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1.
Bioorg Med Chem Lett ; 30(23): 127510, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32898693

RESUMO

Here, we report the discovery of a new class of NPBWR1 antagonists identified from a fragment-based screen. Compound 1 (cAMP IC50 = 250 µM; LE = 0.29) emerged as an initial hit. Further optimization of 1 by SAR-by-catalogue and chemical modification produced 21a (cAMP IC50 = 30 nM; LE = 0.39) with a 6700-fold increase in potency from fragment 1. Somewhat surprisingly, Schild analysis of compound 21a suggested that in vitro inhibition of NPW-mediated effects on upon cAMP accumulation were saturable, and that compound 21a dose-dependently increased [125I]-hNPW23 dissociation rate constants from NPBWR1 in kinetic binding studies. Collectively, these data are inconsistent with a classic surmountable, orthosteric mechanism of inhibition. The benzimidazole inhibitors reported herein may therefore represent a mechanistically differentiated class of compounds with which to form a better appreciation of the pharmacology and physiological roles of this central neuropeptide system.


Assuntos
Benzimidazóis/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Células CHO , Cricetulus , Descoberta de Drogas , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
2.
J Org Chem ; 78(2): 706-10, 2013 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-23215022

RESUMO

The stereoselective addition of 2-phenyloxazol-4-yl trifluoromethanesulfonate to N-sulfinylimines is described. Vinyl anions derived from enol triflate 2 undergo 1,2-addition with a variety of aldimines to afford the corresponding secondary sulfonamides as single diastereomers. The absolute stereochemistry was confirmed by X-ray crystallography which provides support that the reaction proceeds through an open, nonchelate transition state. This methodology has been applied to the synthesis of the ketoamide fragment of the protease inhibitor boceprevir.


Assuntos
Hepacivirus/química , Hepacivirus/efeitos dos fármacos , Iminas/química , Mesilatos/química , Oxazóis/química , Prolina/análogos & derivados , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Cristalografia por Raios X , Estrutura Molecular , Prolina/síntese química , Prolina/química , Estereoisomerismo
3.
J Org Chem ; 77(7): 3297-310, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22423625

RESUMO

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.


Assuntos
Álcoois/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Crisenos/química , Crisenos/síntese química , Equinocandinas/química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Paládio/química , Triterpenos/química , Catálise , Estrutura Molecular , Estereoisomerismo
4.
Bioorg Med Chem Lett ; 22(2): 1014-8, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22197390

RESUMO

The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i).


Assuntos
Benzilaminas/farmacologia , Piperazinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Benzilaminas/síntese química , Benzilaminas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Piperazina , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 22(9): 3203-7, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22483609

RESUMO

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.


Assuntos
Amidas/síntese química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/química , Piperidinas/química , Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Peptídeos beta-Amiloides/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Camundongos , Fragmentos de Peptídeos/biossíntese
6.
Bioorg Med Chem Lett ; 21(6): 1865-70, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21353541

RESUMO

A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.


Assuntos
Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Pirrolidinas/química , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Modelos Moleculares
7.
Bioorg Med Chem Lett ; 20(7): 2311-5, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20207138

RESUMO

Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.


Assuntos
Azepinas/química , Azepinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/metabolismo , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Cristalografia por Raios X , Cães , Humanos , Modelos Moleculares , Receptores de Orexina , Ratos , Ratos Sprague-Dawley , Transtornos do Sono-Vigília/tratamento farmacológico
8.
Bioorg Med Chem Lett ; 20(7): 2106-10, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20207541
10.
Bioorg Med Chem Lett ; 19(11): 2997-3001, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19406641

RESUMO

NMR spectroscopy, X-ray crystallography, and molecular modeling studies indicate that N,N-disubstituted-1,4-diazepane orexin receptor antagonists exist in an unexpected low-energy conformation that is characterized by an intramolecular pi-stacking interaction and a twist-boat ring conformation. Synthesis and evaluation of a macrocycle that enforces a similar conformation suggest that this geometry mimics the bioactive conformation.


Assuntos
Compostos Heterocíclicos com 1 Anel/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Cristalografia por Raios X , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Receptores de Orexina , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo
11.
J Am Chem Soc ; 130(22): 7060-6, 2008 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-18461935

RESUMO

The Candida albicans Fitness Test, a whole-cell screening platform, was used to profile crude fermentation extracts for novel antifungal natural products with interesting mechanisms of action. An extract with intrinsic antifungal activity from the fungus Fusarium larvarum displayed a Fitness Test profile that strongly implicated mRNA processing as the molecular target responsible for inhibition of fungal growth. Isolation of the active components from this sample identified a novel class of isoxazolidinone-containing natural products, which we have named parnafungins. These natural products were isolated as an interconverting mixture of four structural- and stereoisomers. The isomerization of the parnafungins was due to a retro-Michael ring-opening and subsequent reformation of a xanthone ring system. This interconversion was blocked by methylation of an enol moiety. Structure elucidation of purified parnafungin derivatives was accomplished by X-ray crystallography and NMR analysis. The biochemical target of these natural products has been identified as the fungal polyadenosine polymerase. Parnafungins demonstrated broad spectrum antifungal activity with no observed activity against gram-positive or gram-negative bacteria. The intact isoxazolidinone ring was required for antifungal activity. In addition, the natural products were efficacious in a mouse model of disseminated candidiasis.


Assuntos
Antifúngicos/isolamento & purificação , Fusarium/química , Oxazolidinonas/isolamento & purificação , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Oxazolidinonas/química , Oxazolidinonas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
12.
J Med Chem ; 51(7): 2108-14, 2008 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-18333607

RESUMO

X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.


