- Inaugural -- - Lecture Series 204 4

NATURAL PRODUCTS CHEMISTRJ7 : THE RECENT TRENDS AND IMPACT,

, ON THE SOCIETY -

J . A. Aladesanmi Professor of Phannacognosy

I

I . , . - . , :.: .. . ' C . ..

$~T~.~OSEPI AOETONH ACA~ESANMII Professor of Pharmacognosy

NATURAL PRODUCTS CHEMISTRY : THE RECENT TRENDS AND IMPACT ON THE SOCIETY

Joseph Adetunji Aladesanrni

Professor of Pharmacognosy

An Inaugural Lecture Delivered at Oduduwa Hall Obafemi Awolowo University

Ile-Ife, Nigeria

On Tuesday 1 1 th September, 2007

f Pharmacognosy

Inaugural Lecture Series 204

0 Obafemi Awolowo university Press Limited 2fJ07

ISSN 0 189-7848

Printed by Obafemi Awo;owo University Press Limited

Ile-Ife. Nigeria.

NATURAL PRODUCTS CHEMISTRY: TTHE RECENT ENDS A 3N THI

nted hy -1niversity Press Limited 2. Nigeria.

CODUCTION

md their ,..-

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ladies a aids of tl

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with see ; done ev

- . - .

Mr. V ncellor, ! start r re by refi of natural products on man and her society by God himself. The creation of heaven and earth is recorded in the Ho!y Bible (Genesis 1-2) and on the third day then God said, "let the land produce vegetation: seed-bearing plant3 and trees on the land thct bear hlit d in it. accordhg :o their various kinds" (Genesis I: 11). This wa: ,er before $e creation of mankind, also in Genesis 1 : 29-30, God said, "I give you every seed- becuingplant on the surface of the whole ear.:: and every tree that has fruit .vib seed in it.. . I give every green plant for food." God created all forms of life on earth, - plants, animals, parasites a:ld mankind, as attested by the Bible. There are also l-eferences on the vegetation with healing properties c.g. use of poultice applied, to the ulcer of King Hezeki'ah ((2 Kings 20: 7). laves of fruit trees growing along river t "their fn me for food 2 leaves for healing" (Ezeki ). My vel ve into the sea 01 ~ a t u r a l Products Chemistry (NrcJor Phytochemistry was abo~lt four decades ago during my Higher School Certi I.S.C.) final year practical examination. Then, we were doing the ' cetone extract of dried leaves with reference compounds in order to ascertain its constitiients This inspired my taking NPC as a career. This was followed by a summer 1978 pre-doctoral study visit to Dr. E. A. Sofowora's (now Prof. A.Sofowora) labomtory that resulted in University of Ife (nr-!. Obafemi Awolowo University) scholarship for the completion of n;; Doctoral studies.

,ank that el47: 13 ,. -.-. -.

- lit will se ry fmt di

ficate (F TLC of a

The subject Pharmacognosy includes Echnomedici Phytochemistry a d Natural Products Chemistry

Ethnomedicine -The World Health Organization (1 978b) has defi~cd traditional medicine as the total cambination of knowledge and practices whether explicable or inexplicable. used in diagnosing, preventing or eliminating a physical, mental or social diseases. These knowledge and

- -- -

the practices may rely exclusively on past experiences and observations handed down from generation to generation verbally or in writing. The practices are predicated on the original concepts of nature which include the material world, the sociological environmznt whether living or dead and the metaphysical forces of the universe (WHO, 1978b),

Pharmaqnosy -derived from two Greek Words,"pharmakon" or drug, and "gnosis" or knowledge. Like many contemporary fields of science, Phmwgnosy has undergone significant change in recent y m and today represents a highly interdisciplinary science which is one of five major areas of pharmaceutical education. Its scope therefore includes the study of physical, chcmical, biochemical and biological properties of drugs, drug s&stnnces, or potential drugs or dmg substances of natural origin as well IS the X L T ~ for new drugs from naiurd sowczs. Thus, rcsemch problems in pharrnacognosy now include studies in the areas of phytochemistry, microbial chemistry, biosynthe~is, biotransforrnation, chemotaxonomy, and %her biolbgi~al and chemical sciences (The American Society of Pt,armacognosy V tbmaster, 2002).

Phytochemistry - is simply the study of thexhemistry of the constituents of plants, with the aim of identification, isolation and characterization of biologically active compounds, evaluation of their effects in animals and hiunan (clinical trials).

Natural Products Chemistry - has a greater or wider scope than phytochemistry, and is the chemistry of plants, animals, fungi, bacteria, viruses, marine plants and animals, rocks, and other life fonns as well as minerals and soils.

Therefore, Pharmacognosy as centre point of these five areas is very indispensable in my work and as is the link between or at the interphase of biology and chemistry and between nature and drugs.

Mr. Vice-Chancellor Sir, this Inaugural Lecture Series 204 titled "Natuml Products Chemistry: The Recent Trend and Impact on the Society" attempts to give the account of my about 30 years of work in the above mentioned tive ma-jor m a s of medicinal natural products research.

!: on past experiences and observations ) generation verbally or in writing. The iginal concepts of nature which include cal environrn~nt whether living or dead le universe (WHO, 19781.3).

Natural products h m plants in human histoy have been used as medicines, fragrances, food additives and pesticides. Though the use of plants, human beings have taken advantages of the defensive, attractive and medicinal compounds present in leaves, flowers, roots, sap and bark of species around the World (Evans, 1989). Even though very large numbers of plants are constantly being screened for their possible pharmacological value, it is estimated that only about one percent of Nigerian medicinal plants has been subjected to scientific evaluation for potential chemotherapeutic value (Inyang, 2004).

Iwo Greek Words."phmakon" or drug. contemporary fields of science,

ifjcnnt change in recent years and today ar?, science which is one of five major

b. Its scope therefore includes the study I and biological properties of dnlgs, dm; )mg substances of natural origin as well

Today, plants are the almost exclusive so hugs for d ty of the world's population. In the industrializes counmes, substances a p n d

from higher plants constitute exactly 25% of prescribed med (Farnsworth and Bingel, 1977).

the maja - . I

w.. 7-

icines -

a:llra! sowczs. Thus, research problems studies in the areas of phytochemistry, biotmxformation, chemotaxonomy, and cciences (The American Society of I*).

PHYTOCHEMICAL METHODS

ontain The screening process all over the world has shown that plant5 ct hundreds or thousands of metabolites. Thus, any 'phytochen investigation' of a given plant will reveal only a very narrow spectrum I constituents. The process that leads from the plant to a phmacolqgic-., active, pure constituent is very long and tedious, and requires a multidisciplinary collaboration of botanists, ethnobotanists, traditional healers, phmacognosi nists, pharmacologists and toxicolc -

This approach involve llowing steps (Fig. 1) (Hamburg1 Hostettmann, 199 1).

lical of its mallv

iudy of the-chemistry of the constihcnts lation, isolation and characterization of valuation of their effects in animals and

- I lu.7 greater or wider scope than try of plants, animals, fungi, bacteria, s, rocks, and other life forms as well as

ists, cher :s the fol

ogists. er and

kntre point of these five areas is very i the link between or at the interphase of tn nature and drugs.

81-w el-

l

p a l Lecture Series 204 titled "Natiual nt Trend and Impact on the Society" ~y about 30 years of work in the above :licinal natural products research. Fig 1: Proced~ ure for ( ~g the ac tive prh b m pla

- Information of folkloric use by traditional healers and other ;todim of this knowledge.

Ilection, proper botanical identification and drying of the plant material.

- Preparation of appropriate extracts and preliminary chromatographic analysis by TLC and HPLC.

- Biological and pharmacological screening of crude extracts.

- Several consecutive steps of chromatographic separation, where each fraction obtained has to be submitted to bioassays in order to follow the activity (activity-guided fractionation). .-

- Verification of the purity of the isolated compounds.

- Structure elucidation by chemical and physicochernical methods.

- Partial or total synthesis.

A A.

stn

T nq

- . P-paration of derivatives/analogues for the investigation of ~cture- activity relationships.

- Jduu

tes rge scale isolation for further pharmacological and toxicolo~cal ts.

Major art:& in current research on bioactive plants and cumnt trends can be identified by a survey of current publications by Hamburger and Hostettmann, 1991; Cordel, 1995; from Singh et al., 2005: Furia, 1997, Olaniyi, 1981,1992.

DRUGS DEVELOPED FROM PLANTS

Less than 100 years ago, therapeutic agents from medicinal plants have been incorporated into orthodox medicine and examples include the sesqui terpenc endoperoxide, artemisinin from the Chinese plant Artemkia nnnua for the tre:;:rzent of malaria (Trigg, 1989); and tax01 from Taxus brevifolia, used in metastatic breast cancer (Lenaz, 1993). Other classical examples include atropine, an alkaloid from Atmpa belladonna as ophthalrnics and synthetic spasmolytics, morphine and paraverine from

4

use by traditional healers and other IP.

11 identif ication ant

priate extracts by X C and HPL

d drying of the plant

and prr C.

f crude e, .,-. bf chrornato3gaphlL X ~ U ~ ~ L I U I ~ , wnere

I to be submitted to bioassays in order I ty-guided fractionation).

