

O

OHHO

HO

OO

OH

OH

OH

HO OH

H

O

189 Cinnamoside185

HO OH

H

O

HO R

H

O

HO

HOH

OH

181

182 R = Me183 R = OH

AcO

HOH

O

184

9. Allenic carotenoids

9.1. Distribution in nature

Carotenoids, which exhibit purple, red, orange, and yellow color, are tetraterpene pigments distributed inbacteria, fungi, algae, as well as in higher plants and animals. To date, more than 700 carotenoids have beenfound in nature [203]. Of approximately 700 naturally occurring carotenoids, about 43 carotenoids contain theallene group. The principal allenic carotenoids are fucoxanthin (192) in brown algae and diatoms, and perid-inin (193) in dinoflagellates and neoxanthin (194) in higher plants and algae [204–206]. They serve as light-har-vesting pigments in photosynthesis and occur as carotenoid–chlorophyll–protein complexes in chloroplasts[204]. Some marine animals, such as sea anemones, shellfishes, sea urchins, and tunicates also contain alleniccarotenoids [22,24].

9.1.1. Marine and freshwater algal species

Fucoxanthin (192) is a one of the most abundant marine carotenoids, which is widely distributed in brownalgae and diatoms [204–206]. Fucoxanthin contributes more than 10% of the estimated total production ofcarotenoids in nature [206]. Fucoxanthin was first isolated by Willstatter and Page in 1914 [17]. About 50 yearslater, its structure was found to be 5,6-epoxy-3 0-ethanoyloxy-3,5 0-dihydroxy-6 0,7 0-didehydro-5,6,7,8,5 0,6 0-hexahydro-b,b-caroten-8-one by Bonnett et al. [207–209]. Subsequently, (3S,5R,6S,3 0S,5 0R,6 0R)-chirality


was established by X-ray crystallographic analysis of an oxidative degradation product of fucoxanthin [210].Geometrical isomers, so-called neo fucoxanthin A and neo fucoxanthin B, were also isolated frombrown algae [211]. Iodine-catalyzed stereomutation of all-E-fucoxanthin provided 9 0Z,13 0Z,13Z,9 0,13 0di-Z,13,9 0di-Z,13,13 0di-Z, and 15 0Z isomers, which were fully characterized by detailed 1H NMR analysis[212,213]. Detailed HPLC studies of fucoxanthin in brown algae revealed that all-E-(3S,5R,6S,3 0S,5 0R,6 0R)-fucoxanthin was the only naturally occurring stereoisomer and other geometrical isomers appeared to beisolation artifacts formed in solution [214]. Geometrical isomers, such as neo fucoxanthin B, was identifiedas 13 0Z-fucoxanthin, and neo fucoxanthin A was found to be in mixtures of 13Z- and 9 0Z-fucoxanthin byHPLC analysis [214].

15'

15

3

6

18

1617

19

9 13

20

13'

20' 19'

9' 6'

18'

3'

16' 17'

OCOMeHO

HO

O

O

CH2OR

235 Fucoxanthinol 3'-sulphate, R = SO3Na

17'16'

18'

19'

20

18

1617

17'16'

18'

19'20'

2019

18

17 16

13119 10'

11'

12'

15'

156

3

9'

6'

3'

3'

15'

15

6

3

139

13' 9'

6'

