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Bioorg Med Chem Lett ; 28(4): 732-736, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29398543


A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .

Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Microssomos Hepáticos/metabolismo , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Relação Estrutura-Atividade
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682


Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683


JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

J Org Chem ; 71(19): 7329-36, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16958527


Several different approaches to the A-ring functionalization of an advanced, highly functionalized diosphenol precursor to Taxol are described. The first phase of the undertaking consists of an assessment of those reagents conducive to reaction at the enolic oxygen (silylation, methylation, allylation, and acylation). Transformations involving an alternative attack at the enol carbon center (bromination, selenation) have also been defined. Sodium borohydride reduction operates from the beta-face of C-14 as long as the C-1 hydroxyl is not protected so as to offer steric exclusion. Complications associated with various aspects of these methodological undertakings are addressed. The most advanced oxygenation achievements were realized by way of a noteworthy sequence involving epoxidation of the O-methyl ether, methanolysis under mildly acidic conditions, and regioselective oxidation of diol 38 to give 39.

Paclitaxel , Fenóis/química , Pró-Fármacos , Estrutura Molecular , Paclitaxel/síntese química , Paclitaxel/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Estereoisomerismo
J Am Chem Soc ; 128(4): 1094-5, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16433523


A total synthesis of cylindramide A has been completed in 19 steps. The key step of the synthesis is a tandem ring-opening-ring-closing-cross metathesis that converts a readily available norbornene into an advanced intermediate.

Compostos Macrocíclicos/síntese química , Pirrolidinonas/síntese química , Animais , Compostos Macrocíclicos/química , Norbornanos/química , Poríferos/química , Pirrolidinonas/química
J Org Chem ; 63(20): 6770-6771, 1998 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-11672288