F the isola ted comp 3 - - * ~ . emical ana pnys~cochernical methods.

sfanalogues ror the investigation of

n u i u v e plants and current trends can :nt publications by Hamburger and from Singh et al., 2005: Furia, 1997,

PLANTS

IC agents from medicinal plants have nedicine and examples include the ini in From the Chinese plant Artemisia (Trigg, 1989); and tax01 from Taxus :ancer (Lenaz, 1993). Other classical kaloid from Atropa belladorzna as ytics, morphine and paraverine from 1

Ptrptr\*,*r soniriiferrrr~i for the synthesis of' analgesic and spnsmolytics: quinine and quinidine from Cirtc*llorto srtcc-irrrhm bark. for malaria and antiairythma, and digitoxin. most important cardiotonic d n ~ g in orthodox medicine from Digitalisprrrprtrro for semi-synthetic cardiac glycosides. Cocaine from E~~tltro.ryl~rm cocn for synthetic local aenestherics. Ephedrine fro111 Epkcdrtr sir:ictr for synthetic sympathomilnctics; Reserpine, ajmaline and other alkaloids from Rauuvlfia serpc~ritiritr for synthetic antihypertensives and antiarrythmics. Strophantin from Straphantus seeds. emetine from Ipecac. mthraquinone glycosidcc from Cassia leaf. etc are also used clinically.

From podophyllotoxin, isolated from Poiiophyllr~m peltntrrm used as cathartics in folklorc medicine. was developed etopside and teniposide as

7 potent d111gs used in the treatment of small-cell I~mg cancer, testiculnr cancer, lyniplnomas and leukeamia (Stahclin et (11.. 199 1).

A strong effort has been the search for novel anticancer agents since thc early 1950s led to the first clinically usefirl anticancer compounds. Isolation of Cotltnrcrritlirts rnselrs G Don alkaloids, his-indole alkaloids vint. -

.

vinclistine, Icurosine and Icurosidine between late 1950 and early Two of them, vinblabtine mid vincrisrine. have been developcc~ as coln with Hodgkin's tiisciisc. nan- ~r. head and neck c;~nccl:

mcrcial( Hodgkir

r the trca 1QInaS. a1

tment of nd renal.

'patients testicula

The identification of the human immunodeficiency vinrs (HIVI as the causative agent of AIDS h a stim~~lated the search for novel ant ivilnl agents. Two plant derived compounds have emerged as: castanospenninc and hypericin from Ca,stano,spermlr~n arrstrirle A. Cunn ct Fras. (Leguminocac). The ccmpound is a potent inhibitor of d -glucosidnse. ;i - glucocerebrosinase and lysosomal6- and fi -glucosidascs. It is recently rwnd to inhibit replication of HIV. Another interesting lead is hypcricin ''r~rn H\y>cric.rrrn pc~fortrtrrrtt L. with anti-retroviral activity. AIDS has bcc~j ~ u s c of tlcnth in P d fourth worldwide. The nun1 cxliibiting anti-HI 4 and isolatd fi.o~n nnr~unl

at an aln~ming rate in Illdin and Soirthen(;tAsia. Examplcs arc Cillnnolirlc

irnc thc I ( k r of tor . . .-., ... .* .,...

A, a coun~rtrin isolated from C(r1loplzj~lllrn~ lailigerrrrn. and two other natural product-derived molecules which are phase I1 clinical candidates (Singh et al., 2005).

A novel plant-derived cardiovascular drugs, forskolin was isolated from Colelqforskolii Brig. (Larniaceae). It's main physiological and biochemical effects are:

(a) Vaso dilatator . . . .& - - - 4

y activity

(b) ~ 0 ~ 1 1 1 vc ~ ~ ~ u i r o p i c action on the heart

(c) decreased intraocular pressure

(d) inhibition of platelet aggregation.

The toxicity of forskolin is low and the clinical studies have so far focused on cardiovascular and bronchospasmolytic effects and on the treatment of glaucoma.

Saudi At ti2 Indiar

ns, Italia sickle ct

Sickle Cell Disease (SCD) is genetic disorder found in Africans, Turks. Greeks,, .abians, Egyptians, Irania ns, Latin Americans and Asia IS. Nigeria hcs the highest :I1 disease population in the world estiniatcd at between four and six million sufferers, roughly three to five percent of the country's population. The Fagara (Zantl~o.\,~.Irrtn zantho~lodes (Lam.) Waterm. (Rutaceae) popularly known "Orin ata" inYoruba language the root is used as chewing sticks in Western Nigeria from which a number of anti-sickling compounds were isolated (Sofowon et ol., 1975; Elujoba et al., 1985). A drug named NIRISANI NICOSAP' (HEMOXIN) has been developed and found very effective in treating SCD for which there is no non-toxic drug in the market (Wambebe r t al, 2001 ;Pandey et al. 2002'

sl Pharm ," beans

' - = I -

. ).

:ase nam .ed Cikla . -- -

Another natural product for sickle cell dise vit has been developed by Neimeth Internation; aceuticals Ylc. Lagos from an extract of Chjailus cajarr "Otili , in collaboration with the' Department of Paediatrics, College or ~ e d i c i n e , University of Lagos, Nigeria (Akinsulie et al., 2005).

4

h

tlp!l~llrrrn lar~igrrrrm. and two other khich are phase I1 clinical candidates

!as dmgs. Sorskolin was isolated from I*\ main physiological and biochemical

: heart

* " I . -. le clinical studies have so far focused nolytic effects and on the treatment

pulation - . . - 1 I

: disorder found in Africans, Turks. .

Iranians, Italims, Latin An i~he.;t sickle cell disease pol sand six million sufferers, n)ugnly >pulation. The Fagara (Zantl~a~:\.l~nrt ~ceae) popularly known "Orin ata" chewing sticks in Western Nigeria :ompounds were isolated (Sofowora 15). A drug named NIRISANI jeveloped and found very effective no non-toxic drug in the market 2002).

I disease named C harmaceuticals Plc. u g o s tlvlll eans, in collabor f Medicine. Unive

iklavit hi 3s been mm .-... ith the, Lagos,

F r m the vcno~tl of the pit viper Botliro~~.v,jc~ruruc.u was discovered angiotensin converting enzyme. This eventually lcd to Ihe development of the potent antihypertensive drug, capropril and enalapril (Fcirera e; ul., 1970).

There are indeed many reviews on the potential of medicinal plants as sources of new.therapeutic gents (Soejarto and Farnsworth, 1989; Hamburger and Hostettmann, 199 1 ; Balandrin et el., 1995. Cordell 1995, 2000; Clark, 1996 Mukherjee et al, 2001 )

As a result of what is already in literature, it is very obvious that scientists, phytochemists and/or natural products chemists and pharmacognosists must continue to screen our endowed medicinal plants for biological activities with the use of advanced bioactivity directed isolation and characterization of active compounds. Our University has found itself to be the leader inTraditiona1 Medicine and Natural Products Research in Nigeria as attcsted to by the recent compilation of work done on plants from 1970 - 2005 (Okujagu er al., 2005).

:, to giv doitation

ie estim; 1 forests,

ated ( 2 3 which ar

The last fifty y e m has seen much activity in this area and many thousands of novel compounds have been isolated and characterized. The research for drugs froin ~ lan t s should focus on tropical countries, because over 50 percent of tl 1,000) plants species found on earth come from tropica e currently being destroyed at very alarming ratc e way for construction and or mineral development or

exF .. (Verpoorte. 1998).

Recent Trend, Challenges, Impact and Future Trend

Recently, there h2s been a renewed interest in natural product research due to the failure of alternative drug disc~very methods to deliver many lead compounds in key therapeutic areas such as immunosupprerssion, anti-irlfectives, and metabolic diseases.

ous trenc propriate . .

As I have reviewed the previ Is of over four decades. discussed the current trend, it is also apl : to highlight some insight into the future of natural product chemlsrry research. The scientific professionals must face the very enormous challenges of the 21" ceentury with

7

cletcnninat ion a~ncl opcn ~nindedness. awareness for increased collaboration in n m~~ltidisciplinr~~y world for faster, meani~igf~~l and better d n ~ g research and develop~l~cnt from nature. Traditional medicine must be integrated in consonance with globalization by reassessing and opening itself to the requirements of scientific rationalijration which requires the use of modem medicinal diagnostic methods and therapies. Natural products have long been our singlc most important source of medicines. Each plant is a chenlical factory capable of syntllesizing unlimited nunnber of highly complex and unusual con~pounds with structures that otherwise escape the imagination of man forever. 'There are at least 120 distinct chemical substnnces derived from plants that are considered important drugs currently in clinical use in the world. while several other drugs are simple synthetic modifications of these natural products (WHO, 2002). The completion of human genome project and role of genomic and proteomics have , revolutionized natural products based drug discovery. Over 50% of the best - selling pharmaceuticals in LL$e today are derived from natural products (Editorials, 2003).