HO

OH

OR

O

198 R=CH3(CH2)4CO 19'-Hexanoyloxyfucoxanthin200 R=CH3(CH2)2CO 19'-Butanoyloxyfucoxanthin

HO

O

HO

OH

OR

195 Isofucoxanthin, R = Ac196 Isofucoxanthinol, R = H

ORHO

HO

O

OO

193 Peridinin, R = Ac208 Peridininol, R = H

ORHO

HO

O

O

194 Neoxanthin, R = H211 Dinoxanthin, R = Ac

192 Fucoxanthin, R = Ac197 Fucoxanthinol, R = H


Allenic (6 0S)-isomers of fucoxanthin were obtained from natural (6 0R)-fucoxanthin by iodine-catalyzed1
stereomutation in benzene under strong light and were characterized by H NMR [215]. However,
(6 0S)-fucoxanthin has not been found in nature [214]. Treatment of fucoxanthin with base produces yellowhemiketals and isofucoxanthin (195) as well as isofucoxanthinol (196) [216] and acid, which leads to theformation of blue oxonium ions [217]. Fucoxanthin is distributed in marine algae such as Chrysophyceae,Prymnesiophyceae, Bacillariophyceae and Phaeophyceae as a major carotenoid [204–206,218]. Total synthe-sis of all-E-(3S,5R,6S,3 0S,5 0R,6 0R)-fucoxanthin was achieved by Yamano et al. [219]. Fucoxanthiol (197), adeacetyl product of fucoxanthin, was distributed in some marine algae as a minor carotenoid along withfucoxanthin [220–223]. Prymnesiophyceae (Haptophyceae) are characterized by 19 0-Acyloxyfucoxanthinderivatives. 19 0-Hexanoyloxyfucoxanthin (198) was isolated from Emiliania (Coccolithus) huxleyi [224]and Chrysochromulina polylepis [225,226] as a major carotenoid. 4-Keto-19 0-hexanoyloxyfucoxanthin(199), which was first misidentified as 19 0-hexanoyloxyparacentrone 3-acetate [224], was also isolated asa minor component from E. huxleyi, and its structure was fully characterized by detailed spectral analysis[227]. Furthermore, 19 0-butanoyloxyfucoxanthin (200) was found in Pelagococcus subviridis (Chrysophy-ceae) [228].

A series of apo-fucoxanthin, apo-10 0-fucoxanthinal (201), apo-12 0-fucoxanthinal (202), apo-12-fucoxanth-inal (203), and apo-13 0-fucoxanthinone (204) were isolated from the marine diatom Phaeodactylum tricornu-

tum [229]. Apo-9 0-fucoxanthinone (205) was isolated from the cultured marine dinoflagellate Amphidinium sp.[230]. Apo-13-fucoxanthinone (206) was isolated along with 9 0-apo-fucoxanthinone, and apo-13 0-fucoxanthi-none was isolated from brown alga Scytosiphon lomentaria [231]. These apo-fucoxanthins were assumed to beoxidative cleavage products of fucoxanthin in algae. Vaucheriaxanthin (207) was first isolated from Vaucheria

virescens, belonging to Raphidophyceae (Xanthophyceae) and its structure was found to be 19 0-hydroxyneo-xanthin after saponification [232]. Vaucheriaxanthin is characteristic for Eustigmatophyceae but also occurs inXanthophyceae [205,233] and is presented as a free and esterified form in Nannochloropsis salina (Eustigmat-ophyceae) [233].

HO

O

OO

202 Apo-12'-fucoxanthinal

HO

O

OO

201 Apo-10'-fucoxanthinal

HO

O

CH2OCO(CH2)4CH3

O

OCOMeHO

O

199 4-Keto-19'-hexanoyloxyfucoxanthin

OCOMe

206 Apo-13-fucoxanthinone

HO

O

OO

205 Apo-9'-fucoxanthinone

O

OCOMeHO

204 Apo-13'-fucoxanthinone

203 Apo-12-fucoxanthinal

O

HO

O

OCOMeHO

Peridinin (193), which is a unique C37-skeltal carotenoid characteristic of dinoflagellates, was first iso-lated in 1980 by Sch}utt [234]. Its structure was found to be 5,6-epoxy-3 0-ethanoyloxy-3,5 0-dihydroxy-6 0,7 0-didehydro-5,6,5 0,6 0-tetrahydro-12 0,13 0,20 0-trinor-b,b-caroten-19,11-olide by Strain et al. [235]. The(3S,5R,6S,3 0S,5 0R,6 0R) chirality for peridinin was determined by ozonolytic degradation of its p-bro-mobenzoate to derivatives of known chirality obtained from fucoxanthin and violaxanthin [236]. Totalsynthesis of all-E-(3S,5R,6S,3 0S,5 0R,6 0R)-peridinin was achieved by Yamano et al. [237] and Furuichet al. [238]. The (6 0S)-allenic isomer of peridinin was prepared from (6 0R) natural peridinin by iodine cat-alyzed photoisomerization and its stereochemistry was confirmed by chemical synthesis [239,240]. How-ever, (6 0S)-peridinin has not been found in nature. Furthermore, iodine-catalyzed stereomutation of all-

