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1.
Bioorg Med Chem Lett ; 20(17): 5027-30, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20675137

RESUMEN

Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.


Asunto(s)
Prolina/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Triazinas/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Triazinas/farmacología
2.
J Med Chem ; 48(7): 2258-61, 2005 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-15801816

RESUMEN

A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.


Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Camptotecina/farmacología , Carbazoles/síntesis química , Glucósidos/síntesis química , Indoles/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Glucósidos/química , Glucósidos/farmacología , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Irinotecán , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Topoisomerasa I , Trasplante Heterólogo
3.
Org Lett ; 7(7): 1271-4, 2005 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-15787484

RESUMEN

[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.


Asunto(s)
Carbazoles/síntesis química , Carbono/química , Inhibidores Enzimáticos/síntesis química , Flúor/química , Glicósidos/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Hidrocarburos Fluorados/síntesis química , Indoles/síntesis química , Inhibidores de Topoisomerasa I , Animales , Carbazoles/farmacología , Inhibidores Enzimáticos/farmacología , Glicósidos/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Hidrocarburos Fluorados/química , Indoles/química , Leucemia P388 , Conformación Molecular , Estructura Molecular , Relación Estructura-Actividad
4.
Curr Med Chem Anticancer Agents ; 2(2): 255-66, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12678746

RESUMEN

A fermentation directed product search for potential anticancer drugs conducted by Bristol-Myers in the 1970s and early 1980s resulted in the identification of a novel indolocarbazole (IC) rebeccamycin (RBM) as a potential drug development candidate. Subsequently, an analog program designed to impart distal site in vivo antitumor activity resulted in the discovery of diethylaminoethyl analog of RBM (DEAE-RBM), which is presently undergoing clinical evaluation as NSC 655649 and BMY-27557. Strong DNA intercalation is the primary mechanism of action of DEAE-RBM resulting in the potent catalytic inhibition of both topoisomerases I and II. Precursor feeding fermentation experiments with fluorine-substituted tryptophans yielded novel fluoroindolocarbazoles (FICs). These FICs were identified as targeting topoisomerase (topo) I in a mechanism-based screen and their action on topo I was confirmed by production of topo I-mediated single-strand breaks in DNA at sites essentially identical to those induced by camptothecin. Topo I dependent cytotoxicity was demonstrated for specific FICs using a P388 and camptothecin-resistant P388/CPT45 pair of cell lines, the latter expresses little or no functional topo I. For example, topo I selectivity was greatest with 3,9-difluoro substituted FIC and was least significant and least cytotoxic with 4,8-difluoro substituted FIC. The review focuses on the discovery of the rebeccamycin class of compounds and their structure-activity relationships leading to the development of the clinical candidate BMY-27557 (NSC 655649), as well as the lead identification of the fluoroindolocarbazole class of compounds.


Asunto(s)
Aminoglicósidos , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Carbazoles/farmacología , Indoles/farmacología , Animales , Antibacterianos/síntesis química , Antibióticos Antineoplásicos/síntesis química , Carbazoles/síntesis química , Diseño de Fármacos , Glucósidos , Humanos , Indoles/síntesis química , Neoplasias/tratamiento farmacológico , Relación Estructura-Actividad
5.
J Med Chem ; 47(7): 1609-12, 2004 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-15027851

RESUMEN

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.


Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Glucósidos/síntesis química , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Carbazoles/química , Carbazoles/farmacología , Glucósidos/química , Glucósidos/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Solubilidad , Relación Estructura-Actividad , Agua , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Org Lett ; 11(22): 5154-7, 2009 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-19827772

RESUMEN

Generation of imino-quinone methide type intermediates from 2-aminothiazole-5-carbinols using alkylsulfonic acids in nitromethane followed by trapping with a wide range of nucleophiles effects C-C, C-O, C-N, C-S, and C-P bond formation.


