Supplementary Material: Hydroxamate, A Key Pharmacophore Exhibiting a Wide Range of Biological...

Mini-Reviews in Medicinal Chemistry – Complementary Information 1

HYDROXAMATE, A KEY PHARMACOPHORE EXHIBITING A WIDE RANGE OF BIOLOGICAL

ACTIVITIES

Samuel Bertrand1, Jean-Jacques Hélesbeux

1, Gérald Larcher

2, Olivier Duval

1,*

1Laboratoire des Substances d’Origine Naturelle et Analogues Structuraux, UPRES-EA 921, IFR 149 QUASAV, UFR des Sciences

pharmaceutiques et ingénierie de la santé, Université d’Angers, 16 Bd Daviers, 49045 Angers Cedex, France.

2Groupe d'Etude des Interactions Hôte-Pathogène, UPRES-EA 3142, IFR 132, Université d’Angers, Institut de Biologie en Santé PBH-

IRIS CHU 4, Rue Larrey 49933 Angers Cedex, France.


TABLE I. LIST OF BIOCHEMICAL ACTIVITIES OF HYDROXAMIC ACID DERIVATIVES SORTED BY

PHARMACOLOGICAL ACTIVITIES

Pharmacological activities Biochemical activities

Antibacterial and antifungal

activities

Inhibition of fructose bis-phosphate aldolases [1]

Inhibition of glyoxalase [2]

Inhibition of methionine aminopeptidase [3-5]

Inhibition of peptide deformylase [3, 6-9]

Inhibition of phosphomannose isomerases [10]

Inhibition of UDP-3-O-[R-3-hydroxymyristoy]-N-acetylglucosamine deacetylase

[7, 11-15]

Iron chelation [16]

Vectorisation of therapeutic agents [17-22]

Antidiabetic activity activation of Akt signaling pathway [23]

inhibition of 11 -hydroxysteroid dehydrogenase 2 [24]

inhibition of insulin-degrading enzyme [25]

Anti-inflammatory activities inhibition of 11 β-hydroxysteroid dehydrogenase 2 [24]

inhibition of aminopeptidase [26]

inhibition of cyclooxygenases [27-30]

inhibition of dipeptidylaminopeptidase [26]

inhibition of histone deacetylase [31]

Inhibition of leukotriene A4 hydrolases [32, 33]

inhibition of lipoxygenases [27-29, 34]

inhibition of TNF-α converting enzyme [7, 35-40]

Anti-neurodegenerative activities inhibition of glutamate carboxypeptidase II [41-44]

inhibition of histone deacetylase [45, 46]

Inhibition of kynurenine aminotransferase [47]

inhibition of matrix metalloproteinases (MMP) [45, 48]

inhibition of serine racemase [49-52]

iron chelation [53-66]

Anti-osteoarthritis activity inhibition of aggrecanases [7, 67-70]

inhibition of histone deacetylase [71]

Anti-osteoarthritis activity inhibition of matrix metalloproteinases [67, 68, 72-74]

Anti-oxidant activities Electron scavenging capacity [75-86]

Iron chelation [53-66, 83, 84, 87,

88]

Antiparasitic activities Inhibition of aminopeptidase [89]


Inhibition of histone deacetylase [90-93]

Inhibition of metalloproteases [90, 91]

Iron chelation [28, 94-96]

Anti-scarring activity Inhibition of procollagen C-proteinase (MMP family) [97, 98]

Anti-toxin activities Inhibition of botulinum neurotoxin [99-105]

Inhibition of collagenase from Clostridium histolyticum [7, 106]

Inhibition of thermolysin from Bacillus thermoproteolyticus [107, 108]

Inhibition of ureases from Helicobacter pylori [3, 94, 109-113]

Antitumor activities inhibition of carbonic anhydrase [3, 114-117]

inhibition of cyclooxygenases [118, 119]

inhibition of eukaryotic translation [120]

inhibition of glutamate carboxypeptidase II [41-44]

inhibition of glyoxalase [2]

inhibition of histone deacetylase [3, 7, 121-144]

inhibition of lipoxygenases [118, 119]

inhibition of matrix metalloproteinases [3, 7, 35, 127, 145-

158]

inhibition of methionine aminopeptidase [5, 159]

inhibition of phosphatases alcalines, acides ou les 2 ? [160, 161]

inhibition of phospholipases C [162]

inhibition of ribonucleotide reductase [87, 127, 163, 164]

Iron chelation [87, 163, 165-167]

Antiviral activities inhibition of histone deacetylase [168-171]

Inhibition of HIV integrase [172, 173]

Depigmenting activity inhibition of tyrosinase [83]

Hypotensive activities inhibition of vasopeptidase [174-177]

Activation of nitric oxide formation [28, 178-182].