E-(3S,5R,6S,3 0S,5 0R,6 0R)-peridinin provided 9 0Z, 11Z and 13Z isomers, which were fully characterizedby detailed 1H NMR analysis [241]. Incorporation experiment of 14C, 3H-labeled mevalonate in intact cells[242] and 14C labeled zeaxanthin in a cell-free system [243] of the alga Amphidinum carterae (Dinophceae)revealed that C37-skeltal peridinin was formed from neoxanthin by deletion of the three carbon atoms atC-13 0, C-14 0, and C-20 0. Peridinin derivatives were isolated in dinoflagellate. Peridininol (208), a deacetylproduct of peridinin, was isolated from dinoflagellate, along with peridinin [244]. Two C8 epimeric furano-ide derivatives of peridinin (209 and 210) were isolated from the cultured dinoflagellate of the genus Sym-biodinium, a symbiont of the Okinawan soft coral Clavularia virdis [245]. Dinoxanthin(neoxanthin 3-acetate) (211) was also found in several dinoflagellate algae, along with peridinin [244,246]. Two C8 0 epi-meric furanoxide carotenoids, dinochrome A (212) and dinochrome B (213), were isolated from the freshwater red tide Peridinium bipes [247]. Gyroxanthin (214), the first allenic acetylenic carotenoid, was iso-lated from dinoflagellate Gymnodinium galatheanum [248]. A carotenoid termed P457 (215) is a minorcarotenoid disaccharide that is encountered in several dinoflagellates [244,249]. Its structure was foundto be (3S,5R,6R,3 0S,5 0R,6 0S)-13 0Z-7 0,8 0-dihydroneoxanthin-20 0-al 3 0-b-D-lactoside. This carotenoid repre-sents one of the most complex carotenoid structures known, containing structural elements such as a lac-toside, cross-conjugated C40-carotenal, allene, 5,6-epoxide and saturated C-7,8 bond [250,251]. Neoxanthin(194) is widely distributed in algae [204–206].



215 P457

.

OH

OH

O

O

O

HOOH

OH

O OH

OHHO

HO

O

O

8'

8

214 Gyroxanthin

OCOMeHO

CH2OH

HO

O

OH

MeCOO

OH

OH

212 (8'R) Dinochrome A 213 (8'S) Dinochrome B

209 (8R) Peridinin furanoxide 210 (8S) Peridinin furanoxide

O

OCOMe

O HO

HOO H

207 Vaucheriaxanthin HO

CH2OH

OH

O

OH

9.1.2. Higher plants

Neoxanthin (194) is a common carotenoid, widely distributed in higher plants and algae, first isolated fromthe green leaves of barley by Strain in 1938 [252] . Its structure was found to be 5 0,6 0-epoxy-6,7-didehydro-5,6,5 0,6 0-tetradehydro-b,b-carotene-3,5,3 0-triol, and 9Z geometry was assigned to a major neoxanthinobtained from maple leaves by Cholnoky et al. in 1969 [253]. all-E-Neoxanthin was isolated from the petalsof flowers and characterized by 1H NMR [254]. The structures of all-E-neoxanthin [255] and 9 0Z-neoxanthin[256] were fully confirmed by chemical synthesis. Takaich and Mimuro reported that only the 9 0Z form wasfound in chloroplasts. On the other hand, the all-E form was found in nonphotosynthetic organs such as fruit,petal, and root [257]. Iodine-catalyzed stereomutation of all-E-neoxanthin provided 9 0Z,9 0Z,13Z,13 0Z,15Z,and three minor di-Z-isomers, which were characterized by 1H NMR, UV, and HPLC [258]. Neoxanthinwas converted from violaxanthin by neoxanthin synthase (NSY) in plants [259,260]. A gene of neoxanthin


synthase was isolated from tomato [259] and potato [260]. Neoxanthin is converted to two stereoisomers ofneochromes 216 and 217, by acid catalyzed epoxy-furanoxide rearrangement, and these structures were char-acterized [261]. Two C6 epimeric pairs of pentahydroxy allenic carotenoids, neoflor (218) and 6-epineoflor(219), were isolated from the petals of Trollius europaerus [254]. They were assumed to be hydrolytic cleavageproducts of epoxy end groups in neoxanthin [254,261]. A symmetrical di allenic carotenoid, mimulaxanthin(220), was isolated from the petals of the monkey flower Mimulus guttatus [262], and yellow flowers of Lami-

num montanum [263] and its structure was found to be (3S,5R,6R,3 0S,5 0R,6 0R)-6,7,6 0,7 0-tetrahydro-5,6,5 0,6 0-tetrhydro-b,b-carotene-3,5,3 0,5 0-tetrol by chemical and spectroscopic data. Its structure was also confirmedby chemical synthesis [264]. Deepoxyneoxanthin (221) was also found in Mimulus guttatus [263]. Allenicseco-carotenoids termed tobiraxanthin C (222) [265] and 5-hydroxy-tobiraxanthin C (223) [266] were isolatedfrom the seeds of Pittosporum tobira. They were assumed to be oxidative cleavage products of epoxy endgroups in neoxanthin. Furthermore, a novel carotenoid tocopherol complex, termed pittosporumxanthinC1 (224) and C2 (225), were isolated from the seeds of P. tobira. These structures were found to be 11 0,12 0-additional products of 9 0Z-neoxanthin with a-tocopherol [267]. Capsoneoxanthin (226) was isolated fromthe fruits of Asparagus falcatus along with capsanthin, capsorubin, capsocrome, and capsanthin 5,6-epoxide[268]. This compound was assumed to be the pinacol rearrangement product of neoxanthin catalyzed by cap-santhin-capsorbin synthase.