In natural product drug discovery. the conventional approach of extraction, isolation, separation, identification. characterization and test for the desired biological activity suffers from problems like low yields, dereplication, difficulty in separation and inconsistent biological activity. However. the introduction of innovative technologies like high throughput screening (I-ITS) and recent advances in extraction like Supercritical Fluid Extraction (SFE) using tluid such as CO,, ethane, NO, and ethylene has made significant positive impact on natural product disiovery. It has been used successfully in combination with enzyme immunoassay analysis, anion exchange disk

'

sorption and gas chromatography (Bruni. 2002). Computerization and - ,

automation of extraction processes have accelerated the pace of natural product drug discovery while chromatography, electrophoresis and spectroscopy has revolutionized the entire natural products research. Recently. traditional analvtical methods are replaced by modem methods. which include hyphenation techniques, high throughput technologies, miniaturization. robotics, pharmacophore. modelling. virtual screening, dclcking and neural networking to efficiently access the bioactive

a m w for increased collabora(ion ?cani~l:f~c\l\ ic\nd better dny research n:il medicine must be integrated in \.i.h.ins and opening itself to the 11 n.hic'n rcq~lircc thc use of modem .;!t ick. Sar~~rul products have long C< ol'~nctlicincs. Each plant is i l

i~!:Ii~vited n~unbcr of highly complex :~rrc\ that otherwise escape the 1.' at least 120 clisrinct chemical lnsidered important dntgs c~urently I! other dn12s are simple synthetic (WHO. 2002). The completion

1 senomic and proteomics have - 31.9 discoveql. Over 50% of the ! arc derived from natural produc~

iventional approach of extraction. ~cte~ization and test for the desired 114 like low yields. dereplication, b~olo~ical activity. Hourever, the c lligh throilghp~~t screening (HTS) percritical Fluid Extraction (SFE) 1 ~ 1 cthylene has made significant rn. It has been used successfully

analysis. anion exchange disk :ii. 2002). Computerization and c. accelerated the pace of natural ~topraphy. electrophoresis and itire natural products research. ire replaced by modem methods. , high throughput technologies, rt. modelling, virtual screening. . . i iciently access the bioactive

~nctnholitcc. These tcchniqucs frrcilitatc rapid and eflicien~ screclling of extracts and their online characterizat~ol~, being automated and highly sensitive, they require very let\ amount of sample and save analysis time (Kithe. 2003). For a rnpicl phytochelnical investigation of plant extract$ and to pc~*form efficient screening ofextracts, the combined techniquec such nc HPLC cottplcrl to UV photodiode nrray detection (LCNV) and to lnnqs spectrometry (LCIMS or LC/MS/MS) or LCINMR or LCRPS - MS-MS is nppropriate (Hostetilnnnn er a/. , 1997). Separation and detection cfficicncy of present methods can be greatly enhanced by using cornbinations like HPLC - electro spray ionization - MS-MS analysis - (Hoi et trl., 2003), HPLC-UV and HPLC-positive - EST -MS analysis (Bicchi et ul., 2001).

ave s h o ~ )phores is

- -

mtened th (CE) is a . . c- . . I .

-, As advances in biotechnology pi iarious genetically modified cell lines, culhues and organism have become available for screening purposes that 11 le screening time (Houghton, 2000). Capillary electrc versatile rnicroJmacro analytical technique gaining widespreau usage ror 1r.e separation and analysis of natural substances. It has several zdvantages over the conventional thin-layer, gas and high performance liquid clu-omatographies, such as low capillary cost, reduced operational costs, small sample size, low production of waste materials, short analysis time, complete automation in sample handling and data treatment. It is anticipated that this hyphenated technique could have a considerable expansion in the coming years (Bossi et al.. 2000).

One key challenge to nah~ral ~roducts chemistry research in the ve~y near future is the loss of presently cheap and ready availability of OLU medicinal plants to the present rate of destnlction of vegetation to make way for human development and economic exploitation. Therefore, the atltivation and conservation of medicinal plrnts in the world, especially Nigerian biodil.nrsity, has never been more important and urgent t h i ~ . now. The Conv,?ntion on Biological Diversity has provision for medicinal plants conservation and this should be vigorously undertaken for the benefit of mankind. A procedure should be developed to compensate the custodians of traditional medicines (Herbalists) for the utilization of their knowledge

and their biological resources. It is equally important that all medical proeralnlnes include the recognition of traditional healers and the incorporation of tratfitional health practices that enhance the health htatu\ of the populations as it is currently being practice in China. Lndia etc. The recent trend in support for traditional n,~,dicine and natural products researches in Nigeria is very encouraging. The Federal Government has declared its commitment to this cause. Recently, the Nigeria government, may be in response to the WHO call on the developing world to institutionalize traditional medicine, has taken major steps to boost research into traditional medicine in an effort to preserve the country's indigenous medical knowledge. A book has been published, which is a collection of 1,050 research efforts by Nigerian Scientists or Traditional Medicine Scholars, published in 1,020 reputable international journals from 1970 to 2004 (Okijagu clt crl., 2005). The former President, Chief Olusegun Obasanjo has also expressed his desire by setting up the National Co~mcil for Traditional Medicine, (Presidential Initiative Committee) that wil set . up a training and research institute in the field, which would improve Nigeria's "negligib1e"contrtibution to the global $60 billion dollar traditional medicine market. Thic; High profile council which will help to develop. promote and commercialise traditional medicine products, could help Nigeria earn at least $1 billion over its first ten years (Sci.Dev.Net., 2006). It is worthy of note and in confirmation of OAU leadership in this area. that one of us, the one and only, Professor Abayomi Sofowora has been named to be the Vice-chairman of the Council.

NATURAL PRODIJCTS CHEM1STRI'- MY CONTRIBUTION

Mr. Vice Chancellor, Sir, from my bird's eye view. after a review of literature and my contribution to scientific knowledge in the area of Nahual products chemistry, biological and pharmacological activities are hi~fiighted below:

It is in the pursuance of this noble objective that I chose today's lecture, liighlightulg my career contribution to this position of eminence of natural products chemistry and phytochemistry in our lives.

As a Chemist, I started with phytochernistry. limiting myself then to isolation and characterization. I-lowever. I got caught u? with the vogues of

10

c q ~ ~ a l l y important that all medical tion of traditional healers and [he r:~clices that enhance the health statlus ring practice in China. lndia etc. The :mnl ndicine and natural prodtucts ragin?. The Federal Government has )e. Recently. the Nigeria government,

call on the developing world to a?; taken major steps to boost research

determining the character of the isolates. NOW, I am solely onto activity- directed isolation of bioactive drugs.

A. Phytochemistry (Isolation and Characterization) of Alkaloids, Terpenoids, Flavowids, volatile oils and Coumarins,

B . Biological and Pharmacological Activities of Anti-infective (antimicrobial), canIiwascular, rnolluscicidaVtxypanocidal, antimalarial, CNS (smooth muscle- contraction), insecticidal, antioxidant, antidiabetic, fertility regulation (anti-implantation).

7 - /to preserve tile country's indigenous Fn pr~blished. which is a collection of A. PHYTOCHEMISTRY - ISOLATION AND .

GIfBRACTERIZATION i Scientists or Traditional Medicine ble international journals from 1970 T. . *4 - A'KALOIDS -: Wk have isolat&a& identified a variety of groups ! former President, Chief Oluseg~ln of alkaloids from many plants and some of them are highlighted- re hy settin: LIP the National Cotmcil ial Initiative Committee) that will set . in the field, which would improve

the ~lobal S60 billion dollar traditional council which will help to develop. ~nal medicine products, could help i first ten years (Sci.Dev.Net., 2006). :ion of OAU leadership in this area.

a)Dpswry lm lenticlkllare Gillespie (Meliaceae) -AFiji plant is used as fnbpoim and for alleviating aches and pains. After some years of active b t vigorous work, two new alkaloids possessing the 1-phenyl ethyltetrahydroisoquinoline skeleton, Dysoxyline, and S- (+) Homolaudanosine were isolated from the chlorofoxm partitioned fraction of the leaf &ol mt, along with known homoerythnna alkaloids 3epir m e n rohomoerysotrine. e and 2,;

. - re\aorAbayomi Sofowora has been ,n le Council.

[STRI' - MY CONTRIBUTION .. +u-n." , T

' 5 eye view. after a review of literature iledge in the area of Natural products e'

sical activities are hizlighted below: E H 3

!lective that I chose today's lecture, ) this position of eminence of natural . .?. . Y . i .. ?.A

. .k"' ..+- 't., . ",', +* ' n

:qr in our lives. ..-. ::$,, , . !.:- .. . . . cine

- 7 -. >

r . r I.,

m . ). *

ustry. limiting myself then to isolation P, = - CH, (Homolaudanosine), R= - CH, (2,7-dih~dmhomoerysotrine), !ot caught Lip with the vogues of I 11

Scheme 1: Biogenesis of Erythrina and Homoerythrina Alkaloids

Also isolated was a novel dibenz [d, fJ azecine skeleton named Dysmine, which represents the trapping of a biosynthetic intermediate in the postulated conversion of the phenyl ethylisoquinoline skeleton to the homoerythrina skeleton (scheme 1). These alkaloid skeletal was new in plants of the Meliaceae, which may be a good marker in chemotaxonomy (Aladesanmi et al., 1983). They are proven to have cardioactive. molluscicidal, analgesic properties (Aladesanmi and Adewunmi. 1990; Aladesanmi et al, 1988; Alaksanmi and Ilesanmi, 1987; Adewunmi and Aladesanmi, 1988; Aladesanmi and Adewunmi, 1995).

R' = R2 = I1 (Schelhammericine), R' = 11, R2 3 011 (3-epi-12-hydoxyscheIhammericine) R'= OMe, R2 = I1 (Dyshomerythdne), - - - - - - - - - - -

- - - - - - - - - - - - - - - -

12

Vna and IIomoerythrina Alkaloids *

I fl mcine skeleton named Dysazecine, F a biosynthetic intermediate in the pyi ethylisoquinoline skeleton to the I). These alkaloid skeletal was new in be a good marker in chernotaxonomy

y are proven to have cardioactive, 5 (Aladesanrni and Adewunmi. 1990; bi and Ilesanmi, 1987; Adewunmi and $ Adewunrni, 1995).