Metal detoxification Iron chelation [53-66]

Other metal chelation [183-185]


TABLE II. LIST OF BIOCHEMICAL ACTIVITIES OF HYDROXAMIC ACID DERIVATIVES SORTED BY

PHARMACOLOGICAL ACTIVITIES

Biochemical activities Pharmacological activities

Activation of Akt signaling pathway Antidiabetic activity [23]

Electron scavenging capacity Anti-oxidant activities [75-82, 84-86]

inhibition of 11 β-hydroxysteroid dehydrogenase 2 Anti-inflammatory activities [24]

Antidiabetic activity [24]

inhibition of aggrecanases Anti-osteoarthritis activity [7, 67-70]

inhibition of aminopeptidase Anti-inflammatory activities [26]

Antiparasitic ativities [89]

Inhibition of botulinum neurotoxin Anti-toxin activities [99-105]

inhibition of carbonic anhydrase Antitumor activities [3, 114-117]

Inhibition of collagenase from Clostridium histolyticum Anti-toxin activities [7, 106]

inhibition of cyclooxygenases Anti-inflammatory activities [27-30]

Antitumor activities [118, 119]

inhibition of dipeptidylaminopeptidase Anti-inflammatory activities [26]

inhibition of eukaryotic translation Antitumor activities [120]

Inhibition of fructose bis-phosphate aldolases Antibacterial and antifungal

activities

[1]

inhibition of glutamate carboxypeptidase II Anti-inflammatory activities [41-44]

Anti-neurodegenerative activities [41-44]

Inhibition of glyoxalase Antibacterial and antifungal

activities

[2]

Anti-inflammatory activities [2]

Inhibition of histone deacetylase Anti-inflammatory activities [31]

Anti-neurodegenerative activities [45, 46]

Anti-osteoarthritis activity [71]

Antiparasitic activities [90-93]

Antitumor activities [3, 7, 121-141, 143, 144,

186]

Antiviral activities [168-171]

Cardiovascular protective activities [187]

Inhibition of HIV integrase Antiviral activities [172, 173]

Inhibition of insulin-degrading enzyme Antidiabetic activity [25]

Inhibition of kynurenine aminotransferase Anti-neurodegenerative activity [47]

Inhibition of leukotriene A4 hydrolases Anti-inflammatory activities [32, 33]

inhibition of lipoxygenases Anti-inflammatory activities [27-29, 34]



Inhibition of matrix metalloproteinases Anti-neurodegenerative activities [45, 48]

Anti-osteoarthritis activity [67, 68, 72-74]

Antitumor activities [3, 7, 35, 127, 145-158]

Inhibition of procollagen C-proteinase (MMP family) Anti-scarring activity [97, 98]

Inhibition of metalloproteases Antiparasitic activities [90, 91]

Inhibition of methionine aminopeptidase Antibacterial and antifungal activities

[3-5]


Inhibition of peptide deformylase Antibacterial and antifungal activities

[3, 6-9]

inhibition of phosphatases Antitumor activities [160, 161]

inhibition of phospholipases C Anti-inflammatory activities [162]

Inhibition of phosphomannose isomerases Antibacterial and antifungal activities

[10]

inhibition of ribonucleotide reductase Antitumor activities [87, 127, 163, 164]

inhibition of serine racemase Anti-neurodegenerative activities [49-52]

Inhibition of thermolysin Anti-toxin activities [107, 108]

inhibition of TNF-α converting enzyme Anti-inflammatory activities [7, 35-40]

Inhibition of tyrosinase Depigmenting activity [83]

Inhibition of UDP-3-O-[R-3-hydroxymyristoy]-N-acetylglucosamine deacetylase

Antibacterial and antifungal activities

[7, 11-15]

Inhibition of ureases Anti-toxin activities [3, 94, 109-113]

inhibition of vasopeptidase Hypotensive activities [174-177]

Iron chelation Antibacterial and antifungal activities

[16]

Anti-neurodegenerative activities [53-66]

Anti-oxidant activities [53-66, 84, 87, 88]

Antiparasitic activities [28, 94-96]

Antitumor activities [87, 163, 165-167]

Metal detoxification [53-66]

Other metal chelation Metal detoxification [183-185]

Nitric oxide formation Hypotensive activities [28, 178-182].

Vectorisation of therapeutic agents Antibacterial and antifungal activities

[17-22]


CHEMICAL STRUCTURE OF SOME HYDROXAMIC ACID DERIVATIVES AND THEIR RELATED PHARMACOLOGICAL/BIOCHEMICAL ACTIVITIES

Name Structure Related activities

(±)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-triazaspiro[4.5]decan-2-one

Hypotensive activity / Nitric oxide formation [182]

(Arylalkyl)hydroxamic acids

N

O

OH

O

N

O

OH

Anti-inflammatory / 5-lipoxygenase inhibitor [188]

(S)-HDAC42

Antitumor / Histone-deacetylase inhibitor [189]

[(Aryloxy)alkyl]hydroxamic acids

N

O

OHO

O

N

O

OHO

O


Actinonin

HONH

OHN

O

N

OOH

Antibacterial / Peptide deformylase inhibitor [8]