216 (8'R)-Neochrome217 (8'S)-Neochrome

OH

HO

OH

OH

218 Neoflor

8'

OHHO

HO

OH

OH OHHO

HO OH

OH

219 6-Epineoflor

OHHO

220 Mimulaxanthin

HO

OH

221 Deepoxyneoxanthin

OH

HO

OH

9.1.3. Invertebrates and animalsAnimals generally do not synthesize carotenoids de novo and those found in animals represent either a

direct accumulation of carotenoids from the food or are partly modified through metabolic reactions[22,24,269]. Several marine invertebrates, such as sea anemones, shell fishes, sea urchins, and tunicates are


filter feeders and accumulate carotenoids from dietal micro algae. Peridinin was found in sea anemones[270,271], gorgonians [272], shellfishes [22], and tunicates [273]. Fucoxanthin and fucoxanthinol were alsofound in shellfishes [22,274,275], sea urchins [276–278], and tunicates [279]. They represent free and esterifiedforms in shellfishes [274,275]. 3-Acylated fucoxanthinols were found in the clam Mactra chinensis [275]. 19 0-Hexanoyl-oxyfucoxanthin was isolated from the mussel Mytilus edulis [280,281].

Several metabolites of fucoxanthin and peridinin in marine animals have been isolated. A C31 allenic apoc-arotenoid named paracentrone (227), which is an oxidative cleavage product of fucoxanthin, was isolated fromthe sea urchin Paracentrotus lividis, along with fuxoxanthin and fucoxanthinol [282]. Hydratoperidinin (228), ahydrolytic cleavage product of epoxy end group in peridinin, was isolated from the corbicula clam Corbicula

japonica [283,284]. A C37-skeltal apocarotenoid (229), found in the oyster Crassostrea gigas [285], was assumedto be a dehydroxy and oxidative metabolite of (228). An enol carotenoid (230), which was assumed to be a met-abolic intermediate of fucoxanthin to mytiloxanthin, was isolated from C. gigas [285]. Two allenic carotenoids,named corbiculaxanthin (231) and 7 0,8 0-didehydro-deepoxyneoxanthin (232), were isolated from the clam C.

japonica [283,284]. The 7 0,8 0-didehydro-deepoxyneoxanthin (232) has an interesting structure with both alleneand acetylene bonds, and it was assumed to be one of the possible precursors of the di-acetylenic carotenoid,alloxanthin in shellfish [284]. Amarouciaxanthin A (233), a metabolite of fucoxanthin, was first isolated fromtunicate Amaroucium pliciferum [279,286]. It was also found in bivalve Paphia euglypta as an esterifiedform [287]. 19-Ethanoyloxy derivatives of amarouciaxanthin A, termed muricellaxanthin (234), were isolatedfrom a dark red gorgonian Muricella sp. [288].

R2R1

HHHH

223 5-Hydroxytobiraxanthin C

OHHO

O

OH O

C O

(CH2)12

CH3

CH3

)12OH

HO

O

O O

C O

(CH2

226 Capsoneoxanthin

224 Pittosporumxanthin C1225 Pittosporumxanthin C2

222 Tobiraxanthin C

OHO

O

O

R1

R2

HO

OH

OH

O

HO

OH


It was reported that allenic carotenoids were converted to corresponding acetylenic carotenoids in mar-ine invertebrate [22,269]. Feeding experiments of M. edulis with the micro algae, Skeletonema costatum

(diatom), Emiliania huxleyi (haptophyte), and Heterocapsa triquetra (dinoflagellate) revealed that fucoxan-thin and peridinin were metabolized to halocynthiaxanthin and pyrrhoxanthinol, respectively [281]. Somefreshwater fishs take-up fucoxanthin from their dietary algae or aquatic insects [289]. However, fish cannotaccumulate fucoxanthin and its derivatives in their bodies [289]. Fucoxanthinol 3 0-sulfate (235) and para-centron were found in egg yolk after feeding a diet supplemented with the seaweed Fucus serratus, themajor carotenoid of which is fucoxanthin [290]. Fucoxanthinol and amarouciaxanthin A were detectedin plasma and liver after oral administration of fucoxanthin in mouse and human hepatoma cell HepG2incubated with fucoxanthin-containing medium [291]. The conversion of fucoxanthinol into amarouciaxan-thin was predominantly shown in liver microsomes of mouse. This conversion required NAD(P)+ as acofactor [291].