Fig 2. Molecular conformation and numbering scheme for N-methyldyshomerythrinium hexafluorophosphate.

'1, I ! The isolation of the alkaloids was made possible in part with my

r id. development of a unique reversed - phase high performance liquid

I I

chromatography (Aladesanmi et al.. 1986). In continuation of this work.

,.A1 two new homoerythrina alkaloids, 3-epi-18-methoxyschelhamme~cinc named simply Dyshomerythrine and 3-epi-l2-Hydroxyschelhammericine , fitst as a mixture but quatemization of the mixture allowed the purification

(,%' the of the absolute N-methyl stereo derivative structure of (3S, above 5s) as and its the hexafluorophosphate conformation was established salt, which by its X-ray analysis (Aladesanmi et al., 1984) (Fig. 2). From the stem

rhelharnmericine) was isolated, a total of five alkaloids - 3-epischelhammencine, 2,7-

I@, dihydrohomoerysotrine and 3-epi-18-methoxyscheIhammericine,

previously isolated from the leaf and two new alkaloids - lenticellarine and 3-epi-2, 18-di-methoxyschelhammericine along with known p- hydroxyacetophenone (Aladesanmi, 1988). As a result of my continued search for novel homoerythrina alkaloids, 2 B - methoxy-comosivine, 2 B - methoxylenticellarine and 2 B - hydroxylenticellarine were isolated as new alkaloids from the more polar CC fractions of the chloroform fraction in the stem (Aladesanmi and Hoffmann, 1994).

a) An example of plant selection is my work on Fiji plant Dysoxyl~irlt lenticellare Gillespie (Meliaceae) led to identification of over 20 compounds (diterpenes, flavonoids and alkaloids) of which 10 were new while 3 were of novel structures with various potent activities. Fiji, one of the world tropical rain forests, validates an - important factor in research plant selection.

b) Pltellirze conzosa Labill. (Ilicaceae) -A new Caledonia plant, from the heartwood of this plant were isolated 6 homoerythrina alkaloids, of which, 2 B - hydroxy-comosivine and 2 B - hydroxydyshomerythrine were new (Aladesanmi and Hoffmann, 1990; Aladesanmi et al., 1991). They showed various degree of antimicrobial activity (Adebajoet al, 1991).

c ) Newbouldia laevis- This was a project of my M.Sc. student, Mr. R. Nia and also my work in 1995 in Germany. The rootbark of N. laevis, used in the treatment of enlarged spleen, dysentery, worm infestation, migraine, earache, conjunctivitis, and various forms of orchitis, afforded six alkaloids - withasomnine, 4'- hydroxywithasomnine, 4'- methoxywithasomnine, newbouldine, 4' - hydroxynewbouldine and 4'- metghoxynewbouldine. New alkaloids, 4' - methoxywithasomnine and 4' - methoxynewbouldine were also identified (Aladesanmi et al., 1998).

d ) Murraya koenigii (L.) Spreng. (Rutaceae) - This was the work of my first Ph.D student, Dr. Adebajo. It is natural to Central and Southeast Asia and cultivated in Nigeria. Medicinal applications

nd two new alkaloids - lenticellarine ammericine along with known p-

i , 1988). As a result of my continued 1 Bloids, 2 5. - methoxy-comosivine, 2 9 /droxylenticellarine were isolated as !C fractions of the chloroform fraction lann, 1994).

n is my work on Fiji plant Dysoxyll~~~i aceae) led to identification of over 20 ~vonoids and alkaloids) of which 10 love1 structures with various potent ~rld tropical rain forests, validates an plant selection.

licaceae) -Anew Caledonia plant, h n t were isolated 6 homoerythrina - hydroxy-comosivine and 2 9 - :re new (Aladesanmi and Hoffmann, 91). They showed various degree of ajo et al, 1991).

'as a project of my M.Sc. student, ( i n 1995 in Germany. The rootbark ment of enlarged spleen, dysentery, earache, conjunctivitis, and various six alkaloids - withasomnine, 4'- ~ethoxywithasomnine, newbouldine, d 4'- metghoxynewbouldine. New )xywithasomnine and 4' - also identified (Aladesanmi et al.,

ceae) - 1 , It is natu

'his was ~ral to Ce

~g. (Ruta the work 4debaj0, :ntral and I in Nigeria. Medicinal applications

include as tonic, stomachic, carminative, antidysentry, stimulant, febrifuge, anti-periodic and anti-vomiting agents.

The dichloromethane extract of the stembark gave six carbrrzole alkaloids, out of which the non-cyclized possible biogenetic precursors of girinimbine and mnhanimbine, 2-hydroxyl - 3 - methyl-1- (3-methyl-2-butenyl) carbazole (girinimbilol) and 2- hydroxyl-3-methyl-1- (3, 7-dimethyl - 2, 6 - octadienyl) carbazole (mahanimbilol) were novel (Reisch et al., 1994). In all, about thirteen carbazole alkaloids were isolated.

R, = Me, R, = I1 , (Girinim R,= (CII,),CII =CMe,R2= I1

This grc )rm the 1

)up of cc argest gr . ... ..

nbilol)

TERPENOIDS: - ' ompounds were isolated from 2 plants.Terpenoids fc -oup of plant products and are the most common inmed~ent In vo~atlle ota.

a) D. lenticellare -From the pentane soluble fraction of the leaves, were isolated two diterpenes, phyllocladene and 8- hydroxysandaracopimarene while major quantities of the known diterpenes, phyllocladene ,8- A-hydroxysandaracopimarene and p- hydroxysandaracopimarene were identified. This was the first time of their isolation from Meliaceae which may be of chemotaxonornic significance (Aladesanmi et al., 1986). From the n-hexane partition fraction of the stem of D. lenticellare were isolated

three diterpenes, phyllocladene, hydroxy-sandaracopimarene and a new compound named 8 8-methoxysandacopimarene (Aladesanmi, 1988).

Minor quantities of Fermginol and 10-nonacosanol were also identified while a new, unusual bis-diterpene, Fermbietolide (Fig. 3) was also isolated and X-ray diffraction analysis was used to established its structure and stereo-chemistry with moderate antimicrobial activity (Aladesanmi and Adewunmi, 1995; Onan et al., 1985).

Fig 3: A view of the molecular structure of(2) with thermal ellipsoids at the 50% probability level (ORTEP) and the molecular numbering scheme. Hydrogen atoms have been omitted for clarity.

b) Cowainea mexicana D. Don (Rosaceae) -As part of my search for biologically active compounds from desert plants, I did this work as Senior Research Associate at the University of Arizona. The plant has the history of use as a topical anti-infective agent by the Native Americans of the region. The methanol extract yielded a soluble fraction. which when subjected to silica gel CC andMPLC, triterpene ursolic acid and the three known derivatives, pomolic, 2 6 - hydroxyursolic, and 2 -epi- tormentic acids were isolated.

p e . hydroxy-sandaracopimarene and pd 8 2-methox~ opimarene

I nd 10-nonacosano~ were also identified

I . Fermbietolide (Fig. 3) was also isolated as used to established its structure and brtimicrobial activity (Aladesanmi and 1985). . .

~ N C ~ U R of (2) wil a1 ellipsoids eve1 (ORTEP) ; molecular rogen atoms have been omitted for

h them; and the

In (Rosaceae) -As part of my search pounds from desert plants, I did this ssociate at the University of Arizona. Jse as a topical anti-infective agent by re~on. The methanol extract yielded a I sub-iected to silica gel CC andMPLC, e thee known derivatives, pomolic, 2 'pi- tormentic acids were isolated.

Tormentic acid was reported to be an effective topical antibiotic against Streptococcus mutans; pomolic and 2 6 - hydroxyursolic acids were reported to have cytotoxic and potential antitumour activity (Hoffmann et al., 1994).

.ia heudc elotti PI C .. c) Mchil anch ex Oliver (Me1iaceae)- The purification

of the n-nexane rraction led to the isolation of nimbiol, isopimarinol, ketoferruginol and a new diterpene i 12 3- hydroxysandaracopimar-15-ene while the eth e fraction yielded protocatechuic acid, 4hydroxybenzoic acla, L-methylproto- catechuic acid and a new compound named 2-propionoxy- 5- - resorcylic acid (Aladesanmi and Odediran, 2000).

w FZAVONOIDS: -The flavonoids constitute about one-half of the eight- thousand or so recognized phenols. A yellow precipitate (27g) formed during the partitioning of the methanol extract of the leaves of D. 1eu~'ceZIare was subjected to various chromatographic systems to give a novel biflavonoid, robustaflavone4 ', 7"- dimethyl ether (Fig. 4) in addition to two known compounds, isoginkgetin and bilobetin. Their structures were established by spectroscopic data and chemical modifications (He et al., 1996). This was the work of aPh.D. student of mine in U.S.A.

Fig 4: HMBC correlations (solid arrows) and NOE correlations (dotted arrows) for Robustaflavone.

This is a work I did in 200112002 as a Consultant Natural Products Chemist at the Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts, Tufts University Friedman School of Nutrition Science and Policy, Boston, Massachusetts, U.S.A., in collaboration with seven otherIntemationa1 scientists, which researched into major flavonoids in dry tea. Teas are used as beverages worldwide, although consumers very in their preferences for the degree of fermentation, taste and colour.