Acyclic 3-alkyl-O-methyl-azaindole N-methyl hydroxamates

Antiviral / HIV integrase inhibitor [172, 173]

Acyclic 3-aminomethyl-azaindole N-methyl hydroxamates

Antiviral / HIV integrase inhibitor [172, 173]

AHP analogues

Anti-toxin / Inhibition of botulinum neurotoxin [104]

Albomycin δ1

Antibacterial / Vectorisation of antimicrobial agents [17, 18]


Arylacrylohydroxamic acids

N

O

OH

N

O

OH


Arylhydroxamic acids

N

O

OH

NH

O

OH


Azaindole N-methyl hydroxamic acid

NN

F

N

N

O

OH

O

NH2

NN

F

O

N

O

OHO

Antiviral / HIV-1 integrase inhibitor [173]

Caffeoyl-amino acidyl-hydroxamic acid

Antioxidant / Electron scavenging capacity [83]

Depigmenting activity /

Tyrosinase inhibitor [83].

Chlorocinnamic acid hydroxamate HN

OHO

ClHN

OHO

ClCl

Anti-toxin / Inhibition of botulinum neurotoxin A [103]


Ciclopiroxolamine

Antifungal [190-193] Antioxydant / Iron chelation [79, 163] Anticancer [163, 167]

Cobactin ring analogue

Hypotensive activity / Vasopeptidase inhibitor [175]

Cobactin ring analogue


Deferoxamine B

N

O

OH

NH

O

N

O

OHHN

O

N

O

OH

NH3+

Metal detoxification (Fe, Al) [66, 184] Antioxidant [85, 86, 88, 194] Anti-malarial [95, 195, 196] Antitumor [87, 166]

Desferri-tsukubachelin



Dimerumic acid

NH

HNO

O

N

OH

O

N

OH

O

OH

HO

Antioxidant [75, 81]

Enactins OH

N

O

OH

O

H2N X

R1

X : ,OOH

H

Antifungal [198-200]

Ferrimycin

Antibacterial / Vectorisation of antimicrobial agents [19]

Glycosylated -amino hydroxamic acids

Anti-malarial [201]

Hadacin

N

OH

O

OH

O

Antitumor [165, 202, 203]


Hydroxamate derivative of glycyrrhetinic acid

H

OH

O

O

O

N

OH

H

Antidiabetic / Inhibition of 11 -hydroxysteroid dehydrogenase 2 [24] Anti-inflammatory / Inhibition of

11 -hydroxysteroid dehydrogenase 2[24]

Li1 ??????

Antidiabetic / Insulin-degrading enzyme inhibitor [25]

m-Carboxy cinnamic acid bishydroxamic acid (CBHA)

NH

O

HONH

O

OH


Modified pectins Carboxylic acids modified to hydroxamic acids Antioxydant [78]

Neoenactins OH

N

O

OH

O

H2N X R1

R2

R3

X : ,OOH

H

Antifungal [198-200]


N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycyl hydroxamic acid

SNH

HN

OHO

O

OO

Anti-neurodegenerative / Matrix metalloproteinases inhibitor [48, 205]

NVP-LAQ824

NH

O

OH

N

OH

HN


Oxamflatin

NH

O

OH

NHS

O O


Panobinostat

HN

HN

NH

O

OH


PDX 101

NH

O

OHSNH

OO



Phenolic hydroxamic acids

Antidiabetic / Akt phosphorylation activators [23]

Pyroxamide

NH

O

OHHN

O

N


Quinolinylmethyl -sulfone piperidine hydroxamic acid

Anti-inflammatory / TNF-α converting enzyme inhibitor [37]

Scriptaid

NH

O

OHN

O

O



SL142


SL325


Suberoylanilide hydroxamic acid (Vorinostat, SAHA)

HN

O

NH

O

OH

Antitumor / Histone-deacetylase inhibitor [125, 127, 132-134, 137, 204] Antiviral (HIV) / Histone-deacetylase inhibitor [170]

Sulindac hydroxamic acid

F

HN

O

OH

S

O

O

Antitumor / Cyclooxygenase inhibitor [119]


sulindac hydroxamic acid analogue ou isomer ????

F

HN

O

OH

S

Antitumor / Cyclooxygenase inhibitor [119]

Tepoxalin

N

O

OHNN

O

Cl

Anti-inflammatory / Cyclooxygenase [206] and 5-lipoxygenase [206] inhibitor

TMC-69

Antitumor / Phosphatase inhibitor [161]

TPX-HA analogue

NH

NHN

HN

O

O

O

OHN

OOH



Trichostatin A

NH

O

OH

O

N

Antitumor / Histone-deacetylase inhibitor [127, 204]

VRC3375

HONH

O

N

OO

O

Antibacterial / Peptide deformylase inhibitor [8]

VRC3376

HONH

O

N

OO

O

Anti-bacterial / Peptide deformylase inhibitor [8]


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