Asunto(s)
Iminas/química , Indolquinonas/síntesis química , Metanol/análogos & derivados , Tiazoles/química , Indolquinonas/química , Metanol/química , Estructura Molecular , Estereoisomerismo
7.
J Med Chem ; 52(23): 7360-3, 2009 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-19778024
8.
J Med Chem ; 52(21): 6527-30, 2009 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-19821562

RESUMEN

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.


Asunto(s)
Antineoplásicos/síntesis química , Carbamatos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macaca fascicularis , Ratones , Trasplante de Neoplasias , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacología
11.
Bioorg Med Chem Lett ; 17(10): 2828-33, 2007 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-17368025

RESUMEN

Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.


Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Metilaminas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/farmacología , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Metilaminas/química , Ratones , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Pirroles/química , Relación Estructura-Actividad , Triazinas/química , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Bioorg Med Chem Lett ; 17(17): 4947-54, 2007 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-17606372

RESUMEN

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.


Asunto(s)
Química Farmacéutica/métodos , Receptores ErbB/química , Neoplasias/tratamiento farmacológico , Piperidinas/síntesis química , Pirroles/síntesis química , Receptor ErbB-2/química , Triazinas/síntesis química , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Insectos , Modelos Químicos , Trasplante de Neoplasias , Piperidinas/química , Piperidinas/farmacología , Pirroles/química , Pirroles/farmacología , Triazinas/química , Triazinas/farmacología
14.
Bioorg Med Chem Lett ; 15(21): 4774-9, 2005 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-16111887

RESUMEN

A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.


Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Sitios de Unión , Carbamatos/síntesis química , Carbamatos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Modelos Moleculares , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacología
15.
Bioorg Med Chem Lett ; 12(23): 3403-5, 2002 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-12419371

RESUMEN

Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.


Asunto(s)
Antifúngicos/metabolismo , Antifúngicos/farmacología , Antifúngicos/química , Biotransformación , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Diterpenos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Nocardia/metabolismo , Estereoisomerismo
16.
Bioorg Med Chem Lett ; 12(6): 943-6, 2002 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-11958999

RESUMEN

Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.


Asunto(s)
Antifúngicos/síntesis química , Oximas/síntesis química , Antifúngicos/farmacología , Candida/efectos de los fármacos , Diterpenos , Interacciones Hidrofóbicas e Hidrofílicas , Pruebas de Sensibilidad Microbiana , Oximas/farmacología , Relación Estructura-Actividad
17.
Bioorg Med Chem Lett ; 13(3): 519-24, 2003 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-12565963

RESUMEN

Compounds based on sordaricin were prepared via organometallic addition onto a fully protected sordaricin aldehyde. The fungal growth inhibition profiles for these compounds were established and the results are presented here. The synthesis of homologated sordaricin as well as ether and ester derivatives is presented, and structural rearrangement products upon oxidation. These compounds were evaluated as agents to inhibit fungal growth.


Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Aldehídos/síntesis química , Aldehídos/química , Aldehídos/farmacología , Alquilación , Diterpenos , Hongos/efectos de los fármacos , Hidrólisis , Indicadores y Reactivos , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Relación Estructura-Actividad
19.
Bioorg Med Chem Lett ; 12(19): 2757-60, 2002 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-12217370

RESUMEN

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.


Asunto(s)
Antifúngicos/síntesis química , Antifúngicos/farmacología , Hongos/efectos de los fármacos , Oxazepinas/síntesis química , Oxazepinas/farmacología , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Enlace de Hidrógeno , Indenos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad
20.
Bioorg Med Chem Lett ; 13(8): 1419-23, 2003 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-12668003

RESUMEN

The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.


Asunto(s)
Antifúngicos/química , Antifúngicos/farmacocinética , Compuestos Aza/síntesis química , Compuestos Aza/farmacocinética , Administración Oral , Animales , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Compuestos Aza/química , Compuestos Aza/farmacología , Glicósidos/química , Indenos , Inyecciones Intravenosas , Ratones , Pruebas de Sensibilidad Microbiana , Compuestos de Espiro/química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad
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