232 7', 8'-Didehydrodeepoxyneoxanthin

OH

HO

OH

OOH

OCOMeHO

OO

OH

OHHO

228 Hydratoperidinin

HO

OH

OH

OHHO

HO

OH231 Corbiculaxanthin

230

227 ParacentroneHO

OH

O

OCOMeHO

OO

O

OH229

233 Amarouciaxanthin A, R = H234 Muricellaxanthin, R = OAc

OO

OHR

HO

OH


9.2. Functions and biological activities

The principal function of fucoxanthin, peridinin, and neoxanthin in plants is light-harvesting, which is theprimary process in photosyntheses. These pigments occurred as carotenoid–chlorophyll–protein complexes inthe thylakoid membrane of chloroplasts [204]. The fucoxanthin–chlorophyll–protein complex was isolatedfrom brown algae and diatoms and characterized [292,293]. The crystal structure of peridinin–chlorophyll–protein in dinoflagellate Amphidinum carterae was determined by X-ray crystallography [294]. Neoxanthinis also a known component of light-harvesting chlorophyll-protein in higher plants. The crystal structure ofmajor light-harvesting protein in spinach was determined by X-ray crystallography [295,296]. Another impor-tant role of carotenoids in plants is quenching of singlet oxygen. Peridinin [297], fucoxanthin, and neoxanthin[298,299] exhibited quenching activity for singlet oxygen. However, these activities are weaker than those of b-carotene [298,299].

The important roles of carotenoids in marine animals are in antioxidation, immune enhancement, repro-duction, growth, maturation and photoprotection [300]. Fucoxanthin also possesses excellent radical scaveng-ing activity [301,302]. Furthermore, fucoxanthin enhances immunological activity and ovulation in sea urchin[303]. The best known biological function of carotenoids in humans is with pro-vitamin A. However, all alleniccarotenoids cannot be converted to vitamin A. Carotenoids also have been known to reduce the risk of cancerand several life style diseases [304]. Some carotenoids exhibit anti-tumor and anti-carcinogenic activities [304].Recently, fucoxanthin has received increased attention as an anticancer carotenoid. Fucoxanthin inhibitsgrowth of human neuroblastoma GOTO cells [305,306], human leukemia cells [307], prostate cancer cells[308], and activation of Epstein-Barr virus early antigen in Raji cells [309]. Fucoxanthin also inhibits duode-num and skin carcinogenesis in mouse [310,311]. Fucoxanthin induces apoptosis and enhances the antiprolif-erative effect of the cancer cells [312,313]. Anti-mutagenic effects of fucoxanthin and peridinin have also beenreported [314]. Recent studies found that fucoxanthin has antiobesity [315] and anti-inflammatory effects [316].

Neoxanthin was reported to inhibit lipid peroxidation [317], carcinogensis [318] and the generation ofsuperoxides from stimulated leukocytes [319]. Peridinin exhibits antitumor prompting activity in a two-stagecarcinogenesis in the skin of mice, and its potency was shown to be higher than that of fucoxanthin [314,320].Other allenic carotenoids, namely, deepoxyneoxanthin, fucoxanthinol, and isofucoxanthin, also inhibit activa-tion of Epstein-Barr virus early antigen in Raji cells [309]. Peridinin furanoxides [245] and dinochromes [247]exhibit significant growth-inhibitory activity toward cancer cells. In the present paper, the IUPAC-IUB carot-enoid nomenclature was based on the new rules described in the ‘‘Carotenoid Handbook’’ [203].

10. Aromatic and peptide metabolites

A few aromatic and peptide metabolites have been isolated from natural sources. A new lignoid (235) with anovel allene structure was isolated from the bark of the Brazilian medicinal plant Brosimum acutifolium (Mor-aceae), whose common name is ‘‘murure’’. This plant, which has been used in folk medicine in the Amazonianregion, is an anti-inflammatory and antirheumatic agent [321]. Two derivatives of 2-propenoic acid, eucalyp-tene A (236) and B (237) are fungal metabolites of Clitocybe eucalyptorum [322]. Improved production of an

Table 4Inhibitory activities of allenic aromatic ethers against tongue cancer KB and KBv200 cells in vitro (IC50, lM; Ref. [325])

No. KB KBv200

239 22.52 20.86240 27.64 18.96241 17.36 18.27242 29.36 23.38243 40.58 49.56244 71.50 42.52245 75.40 52.92246 48.76 55.47247 34.55 30.27


allenic ether, eucalyptene A (236), from a mangrove fungus Xylaria sp. 2508, was also reported [323]. The fun-gus Hypoxylon chestersii culture solutions yielded a new allenic aromatic ether, chesterseine, 4-(4-methoxy-phenoxy)buta-1,2-diene (238) [324].

