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1.
Bioorg Med Chem Lett ; 26(9): 2297-302, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27020302

RESUMO

Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50=1.0 µM, cell IC50=1.8 µM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50=120 nM and cell potency to IC50=230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine.


Assuntos
Aldeído Liases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Humanos , Relação Estrutura-Atividade
2.
J Org Chem ; 74(13): 4886-9, 2009 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-19489574

RESUMO

The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.


Assuntos
Ácidos Carboxílicos/síntese química , Ciclopentanos/síntese química , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Ácidos Carboxílicos/química , Ciclopentanos/química , Estrutura Molecular , Receptores de Lisoesfingolipídeo/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 18(7): 2414-9, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18337097

RESUMO

Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.


Assuntos
Amidas/farmacologia , Benzimidazóis/farmacologia , Quinolinas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Amidas/química , Animais , Benzimidazóis/síntese química , Sítios de Ligação , Células CHO/efeitos dos fármacos , Cricetinae , Cricetulus , Humanos , Modelos Químicos , Quinolinas/química , Ensaio Radioligante , Receptores CXCR3/metabolismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 18(5): 1573-6, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18242988

RESUMO

High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Receptores CXCR3/antagonistas & inibidores , Estrutura Molecular , Relação Estrutura-Atividade
5.
J Am Chem Soc ; 125(42): 12844-9, 2003 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-14558833

RESUMO

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.


Assuntos
Desoxiglucose/análogos & derivados , Macrolídeos/síntese química , Aldeídos/química , Antineoplásicos/química , Desoxiglucose/química , Compostos de Epóxi/química , Malatos/química , Propanóis/química
6.
Toxicol Sci ; 67(1): 81-7, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11961219

RESUMO

Cylindrospermopsin (CY), a sulfate ester of a tricyclic guanidine substituted with a hydroxymethyluracil, is a cyanobacterial toxin of increasing environmental import as it frequently occurs in drinking water reservoirs. As a toxin, CY mainly targets the liver but also involves other organs. In hepatocytes CY inhibits the synthesis of protein and of glutathione, leading to cell death. The total chemical synthesis of CY has recently been reported (Xie et al., 2000, J. Am. Chem. Soc. 22, 5017-5024). The synthesis has provided analogues of CY to study aspects of the relationship between chemical structure and activity that contribute to toxicity. Protein synthesis inhibition was measured in vitro using a rabbit reticulocyte system. Primary cultures of rat hepatocytes were used to determine the biological activity of CY and analogues in intact cells. Protein synthesis and cell glutathione levels were measured. We could distinguish between CY transport and biological activity by comparing the results in vitro to those in intact cells. The role of the sulfate group in CY toxicity was examined by comparing biological effects of CY with that of CY-DIOL (synthetic CY lacking the sulfate group). The sulfate group was found not to play a role in CY activity or in its uptake into cells, since there was no significant difference in biological activity in vitro or in cells between natural CY and CY-DIOL. The orientation of the hydroxyl group at C7 also had no impact on biological activity or transport of CY, since the C7 epimer of CY (EPI-CY) and the corresponding diol (EPI-DIOL) had activity similar to RAC-CY in vitro and in intact cells. AB-MODEL, the analogue lacking an intact C ring, and the methyl and hydroxyl groups of ring A could inhibit protein synthesis (but at concentrations 500-1000-fold higher than natural CY). Other structurally simpler synthetic analogues lacked biological activity.


Assuntos
Alcaloides/toxicidade , Cianobactérias , Hepatócitos/efeitos dos fármacos , Inibidores da Síntese de Proteínas/toxicidade , Uracila/análogos & derivados , Uracila/toxicidade , Animais , Toxinas Bacterianas , Células Cultivadas , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Hepatócitos/metabolismo , L-Lactato Desidrogenase/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/isolamento & purificação , Coelhos , Ratos , Reticulócitos/efeitos dos fármacos , Reticulócitos/metabolismo , Relação Estrutura-Atividade , Uracila/química , Uracila/isolamento & purificação
7.
J Am Chem Soc ; 124(15): 3939-45, 2002 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-11942831

RESUMO

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).


Assuntos
Alcaloides/síntese química , Uracila/análogos & derivados , Uracila/síntese química , Alcaloides/química , Alcaloides/toxicidade , Animais , Toxinas Bacterianas , Cristalografia por Raios X , Cianobactérias/química , Cianobactérias/metabolismo , Toxinas de Cianobactérias , Humanos , Fígado/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Uracila/química , Uracila/toxicidade
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