Green tea, the non-fermented tea, is widely consumed in China and Japan, and health benefits such as cancer risk reduction have been suggested.

Oolong tea, which is partially fermented by endogenous enzymes in the d

tealeaf, is drunk in many countries.

Black te domina'

:a, the mc tes the m

1st highly fermented, is po arket economically.

Westem ( ; and

Pu'er tea, a rare tea, fermented by anaerobic bacteria rather than the enzymatic fermentation processes that characterize the other teas, is consumed almost exclusively in Asia.

The flavonoids are largely responsible fofthe distinctive taste and colour of tea, and are therefore of commercial interest. There is also growing interest in the positive health effects of tea, which are thought to be associated with the presence of tea flavonoids.

The most common flavonoids in tea are the flavan-3-01s (flavanols or flavans) (Fig. 5) which are present in relatively large amounts in tea and low levels in other foods. Other flavonoids, including the flavonols (quercetin, kaempferol, myricetin) and flavones (apigenin and luteolin) are also present but in lesser amounts than the flavan-3-01s.

Total catechins were 11.6gI100g in green and 4.2gl100g dry weight in black tea. Various methods to calculate the flavonoid content in tea were presented (Peterson et al., 2005).

h Consultant Natural ~ u c t s Chemist l~epartment of Agriculture Human /g at Tufts, Tufts University Friedman plicy, Boston, Massachusetts, U.S.A., emational scientists, which researched 1 2s are used as beverages worldwide, iferences for the degree of fermentation,

I widely consumed in China and Japan, isk reduction have been suggested.

1 endogenous enz!

d, is popular in WI cstern COI untries a1

y anaerobic bacteria rather than the 5 that characterize the other teas, is i.

)le for the distinctive taste and colour rcial interest. There is also growing cts of tea, which are thought to be lavonoids.

:a are the flavan-3-01s (flavanols or n relatively large amounts in tea and lavonoids, including the flavonols id flavones (apigenin and luteolin) are an the flavan-3-01s.

green and 4.2gI100g dry weight in ate the flavonoid content in tea were

Fig. 5: Structure of significant flavan-3-01 in tea. The arubigins are oligomers of unknown structure. Other flavonoids, including the flavonols (quercetin, kaempferol, myricetin) and flavones (apigenin and luteolin), are also present but in lesser amounts than the flavan-3-01s.

C0UMARINS:- The CHCI, extract of Marassana seeds of Murraya koenigii furnished only fimcournarins, 8-ge1anyloxypsoralene, imperatorin, heraclenin, isosaxalin, heraclenol as opposed to carbazole alkaloids, mahanirnbine, girinirnbine, koenimbine, isomahmine and mahanine isolated from Nikaweratiy a seeds. Their fumcoumarinic or carbazo1ic chemotypes was confitmed which may be due to geographical andlor genetic properties (Reisch et al., 1994). The examination of a fresh batch of Marassana plant seeds resulted in the isolation of isoheraclenin, isoimperarorin, oxypeucedanin, isopimpinellin and bergapten minor constituents. The presence of furo-and pyrano-coumarins mav ~ rov ide additional useful

chemotaxonomic data for the genus (Reisch etal., 1994). Further work on the CHCI, extract of the Marassana seeds of M. koenigii, gave indicolactone, anisolactone and a new furocoumarin lactone, 2", 3" - epoxyindicolactone. This represents the first report of furocoumarinswith a monoterpenoid lactone chain in the genus Murraya (Adebajo et al., 1997).

Fig 61 lia herid elotti lea wes and flowers itural habitat.

Fig 7: Eugenia. Unjfora L. showing both ripe and unripe fruits.

20

I (Reisch et al., 1994). Further work lssana seeds of M. koenigii, gave lew furocoumarin lactone, 2", 3" - rhe first report of furocoumarinswith :he genus Murraya (Adebajo et al.,

4. - rl r*-\::*

Fig 8: Seedlings of Mzirraya koenigii collected in Sri Lanka.

~ n d flowers in its natural habitat

ne both ripe and unripe fruits. - - - -

Fig 9: Cmsru ucuiu snuwlng r a v e s , lluwers anu ~ ~ i t s .

, --

Fig 10: Dysoxyhm lenticellare Gillespie showing fruit and its transverse section.

B. BIOLOGICAL AND PHARMACOLOGICALACTIVITY

Anti-inTectivelAntimalarial, Molluscicidal and Tkypanocidal Activity

Parasitic diseases have a devastating effect on public health in especially the developing areas of the world e.g. Nigeria. Our group has devoted efforts on approaches toward the discovery and possibly development of new agents for the treatment of molluscicidal, trypanosomiasis, hichomoniasis, malaria, the protozoal parasitic diseases targeted for control or eradication by the World Health Organization and microbial infections which still plague the third world.

In an effort to identify natural products with these activities, we have worked on several plants which are implicated in our traditional folklores.

r Gillespie showing fruit and its

uscicidal aml 'bypanocidal Activity i g effect on public health in especially e.g. Nigeria. Our group has devoted A?

scovery and possibly development of f molluscicidal, trypanosomiasis, 11 parasitic diseases targeted for control 3rganization and microbial infections

ducts with these activities, we have ~mplicatedin our traditional folklom.

'i) A tot; Bail. 1nt;rn

M, c deco prob c h e ~ cliral

/- -%\ ( a1 of ten ethanolic extracts from two 'leiocems barteri ! (Apocy naceae), "pariomoda" in and Morsdeizin

r . - r r r c r r ulio Schum. (Asclepiadaceae); "ewurodo" In Yoruba (varieties , . t , ,-

o~~hirango Benth and Goilgronen~n latifolizirn Benth) ction of stem and fruits is used as laxative, for digestive

I

lems and as stomachic in dyspepsia. The stem is used as ling stick to cure toothache while the powdered leaf is

ov.,.lowed against malaria. Pleioceros borteri is used as emmenagogue and abortifacient and alkaloids are present in the

. - - . rl rootbark, fruits and seeds. The extracts were tested against seven L I h--+sria and 66.7% were considered active but most of the

cts, particularly I? barteri, were active against the gram ive. The rootbark extract proved the most active due to the

presence of tannins and flavonoids (Aladesanmi et al., 1986).

UUb L\

extra posit

1 plants, P Yoruba, - ... .

(ii) Partition fractions of the root were tested against nine bacteria and four fungi, showed that the methanol extmct and all the Fractions have strong activity against most of the bacteria but none against any fungi, a clear and unequivocal antibacterial activity of I? barteri (Agbedahunsi et al., 1993).

(iii) Investigation of Eligeilia uniJlora L. (Myrtaceae

( iv

led four organic extracts of the leaf. A hot water extract of the fresh leaf 'and unripe fruit is used in Nigeria as an antipyretic and antimalaria remedies. This was purified and 12 fractions were subjected to antimicrobial test along with the fourextmcts against seven bxtexia and three fungi. Only two extracts showed activity while only 2 f--Gons were inactive (Adebajo and Aladesanmi, 1989).

volat time,

'ora, a M le oil-cor ,,, 1,,C"

[yrtaceous shrub, a volatil ltaining . The collrpual~run of the Nigerian E. ~mflortr I G U ~ a d fruit ile oils vary qualitatively and quantitatively depending on the season. stage of maturity and state before the collection and

t~~~ac t ion . The antimicrobial efficacy of the essential oils collected

aspec aerq

have I ullifrt:

a . . ~ r a agai . .

s work vas the

is that most st

the fas~ ~sceptib

..

at different times and their microbial transformed products were assessed against 8 bacteria and 3 fungi. The very consistent and significant activity obtained is a biological confirmation of the variation in the composition of the oils. Perhaps the most significant

:t of thi tidious Pseudontonas ~inosa v le bacterium while T.

nrertmgrophytes was rne most susceptible fungus. The results nation fc doric uses of E. ract dis (Adebajo and

Al~CleSanml. 1 ~ 8 ~ ) .

a scienti inst dig

fic expla estive t

,r the foil

The contractile effects of the organic extracts and volatile oil of the fresh leaves of E. uniflora was assessed on isolated rat duodenum. Though they all showed considerable activity but only the ethylacetate extract yielded higher contractile responses than the reference acetylcholine. The contractile activity was absent in the oil, again, this has further confirmed the basis for using it in our traditional medicine to treat intestinal disorders such as constipation

I . , 1995) (Gbol

V ) Phell,

lade et a,

i~te corllr ill. (Aqu ifoliacei (1 ma Labi 3e), the 1 3d was gradiently extracted and tested against 3 bacteria and 2 fungi. The most active ethylacetate extract was purified and bulked fractions obtained showed profound activity against Bacilltrs

reptococ gainst the fungi I, 1991).

is and Sti mjo It a1

alis, no a

mlc valis mec

1st five bi E active \

. .