Allenic aromatic ethers (239–247), some of which are natural products isolated from the mangrove fungusXylaria sp. 2508, were synthesized [325]. Their antitumor activities against KB and KBv200 cells were deter-mined (see Table 4). All these compounds exhibited cytotoxic potential, ranging from weak to strong activity.Analysis of the structure–activity relationships revealed that the introduction of allenic moiety could generateor enhance cytotoxicity of these phenol compounds.

OHCO

OH

OMe

HO

MeO

OH

235

O

COOMe

O OMe

236 Eucalyptene A, E237 Eucalyptene B, Z

E/Z

238 Chestersiene

O 2

R1

O

O 1

R2

239 R1 = H, R2 = COOMe240 R1 = H, R2 = CH=CHCOOMe241 R1 = OMe, R2 = CH=CHCOOMe242 R1 = OH, R2 = CH=CHCOOMe243 R1 = H, R2 = COOH244 R1 = H, CH=CHCOOH

245 R1 = H, R2 = COOMe246 R1 = H, R2 = CH=CHCOOMe247 R1 = OMe, R2 = CH=CHCOOMe

R

R

A novel cyclic peptide containing an allenic ether of aa N-(p-hydroxycinnamoyl)amide [xyloallenolide A(248)] and two aromatic allenic ethers, the but-2,3-dienyl ether of p-hydroxy-cinnamic acid (249) and the cor-responding Me ester eucalyptene A (250) were isolated from the endophytic fungus Xylaria sp. from the SouthChina Sea [326].

249 R = H250 R = Me

248 Xyloallenolide A

ORO

O

N

N N

NHO

O

O

OH

O


11. Allenic amino acids and derivatives

L-2-Aminohexa-4,5-dienoic acid (249) was isolated from the toxic mushroom Amanita solitaria (=Amanita

echinocephala, Basidiomycetes, Amanitaceae, also known as European Solitary Lepidella) [327]. This mush-room group often smells like chlorine household bleach (sodium hypochlorite). Amanita solitaria also containsin excess of 1000 ppm 2(S)-amino-4,5-hexadienoic acid, 300 ppm of toxic trans-2-amino-5-chloro-4-hexenoicacid, and a chloride ion concentration (2000 ppm) significantly greater than that found in other basidiomyce-tes [328]. The synthetic c-allenic-GABA (250) and related compounds (251, 252) are potent and specific mech-anism-based inhibitors of mammalian GABA-transaminase [329]. Synthetic allenic amino alcohols (253–257)are neoplasm inhibitors, which inhibited the growth of certain transformed cancer cells in rat tissue culture[330].

The a-allenic a-amino acids are potent irreversible inhibitors of their target amino acid decarboxylases[331]. a-Allenic-DOPA (258) rapidly inactivates porcine kidney AADC. The diastereomeric pairs of chiralallenic aroma amino acids (259) differ in their abilities to inactivate mammalian and bacterial AADC.Although there is little variation in the abilities of (258) or the separate diastereomeric pairs of (259) to inac-tivate bacterial tyrosine decarboxylase, one diastereomeric pair was at least an order of magnitude more effec-tive than the other against mammalian AADC. Bacterial aromatic amino acid decarboxylase underwentinactivation by 3-hydroxy-a-1,2-propadienyl-tyrosine (258) [332].

COOH

NH2

R

R1

249

COOH

H2N

250 R = R1 = H251 R = Me, R1 = H252 R = H, R1 = Me

HO R

NH2

253 R = H254 R = Me

HO

NH2

255

OHNH2

R

256 R = H257 R = Me

258 R = H, R1 = OH259 R = Me, R1 = H

R

COOHH2N

HO R1

12. Allenic alkaloids

Several taxa of small frogs contained alkaloids (260–265) similar or identical to compounds previouslyknown only from neotropical poison frogs of the family Dendrobatidae [333–335]. Dihydroisohistrionico-toxin (H2-HTX, 260), discovered from frog Dendrobates histrionicus skin [333,336], inhibits acetylcholinereceptor-dependent 22Na+ uptake of cultured chick muscle cells with a Ki of 0.2 lM. H2-HTX increasesthe affinity of the desensitized form of the receptor for agonists but not antagonists. The obtained resultssuggest that H2-HTX inhibits the acetylcholine receptor by causing an increase in the affinity of the desen-sitized form of the receptor for agonists and thereby stabilizes the desensitized state [337]. Some of these