Assuntos
Amidas/química , Amidas/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células CHO , Células Cultivadas , Simulação por Computador , Cricetinae , Cricetulus , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/genética , Padrões de Referência , Alinhamento de Sequência , Relação Estrutura-Atividade
13.
Org Lett ; 10(14): 3037-40, 2008 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-18563906

RESUMO

The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.


Assuntos
Alcanos/síntese química , Indóis/química , Alcanos/química , Alquilação , Derivados de Benzeno/química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , Estereoisomerismo
14.
Chem Commun (Camb) ; (4): 419-21, 2007 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-17220990

RESUMO

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.


Assuntos
Fosfatos/química , Ácidos Fosfóricos/química , Cristalização , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Fosfatos/farmacologia
15.
Org Lett ; 8(1): 59-61, 2006 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-16381567

RESUMO

[reaction: see text] The chemical behavior of 1,2-bis-triisopropylsilanylsulfanyl alkenes 1 is relatively unexplored, and the weak sulfur-silicon bonds give rise to various transformations. Under acidic conditions (HCl) and in the presence of a Lewis acid at room temperature the bicyclic adduct 2 is obtained in good yield. The structure was confirmed by X-ray crystal analysis with R = benzyl.

16.
J Med Chem ; 45(9): 1887-900, 2002 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-11960500

RESUMO

A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.


Assuntos
Piridonas/síntese química , Receptores de GABA-A/efeitos dos fármacos , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Linhagem Celular , Convulsivantes/síntese química , Convulsivantes/química , Convulsivantes/farmacocinética , Convulsivantes/farmacologia , Cristalografia por Raios X , Epilepsia/tratamento farmacológico , Agonistas GABAérgicos/síntese química , Agonistas GABAérgicos/química , Agonistas GABAérgicos/farmacocinética , Agonistas GABAérgicos/farmacologia , Humanos , Técnicas In Vitro , Ligantes , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Oócitos , Técnicas de Patch-Clamp , Subunidades Proteicas , Piridonas/química , Piridonas/farmacocinética , Piridonas/farmacologia , Ensaio Radioligante , Ratos , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiologia , Relação Estrutura-Atividade , Xenopus
17.
J Med Chem ; 46(12): 2413-26, 2003 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-12773045

RESUMO

A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Álcoois/síntese química , Óxidos N-Cíclicos/síntese química , Inibidores de Fosfodiesterase/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/metabolismo , Piridinas/síntese química , Álcoois/farmacocinética , Álcoois/farmacologia , Álcoois/toxicidade , Animais , Broncoconstrição/efeitos dos fármacos , Cristalografia por Raios X , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Óxidos N-Cíclicos/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Cães , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Cobaias , Humanos , Técnicas In Vitro , Síndrome do QT Longo/induzido quimicamente , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/toxicidade , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/toxicidade , Ratos , Saimiri , Ovinos , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamente
18.
J Med Chem ; 47(21): 5284-97, 2004 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-15456273

RESUMO

Hepatitis C virus infection constitutes a significant health problem in need of more effective therapies. We have recently identified 2'-C-methyladenosine and 2'-C-methylguanosine as potent nucleoside inhibitors of HCV RNA replication in vitro. However, both of these compounds suffered from significant limitations. 2'-C-Methyladenosine was found to be susceptible to enzymatic conversions by adenosine deaminase and purine nucleoside phosphorylase, and it displayed limited oral bioavailability in the rat. 2'-C-Methylguanosine, on the other hand, was neither efficiently taken up in cells nor phosphorylated well. As part of an attempt to address these limitations, we now report upon the synthesis and evaluation of a series of heterobase-modified 2'-C-methyl ribonucleosides. The structure-activity relationship within this series of nucleosides reveals 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as potent and noncytotoxic inhibitors of HCV RNA replication. Both 4-amino-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-amino-5-fluoro-7-(2-C-methyl-beta-d-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine display improved enzymatic stability profiles as compared to that of 2'-C-methyladenosine. Consistent with these observations, the most potent compound, 4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine ribonucleoside, is orally bioavailable in the rat. Together, the potency of the 2'-C-methyl-4-amino-pyrrolo[2,3-d]pyrimidine ribonucleosides and their improved pharmacokinetic properties relative to that of 2'-C-methyladenosine suggests that this class of compounds may have clinical utility.


Assuntos
Antivirais/síntese química , Hepacivirus/genética , RNA Viral/antagonistas & inibidores , Ribonucleosídeos/síntese química , Adenosina Desaminase/química , Administração Oral , Animais , Antivirais/química , Antivirais/farmacocinética , Disponibilidade Biológica , Linhagem Celular , Estabilidade de Medicamentos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Fosforilação , Purina-Núcleosídeo Fosforilase/química , RNA Viral/biossíntese , Ratos , Ribonucleosídeos/química , Ribonucleosídeos/farmacocinética , Relação Estrutura-Atividade
19.
J Org Chem ; 62(3): 503-509, 1997 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-11671441

RESUMO

In our quest for an antagonist or partial agonist of cocaine, access to certain 6- and 7-substituted 3-phenyltropanes of type I was required. Starting from 3-hydroxy-1-methyl-4-phenylpyridinium iodide, we disclose a pyridinium betaine-based dipolar cycloaddition route to tropenones of type II. In turn, we show how this intermediate can be transformed to type I products either through the copper-catalyzed conjugate addition reaction of Grignard reagents to the enones 7-9 or by the copper(I)-catalyzed cross coupling reaction of the allylic acetates 15a and 16a with Grignard reagents.

20.
J Org Chem ; 61(22): 7727-7737, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11667727

RESUMO

Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.

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