(vi) Laportea aestlralts (Linn.) Chev., syn. Flelrrya aestuans Gaud. (Urticaceae) fresh aerial parts, used in Nigeria for the treatment of bums and whitlow (inflammation). This was extracted and partitioned, tested agair acteria and two fungi. The results showed the fractions tot which may be helpful in preventing

robial infections in tne case of bums and in inflammation, dating the use of Laporten s in Nigerian traditional licine. (Adebajo et al., 199

microbial transformed products were 1 and 3 fungi. The very consistent and ~d is a biological confirmation of the 1 of the oils. Perhaps the most significant that the fastidious Pseudornonas pt susceptible bacterium while i? host susceptible fungus. The results txplanation for the folkloric uses of E. /ve tract disorders (Adebajo and

he organic extracts and volatile oil of liflorcl was assessed on isolated rat I showedconsiderable activity but only Ided higher contractile responses than I The contractile activity was absent in /r confirmed the basis for using it in our intestinal disorders such as constipation

[Aquifoliaceae), the heartwood was lested against 3 bacteria and 2 fungi. late extract was purified and bulked Id profound activity against Bacilllis [faecalis, no activity against the fungi

~hev.. syn. Flerlrya aestuans Gaird. parts, used in Nigeria for the treatment lammation). This was extracted and ive bacteria and two fungi. The results ltive which may be helpful in preventing e case of bums and in inflammation, wten nestuans in Nigerian traditional , 1991).

five bal micnx and co. - - - - - - -

valide:

(vii) Cassia alata Linn. (Caesalpinaceae) - In Nigerian traditional medicine, it is used in the treatment of parasitic skin diseases and pustular while the dried leaf infusion is used as apurgative. The leaves were gradien tl y extracted and tested for activity against

cteria and five fungi. The extracts were active against all the ~rganisms and thus purified and fractions were very active mpared favourably with phenol and bacitracin. This work s the use of C. alata in Nigerian ethnomedicine for the ent of skin diseases and also corroborates the findings on species (Ogunti et al., lgn' '

(viii, 111 UllLll

Activit medici hamay showe antibac traditic

Trichili,

tmen t of

!orti Plal

) Dandy (

nation of erial age - - . .

r jagus (Thomps.: ~onvulsant preparations and the treatment ot open sores. y-directed fmctia C. jagirs bulbs, used in traditional ~ne as an antibact~ nt gave four alkaloids, lycorine, ne, crinamine and 6-hydroxcrinamine. Only crinamine d strong antibacterial activity. The possession of strong :terial activity has justified the use of Crinum jagus in the ~nal trea' nl., 199: open sol

~ c h ex C

'Y 1).

(Amaryl . . is used 1 "

res (Ade

)liver (h,

sanya et

leliaceac

2).

crude (i-4 a keuder E) - The methanol and gradient extracts of the leaves showed antimicrobial activity, to be concentrated in the ethylacetate fraction, but none was active against any fungi. T heudelotti leaves can therefore be regarded as having moderate antimicrob (Aladesanmi and Odediran, 2000).

ial proF

Antimic

Oxidal

:robial L

nts (Free

znd Anti,

: radicals

oxidant

;) - Thes

Activitit

e are hi@

?S

;hly reac tive moll that can damage important cellular molecules such as DNA, lipids or other parts of the cell. The body uses antioxidants to destroy, neutralize or deactivate the free radicals. Antioxidants are abund, vegetal Commc;~c;~il~ IWU plwcsslrlg lluwevel ucsuuya LIIC ~~I ILIUAIUI ILS

available in freshly harvested raw fruits and vegetables.

antly avi bles, esp .--:..I c-

I fresh, c here gro\ .--:-- L-

~rganic, vers havt

A.

vine r ip : re-mine --.---.- 61

ts and ie soil. :Am-.-

Ten Nigerian plants were studied based on their ethnomedical uses to possess antimicrobial and possibly antioxidant activities. Their methanol extracts were tested against four bacteria and three fungi at four different concentrations along with thirteen antibiotics. The results showed Marklzamia tomentosa and Tricltilia lzeudelotti leaf extracts were very active even against E. coli and I? aeruginosa. The extracts were partitioned into n-hexane, CHCI,, EtOAc, and aqueous fractions and tested against fifty bacteria clinical isolates along with thirteen antibiotics. At~Smg/ml, the CHCI,, and aqueous fractions of 1: heu&lofti, CHCI,, and EtOAc of M, tonle~ttosa gave the highest inhibition that was stronger than their corresponding methanol extracts. The radical scavenging abilities of the methanol extracts of the ten medicinal plants using rapid DPPH tlc screening was carried out; again M. tomentosa and i? Iteudelotti, gave very impressively strong antioxidant activities. Massularia acuminata with the highest antioxidant activity showed no an ~ial activity. The hat M. tomentosa and T he :ould be further e lotherapeutic agents that COUIU LJC used against infectiu113 wuxu UY 111~1tiple antibiotic resistant strains, very common in Nigeria These activities justified the ethnomedical uses of these plants (Aladesanmi et al., 2007).

" results s xploi ted

,bowed t for chen -.-I L.. -.

scular A ctivity

It has been establishes unequlvocauy that cardiovascular, heart disease or precisely heart attack is the number one killer of both male and female and the incidence is rising at alarming rate. This prompted our m n i n g of plants for biological activities on the cafdiac muscle which was supported with OAU G .27BK: "Phytochemical and Pharmacological Studies o selected Cardioactive Nigerian Medicinal Plants". In this connectton

The card

rant 14 In some

muscles rduced ei .. .

of the ml ither p s i

t, guinea- itive or n8

I medicir . -- .

ral plants . . (9 Lac effects of ten Nigerian snty six

extracts were examined on isolated. electricallvQiven and spontaneously- beating atrial he extracts (100- 800 ig Iml) ir ationdependent - inotropic andlor chronotropic responses. Wenty-two out of the twenty- p p p p p p p - - - p -

- - - - - - - - - - - -

26

4

.pig and 1 egative c -

ed based on their ethnomedical uses to l y antioxidant activities. Their methanol bacteria and three fungi at four different rteen antibiotics. The results showed Iichilia keudelotti leaf extracts were Y and P aeruginosa. The extracts were El,, EtOAc, and aqueous fractions and d isolates along with thirteen antibiotics. ueous fractions of T heudelotti, CHCI,, re the highest inhibition that was smnger ~anol extracts. The radical scavenging s of the ten medicinal plants using rapid ried out; again M. tomentosa and T ssively strong antioxidant activities. r highest antioxidant activity showed no sults showed that M. tomentosa and T loited for chemotherapeutic agents that s caused by multiple antibiotic resistant 'Ihese activities justified the ethnornedical mi et al., 2007).

ocally that cardiovascular. heart disease ~mber one killer of both male and female rming rate. This prompted our smening ties on the catdiac muscle which was n t 1427BK: "Phytochemical and some selected Cardioactive Nigerian lection,

sponses.

26

,gerian medicinal plants wi ~ t y six d, electricallyd~iven and spontaneously- yinea-pig and lizard. The extracts (100- ve or negative concentrationdependent .

Twenty-two out of the twenty-

six extracts demonstrated significant iP < 0.05 - 0.001 ) cardioactivity. acting directly on the cardiac muscle. The effects of most of the extracts are inhibitory on both the amplitude and frequency of atrial contraction. Only extract of Morir~dr Iircida leaves and root produced pronounced excitatoly eff he ampli' on. The resulrs obtained with Pleiocer ri rootwc r~cv-iifhlicc kernel showed a significant llulio~roly effect followeu oy carulac :utythmia and finally carliac a1-re.c 11ni et a/. , 1988; Aladesanmi et (11.. 1986). it (Ilesan

ects on tl tildes of I

~ o d and i -...- J l ...

( i i ) Dj~so.~~lrrrn lenticellom, the cardiac effects of the leiif methanol exh-act and ten isolated pure compounds of D~ao.~?~lrrr,r lenticellrm Gillespie were examined i r l \>;fro on isolated, spontaneously beating. a trial muscles of rat. The extract (8 x 10 -' gltnl) induced negative chronotropic and positive inotropic responses. It demonstrated significant (P < 0.05-0.01) cmdio activity. Of the ten compounds tested, Dysoxyline, homolai~da~~osine (new isoquu~oline alkaloids) 'and 3-epi- 12-Hydsoxy-schelhammericine demonstl-ated significant cardiac ~ffects. (Aladesanmi and Ilesanmi. 1987).

(iii) This experiment was repeated in the following year (Adew~nmi and Aladesannli, 1988). in vivo in cats with the use of phyllocladene as reference compound because it was found in our earlier experiment (Adewunmi and Aladesanmi. 1988) to be a very active cardio depressant agent on B. glahrato. The cardio-depressant effects produced by phyllocladene and the methanolic extract of D. lenticellrrc were antagonized by atropine, suggesting that these effects may be mediated through cholinergic mechanism. The extract (200 igkg, i.v.) significantly (P< 0.05) reduced the arterial blood pressire of anaesthetize cats (Adewunrni and Aladesanmi, 1988).

idal Acti . .

ivity .1 ,. l 7 , Molluscic~aes are agents toxic to snails (IVIOIIUSCS). ~lthough generally

k n e snail notably of the genera I Oncomt re directly implicated in the transmlsslon or scn~stosomiasis (bilnarzia). This parasitic disease

is endemic thlw~gl~out So111h America,Airicn and rhe Far East. affecting more that 200 lnillio~l people in over 70 countries ( i and Hostettmann. 1985).