compounds may have arisen convergently from new biosynthetic pathways in several families of frogs, orthese alkaloids may represent parallel expression of shared-primitive pathways that are unexpressed or lostin related frogs. Distribution and biological activities of frog alkaloids have been reviewed in some recentpapers [338–340]. Pipecolic acid, a lysine metabolite, is thought to be a factor responsible for hepaticencephalopathy [341], and it is a potent inhibitor of some liver cancer cells such as Walker 256 carcino-sarcoma and Morris hepatoma 5123 [342]. Three bioactive derivatives of pipecolic acid (266–268) weresynthesized by Agami et al. [343].

HNHO

H260 Dihydroisohistrionicotoxin

264 R = H265 R = Me263

+NMe2O

O

R

NO

O

262

NH

H

HNHO

261 Isotetrahydrohistrionicotoxin

NO

O

Ph

H

HN

O OMe

NO

OMe

MeO O

266267

268

13. Cumulenic lipids and related compounds

Cumulenes are usually highly unstable compounds, and they do not seem to be widely distributed in nature.Several cumulenic fatty acids and other metabolites have been discovered in nature. Thus, the 2,6,7,8-decatet-raen-4-ynoic acid, 9-(methylthio)-, methyl ester (269) was obtained from the extract of roots of Anthemius aus-

triaca [35]. From the roots of the same plant, two d-lactones of 5-hydroxy-9-(methylthio)-2,4,6,7,8-decapentaenoic acid (270) and its isomer (271) were also isolated [344]. The above-ground portions of Erigeron

canadense (fleabane, Compositae) contained unstable cumulenes (272, 273). These metabolites were biogenet-ically closely related to the lachnophyllum ester cis-Pr(C„C)2CH@CHCO2Me [345]. The 5-(1,2,4-hexatrieny-lidene)-2(5H)-furanone, (274) was isolated from Aster bellidiastrum [346]. Cumulenic fatty acid (275), and twocumulene phenolics (277, 278) were isolated from maruna bezwonna (Matricaria inodora = Tripleurospermum


perforatum, Compositae) [347]. Seven years later 2,3,4-decatrienoic acid, methyl ester (276) was found in oil ofMatricaria inodora [348].

269

SMe

Me

H

MeOOC

271

SMe

Me

H

OO

270

SMe

Me

H

OO

OO

272

OO H

273

OO

274

275 R = H276 R = Me

H COOR

H

CPh

PhC C C C

277 278

Ph

Ph

Families of cumulene compounds (279–290) containing the natural double bonds have been discoveredfrom astronomical sources, where some terminal hydrogen atoms were replaced by deuterium atoms. Thecumulene carbenes are important components of hydrocarbon chemistry in low-mass star-forming cores. Asimple allene (1,2-propadiene-1,3-diylidene) and 1,2,3,4-pentatetraene-1,5-diylidene (279) were detected inthe dark cloud TMC-1 for the first time in the course of a molecular line survey using the Nobeyama 45-mtelescope (Nobeyama Radio Observatory, Nagano, Japan) [349]. More recently, they were also observed bythe IR space observatory in the young planetary nebula NGC 7027 [350].

Several authors from the Jet Propulsion Laboratory (California Institute of Technology, USA) reported thefirst astronomical detection of the long-chain cumulene carbene (279 and 282) in the interstellar cloud TMC-1[351]. In this year other groups from the USA reported the cumulene carbenes (280, 281, 282, and 283) as wellas the cyanopolyynes HC11N and HC13N; the C chain radicals C7H, C8H, C9H, and C11H were observed fromP1 astronomical sources [352]. Cumulene carbenes (284–290) were observed for the evolved carbon star IRC+10216, and discovered by scientists from the Harvard-Smithsonian Center for Astrophysics (Cambridge,MA, USA) [353].

279 ButatrienylideneH2C C C CH2

280 Pentatetraenylidene, R = R1 = D281 Pentatetraenylidene, R,R1 = H

H2C C C C CRR1

290 Decanonaenylidene, R, R1 = D

H2C C C C C C C C C CRR1

288 Nonaoctaenylidene, R, R1 = D289 Nonaoctaenylidene, R,R1 = H

286 Octaheptaenylidene, R, R1 = D287 Octaheptaenylidene, R,R1 = H

H2C C C C C C C C CRR1

H2C C C C C C C CRR1

284 Heptahexaenylidene, R, R1 = D285 Heptahexaenylidene, R,R1 = H

H2C C C C C C CRR1

282 Hexapentaenylidene, R, R1 = D283 Hexapentaenylidene, R,R1 = H

H2C C C C C CRR1


14. Addition to distributions, biosynthetic preparation and synthesis

Two acetylenic antibiotics, cepacins A and B, have been isolated from the fermentation broth of Pseudo-monas cepacia SC 11,783 and assigned structures (291) and (292), respectively. Cepacin A has good activityagainst Staphylococci (MIC) 0.2 lg/mL, but weak activity against Streptococci (MIC 50 lg/mL) and themajority of Gram negative organisms (MIC values 6.3 approx. >50 lg/mL). Cepacin B had excellent activityagainst Staphylococci (MIC <0.05 lg/mL) and some Gram negative organisms (MIC values 0.1 approx.>50 lg/mL) [354,355]. Synthesis of cepacin A has recently been reported [356].

HO

OH

O

291 Cepacin A

HO

O

O

OOH

O

292 Cepacin B

Biosynthetic preparation of 2,3-allenols (293–314) using the lipase B from Candida antarctica, lipase fromPseudomonas fluorescens, lipase from Candida cylindracea, lipase from pig pancreas, lipase from Candida

rugosa, and lipase from Pseudomonas cepacia has been reported [357]. The organic solvents were hexane,cyclohexane, vinyl acetate, dichloromethane, and/or acetone. Both allenes (>95% ee) of 2-methyl-3,4-pentadi-en-1-ol were prepared via 2-stage enzymic kinetic resolution, i.e., a sequence of lipase-catalyzed acetylation(Pseudomonas cepacia) and hydrolysis (Candida antarctica) [358]. Unique an allenic sugar derivative 6,7,8-tri-deoxy-1,2:3,4-bis-O-(1-methylethylidene)-a-D-galacto-octa-6,7-dienopyranose (315) was synthesized fromacetylenic precursors [359].

The first synthesis of (�)-panacene (144) has been accomplished in concise, highly stereoselective fashionfrom compound available 2-methoxy-6-methylbenzoic acid (15 steps, 8.3% overall yield) [360]. Two reviewarticles were devoted to syntheses of allenes have recently been published [361,362], and Liu was preparedthe PhD thesis from Brigham Young University on synthesis of allenes [363].


R

OAc

293 R = Me294 R = Et

R

OH

295 R = Me296 R = Et

PhOR

305 R = H306 R = Ac

R

OH

n

297 n = 1, R = Me298 n = 1, R = Et299 n = 2, R = Me300 n = 2, R = Et301 n = 3, R = Me302 n = 3, R = Et303 n = 4, R = Me304 n = 4, R = Et

PhOR

307 R = H308 R = Ac

Ph

OR

309 R = H310 R = Ac

OR

311 R = H312 R = Ac

HOR

313 R = H314 R = Ac O

OO

O

OH

H

H H

315

15. Concluding remarks

Plant and marine secondary metabolites are unique sources for pharmaceuticals, food additives, flavors,and other industrial materials. Accumulation of such metabolites often occurs in plants subjected to stressesincluding various elicitors or signal molecules. This article consists of the following sections: allenic naturalproducts (linear allenes, carotinoids, and terpenoids, bromoallenes, and other naturally occurring allenesand cumulenes) and pharmacological active allenes: steroids, prostaglandins and carbacyclins, amino acids,nucleoside analogs, and other bioactive allenes. At the present time, more than 200 allenic lipids and relatedcompounds have been isolated from living organisms. Natural and synthetic allenic and cumulenic materials,their analogues and derivatives have been discovered and/or synthesized and evaluated for their biologicalactivity. Inspired by the intriguing biological activities of many allenic natural products, allenic moietiesare now introduced in compounds that have the pharmacologically activity. The many functionalized allenesthus obtained exhibit an impressive array of activities, such as enzyme inhibitor activities, cytotoxic or anti-viral activities. Without doubt, other important new allenic and cumulenic compounds possessing importantbiological activities will be discovered in the near future.

Acknowledgements

Authors are grateful to Professor John L. Harwood (University of Wales, College of Cardiff), and ProfessorJohn Boukouvalas (Laval University, Quebec City, Canada) for critically reading the manuscript, and the con-structive comments, and to Mrs Jannette A. Dembitsky for assistance with the Figures.


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Allenic and cumulenic lipids

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