1-

have be Noteabl 0- ~ ~ ~ ~ - -

Schistosomiasis is perhaps second to malaria as a hea~rn problem in Africa out of the sixTDR (WHOIWorld Bank sponsored Project on Tropic;~l Diseases Research) diseases. About 14 1 million people on the African continent are infected with this tropical disease caused by water borne parasites. Research into fmding c h e a ~ molluscicides led to a look at plants and several plants

:en screened all over Africa for IT vity. !e amongst them are the Endod, Ph tdra.

awcrrrzitr 111udc~gtrsctrrie11.ri.s c - ' ' *yc~prelrru rerraptera L) (Sofou 1007). 13, Alade

In reahzation of the Importance ot molluscicides in this society. therefore I began work 7xyIrrm Ierlticellare Gillespic (Meliaceae). First, the .ild stem were extracted with methanol and tested for activity. The methanolic extract of the leaves produced 100% mortality to B. gltrhruta at 100mzJL while that of the stem gave 60% mortality. The 2 terpenes, 7 alkaloids and a phenone isolated (Aladesannli er 01. 1983) were tested and p-Hydroxy-acetophenone was the most active ( 1 00% at 6ppm). followed by 2,7-dihydrohomoerysotrine (90% at 6ppm), while dysazecine has the least activity (0% at 8ppm and 50% at 20ppm). All the compounds were found to possess cardiodepressive

. . - ld Alade - - 388).

:idal acti dodeccn

~ - - . -~-~.

In con 1 1 1 -

again! = 41

50 stronr

I of the 11 .

on Dysc leaves a

. .

work, a r moerythrina-derived alKalola \vim mo~~uwcidal activity. named lenticellarine, along with 7 other alkaloids were isolated from the leaves of D. 1.rlticc.lIcrre. Lenticellarine proved to be moderately molluscicidal

.;r the snail Biornl gltrhmtc 1 OOppm, LC Oppm -.vithin 24 3:. I I ) hers showed

.. _. .~er G activity but welt: ~ l luwn (Aladehiurrrn eta/., 1988).

7lzaluricr hours ( I

- - - I .--..

r LC,, = while ot -,.---- -.

n \mer.ica.Afric.a ;~nd the I:nr Elst. aikcting kvlc' ill over 70 countries (Mashton and

p,1p4 .;econd to malaria as a health problem

I DR (WHOAVorld Bank sponsored Pro-ject Rcmrch) diseases. About 14 1 million

1 continent are infected with this tropical ~cr hornc parasites. Research into filding bet1 to a look at plants and several plants 111 o\.er Africa for molli~scicidal activity. pl arc the Endod, Phj~tolac.c.cr ~Io(1cctrntlra. Lcirie~tsi.c and Tcrraplerr, 1prcJ rcr I QQ?. Aladesanmi, 2007).

Fig 11: Nuclear Overhauser enhancements used to determine stereochemistry of the cyclopropane ring and the A lJ-ls

double bond of Lenticellarine, from 2D-NOE spectrum. bponance of molluccicides In mis society. brk on Dj-so.xylirin lei~ticcllnre Gillespic he leave< and etem were extracted with br activity. The methanolic extract of thc I mortality to B. gltrhrata at 100mzJL while LOC; mortality. The 2 terpenes. 7 alkaloid4 tl (Aladesann~i et ol. 1983) were tested and none \va\ the moa active ( 100% ai 6ppm). klrohomoer).\otrine (90% at 6ppm), whilc ar activity (Or: at 8ppm and 50% at 20ppm). (yere found to possess cardiodepressive h i and .4lade\anmi 1988).

(iv) The work on the stem of D. lenticellare in which the methanolic extract was reported to give 60% mortality to B. glabrata at

m g L was further purified. Two new alkaloids. 3epi-2,18- ethoxy-schelhammericine and lenticellarine and a new

**tnrpene, 82 - methoxysandaracopimarene were isolated and d against B. glabrata Say and fouind to possess molluscicidal vity though highest with 3-epi-2, 18-

dirnethoxyschelharnrnericine and low- :Ilmine, a decre;lse which may be due to the disruption of tl skeleton (Aladesanmi and Adewunmi, 1990).

U1 L b l

teste acti

tin lentiu le h o r n

we1 s p i ~ :rpene, fr lide isolated from eaves of D. lenticeuurz and tested IUI ~ ~ l ~ ~ ~ u s c i c i d a l activity

against B. gl activity which compared favourable with niclosamide s concluded that the activity of the D. l~nticellare leaves extract is due to the presence of fermbietolide

its congeners (Aladesanmi and Adewunmi, 1995). In the same , the alkaloids isolated from D. lenticellare to date represent

the l int a1 kaloids to have molluscicidal activity.

>ketal (fu ~sed) dite ..- he work. a novel homoerythrina-derived

~cicidal activity. named lenticellarine. along bid.; were isolated from the leaves of D. llarine proved m be moderately molluscicidal br~~n/ln/ario ~lthrtrtc~ LC,, = 1 00ppm, LC I 7.r hours (Fis. 1 1 ) while others showed r l were known (,4ladesanmi et a/. , 1988).

abrata, , . I t wa

and i vein - -

4. Antimalarial Activity

Malaria is the worldwide most important parasitic disease with an incidence of almost 300 milliort clinical cases and over one million deaths per year. Almost 90% of these deaths occur in Sub-Saharan Africa, where young children are the most vulnerable. Malaria is directly responsible for one in five childhood deaths in Africa and indirectly contributes to illness and deaths from respiratory infections, dihoeal disease and malnutrition. While we wait for malaria vaccine, effective chemotherapy remains the mainstay of malaria control.

Therefore, to overcome malaria, new knowledge, products and tools are urgently needed, especially new drugs are required.

Co scn the

uni mo --.,

earch G: 1 A,.,",

(i) With a Res rant 1427BM - "Search for new sources of antimalarial UIU~J uf plant origin", from the University Research

mmittee (URC), we embarked on the iiz vivo and in vitm ~ening of the different parts of nine Nigerian medicinal plants for

...- ir antimalarial activities (Aladesanmi et al., 1988). Seven plant thanolic extracts were evaluated in vivo N. strain of rsmodiunt berglrei berglrei in a four day sup test in mice

and had an ED,, values of 100-500mg/kg/day. not her twenty one plant exmcts were tested in vitm utilizing the inhibition of intake of (G-jH) - hypoxanthine into the mu1 ti-drug resistant, K-1 strain of Plasmodiunt falcipanm c n blood. :ultured :

ion, Alsi

against : lpressive

On an early (in vivo) infect ngensis, congensis, Ocimum gratissinziim, (Efinrin) Sarcocephalus latifolia, (Igbesi) and Gossypiunz arboreum, (Owu) were effective in suppressing malaria infection while Newbouldia leavies (Akoko) failed with

nfected washed red blood cells. In the in vitm test, activity was Ire pronounced in the stem of S latifolia than the leaf. A.

~v~lgeizsis possessed the highest activity while Newbouldia leavies showed the lowest activity. Our findings indicated that Gongonema latifolizlnz (Ewurodo) was the most active followed by Azadiraclzta indica (Dogoyam) while S. latifolia showed the least activity (>500

lost important parasitic disease with an liori clinical cases and over one million b of these deaths occur in Sub-Saharan nre he most vulnerable. Malaria is directly nildhood deaths in Africa and indirectly hs from respiratory infections, d ihoea l lile we wait for malaria vaccine, effective lainstay of malaria control.

ria, new knowledge, products and tools cially new drugs are required. I

427BM - "Search for new sources of t origin", from the University Research tmbarked on the in vivo and in vitro hrts of nine Nigerian medicinal plants for 6 (Aladesanmi et al., 1988). Seven plant ! evaluated in vivo against N . strain of hei in a four day suppressive test in mice If 100-500mg/kg/day. Another twenty kd in vitm utilizing the inhibition of intake into the multi-drug resistant, K-Istrain 171 cultured in human blood.

ection, Alstonia congensis, congensis, finrin) Sarcocephalus latifolia, (Igbesi) n, (Owu) were effective in suppressing lewbouldia leavies (Akoko) failed with >od cells. In the irt vitro test, activity was I stem of S latifolia than the leaf. A. Sghest activity while Newbouldia leavies I. Our findings indicated that Gongonema the most active followed by Azadiraclzta 5. larifolia showed the least activity (>500

tglml). As the activity of S. latifolia was appreciable in the in vivo testing but very low or no activity in the in vitro testing, it may suggest the difference of the two methods. We therefore concluded that any plant that may be termed active must pass the two tests (Aladesanmi et al., 1998).

extrac the dc ......Am.

:t showel )se rang ..:,, 07

d a dose- ;e of 50 Aqm- ...-a

(ii) This was repeated with Eugenia unijlora leaves. The methanolic -dependent chemo-suppressive effect in -200mg/kg/day with the highest dose

~ " V U U U I I ~ o I 21113 the lowest dose 39.87% while dose of 150 showed 83.56%. The partitioned fractions showed chemo suppressive effect at 150mglkglday in which the aqueous residue produce 88.53%, ethylacetate (63.47%), chloroform (43.55%) and petroleum ether showed no activity at all. The chemo suppressive activity of the plant is a function of the polarity and that the anti-malarial principle must be polar compound(s). This work has further validated the ethnomedicinal usage of Eugenia uniflora as febrifuge in Nigeria (Agbedahunsi and Aladesanmi, 1993). It is pertinent to know that work is actively in progress in collaboration with our colleagues in University of lbadan and the United States of America on Eugenia uiiij7ora and Goizgronema latifolium as the candidate plants.

5. Insecticidal Activity

(i) My collaboration in 1987 with the Sittingboum Research Centre of Shell Research Limited, Kent, UK yielded some mutual scientific and economic benefits. The centre has an active programme on the discovery of novel natural products exhibiting agrochemical activity. My work here involved the screening of six new and novel alkaloids, 18 - Methoxy - 3 - epi-Schelhammericine, Lenticellarine,l2 - Hydroxy - 3 - epi-schelhammericine, Dysazecine, Dysoxyline and Homolaudanosine (Aladesanmi et al., 1983,1984,1988 and Aladesanmi and Hoffmann, 1994), isolated from the leaves and stem of Dysoxylum lenticellare

(ii)

Gilespie. were found to be active against vine downg mildew though at low level.

I had the opportunity of spending my 1989190 sabbatical leave at the University of Arizona. Office of Arid Lands Studies, Bioresources Research Facility. Tucson, Arizona, U.S.A. during which I worked on aridldesert land plants for insecticidal activity. In a collabomtion on natural insecticides with a Japanese Company, I worked on Grirtdelia can~porzir~z (Asteraceae) and isolated several compounds of which grindelic acid was the most active. In order to potentate its activity, microbial transformation of grindelic acid by a culture of Aspergillus rtiger produced new 3- ketogrindelic acid and the known grindelanes (8-hydmxygrindelic acid, 7 B - 8 6 - epoxy grindelic acid and methyl-3- 8- hydmxygrindelate (Aladesanmi and Hoffmann, 1991).

R2 R3 0 lvlc $-ketogrindelic acid)

k active against vine downg mildew though

51 spllul1ig my 1989/90 sabbatical leave at ,rizona, Office of Arid Lands Studies. ~h Facility. Tucson, Arizona, U.S.A. during dldesert land plants for insecticidal activity. ~tural insecticides with a Japanese Company, lia cartlponlrlt (Asteraceae) and isolated f which grindelic acid was the most active. I its activity, microbial transformation of lture of Aspergilllis niger produced new 3- the known grindelanes (8-hydroxygrindelic :poxy grindelic acid and methyl-3- 8-

li and Hoffmann, 1991).

R3 (3-ketogrindelic acid)

Nati~ral products still play a ma-jor role as ci~ugs, and ax lead structures for the devclopmcnt of synthetic molecules. About 50%: of thc drugs introduced to the ~narket during thc last 20 years arc derived dil.ectly or indirectly from small biogenic molecules. Screening for new dnlgs in plants implies the screcnirig of extracts for the presence of novel compounds and an investigation of their biological activities. It is c~urently estimated that approximately 420,000 plant species exist in nature. For the puspose of lead discovery, or for scientific validation of a traditional medicinal plant or a phytopharmaceutical active principles in complex matrices. phytochemistry needs to be centered. Therefore, the interfacing of biological and chemical assessment becomes the critical issue.Drug discovery from plants can be guided by new isolation technologies and epidemiologic studies facilitated with computer assisted HPLC rnicro- fractionation and microplate technology. Epidemiologic sh~dies have shown that high dietary flavonoid intake may be associated with decreased risk for cardiovascular disease.

Although a lot of research to discover new, effective and cheap drugs is in progress in the discase endemic developing countries. it is not yet possible to fillly dcvelop leads and drug candidates from natural products, hence. people in these countries continue to rely on traditional medicines. Poor economics and technological capabilities, lack of human resources (experts). and good management and possibly government non chalant attitude or policy in these countries are the major constraints to progress in research and development work for new drugs (Nyigo and Malebo, 2005; Okijagu et ul., 2005).

During my about three decades of search in the jungles of Fiji and Nigerian forest in my phytochemical pursuit to date, I have worked on 40 plants from which I have isolated. characterized and identified 108 compounds (alkaloids, terpenes, flavonoids, coumarins and phenolic acids). out of which 28 are new while 7 are novel bioactive natural products. This has provided the scientific template for the exploitation of some medicinal

plan~s for fuhu-e development as anti-infective, anti-malarial, carciiovascular. insecticidal and molluscicidal agents.

I have equally been widely publishedin science journals around the world. as marly (32) of my publications in form of reprints and/or authentic samples were requested for by various scientists all over the world. I think I can now answer to aTraditiona1 Medicine Scientist amongst the49 of such in Obafemi Awolowo Ur,iversity. This has been made possible by ~cholarships, fellowships and research grants received. which include the Federal Government of Nigeria, Obafemi Awolowo University, Ile-Ife. IJniversity of Arizona, Tucson. U.S.A. and Deutscher Akademischer Austauchdienst (DAAD). In the course of my career. I have produced LWO Ph.Ds. (Drs. C. A. Adebajo and Khan He) and six M.Sc. graduates of this University now in different positions while currently training two Ph.D, two M.Phi1. and one M.Sc. students.

I thank God for the opportunity to be alive today to give this inaugural lecture and that my modest contribution is possible through theco-operation of these students as listed inTable 1.

In order to appreciate and complement the frantic efforts of our scientists, it is hoped that the Nigerian Institute for Pharmaceutical Research and Development (NIPRD), Abuja will take its rightful place in the area of natural products and d n ~ g development by forming effective collaboration with Nigerian Scientists and other stakeholders, otherwise, the volume of isolated bioactive compounds would only be good as archieve materials. With advances in technology, biotechnology, plant tissue culture and separation techniques, it may not be too long when random sampling combined with automated high-throughput screen (HTS) may come to the forefront in d n ~ g design, enabling extensive libraries of active compounds to be built up as an entire rain forest can be screened at pharmaceutical industry's laboratories and rendering our ethnobotanical. local knowledge of fauna and flora largely irrelevant.

]]ti-infective, anti-malarial. cru-dio\lascular. rntx.

ihed in science journals around the world. n form of reprint$ and/or authentic samples cientists all over the world. I think I can rlicine Scientist amongst the 49 of such in ty. This has been made possible by search grants received. which include the o. Obafemi Awolowo University, Ile-Ife, I. U.S.A. and Deutscher Akademischer he course of my career, I have produced :, and Khan He) and six M.Sc. graduates ent positions while currently training two jc. students.

11 t3 be alive today to give this inaugural ibution is possible through the co-operation ble 1 .

dement the frantic efforts of our scientists, stitute for Pharmaceutical Research and 1 will take its rightful place in the area of oprnent by forming effective collaboration ler stakeholders, otherwise. the volume of ,vould only be good as archieve materials. biotechnology, plant tissue culture and not be too long when random sampling h-throughput screen (HTS) may come to ling extensive libraries of active compound9 forest can be screened at pharmaceutical ering our ethnobotanical. local knowledge

Table 1: Present position of Trained Po5rgri~iuarc Sludents

h0.1 PGSTUDENT 1 DEGRFE I I ' E H I PRESENTPOSITION

. Mr. 0 . J. F e r n i - 0 M S c . 9 8 8 Chiel'Pharmxist. State Hospital. Ado-Ekiti and a Ph.D. candidate, Faculty of Administration O.A.U. Ile- Ife.

The

Dr. C. A. Adebajo

Mr. S. A. Odediran

MI: E. 0. Ogunti

Dr. Rene Nia

Dr. Khan He

- --

Dr. K. K. Ajibesin

refore, training pro

sc. 1 ;: 1 ReaderDepartrnentof M Sc. Ph.D. Pharmacognosy. O.A.U..

Ile-Ife.

Chief Pharmacist. Health Centre, O.A.U., Ile-Ife.

M Sc.

M Sc.

Ph.D.

yarnmes in modem drug design and development

-

M.Sc.

should very urgently become an integral part of both Universities and national policy of developing economies of the world.

1990

1994

1995

Hence, in conclusion, a multidisciplinary approach to drug discovery

- -

19%

involving the generation of truly novel molecular diversity from natural product sources. combine with total and combinatorial synthetic

U.S.A.

Senior LecturerDepartment of Pharrnacogno~y. University of Uyo, Uyo. Akwa- Iborn State.

Professor of Pharrnacognosy. Purdue University, West Lafayetta. IN, U.S.A.

-

LecturerDepartrnent of Pharmacognosy, University of Uyo, Uyo.Akwa- Iborn State.

methodologies provides the best solution to increase the productivity in d n ~ g discovery and development (Vuorelaz et al., 2004; Peterson er a/., 20@5l.

- .

* - - *

'\II.. Vice-Chancellor, Sir. Pri~icipnl Clfficers, disti~igirisllcd guests, laclies : ~ n d gentlemen, in [tie course of tny lecture. 1 have reviewed the past- .:ovclaing about fivc decadcs. [he. ciurent trend and insight into the f~~lure of ~;~tirrnl products chcmihtry. my three decatles of hi~tiible contribution to

I I is ficltl of scientific itlnovation. 11cdicn1 u ~ d econoniic inipaa ofthis imiqi~c iiiulti-fncct science kllown ns natural prod~lcts cl-icmistry. I Ilnve also jr~.offcretl some solutions as n wily forward. I t is tl~crefore my hope thnt r I~c~st:keliolclcrs will begin to app~winte the pains, frustrations and sacrifices f ~l'a developing world natural pr~lucts chemist and of course, all scientists, I 1 dnlg research, design and development to tackle the plague of the human lace. I want to conclude by leaving you with, in the worcls of late Professor Va~ro E. Tyler of R~rduc University, U.S.A.. an intenlationally renowned expel-t in the field of Pharmacogosy and Botanical Medicine in his review of Medicinal Plant Research 1953 - 1987 ( I 88), "the most productive period of medical plant research lies ahead of us sdmewhere, perllaps irncler our very noses. lies that one plant, the constituent of which will L~I-tainly cure cancer, AIDS, or even protect against the affliction of old

I

;~ge".

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