RESUMO
In this article, we report the synthesis and biological properties of a series of novel oxazepines related to isoCA-4 having significant antitumor properties. Among them, three oxazepin-9-ol derivatives display a nanomolar or a sub-nanomolar cytotoxicity level against five human cancer cell lines (HCT116, U87, A549, MCF7, and K562). It was demonstrated that the lead compound in this series inhibits tubulin assembly with an IC50 value of 1â µM and totally arrests the cellular cycle in the G2/M phase at the low concentration of 5â nM in HCT116 and K562 cells. Molecular modeling studies perfectly corroborates these promising results.
Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Oxazepinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos Aza/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Células Tumorais CultivadasRESUMO
The synthesis and evaluation of a series of N,N-bis-heterocyclic-methylamines 1 as isoazaerianin analogues are described. It was demonstrated that the replacement of the 3,4,5-trimethoxyphenyl A-ring present in CA-4, isoCA-4 and isoazaerianin by a quinoline or a quinazoline ring is possible and often beneficiary for a high level of cytotoxicity. We have also showed that a carbazole or an indole nucleus are very effective as B-rings in this series, leading to anti-cancer drugs 1 having a sub-nanomolar level of cytotoxicity (1a: IC50â¯=â¯70 pM against HCT116â¯cells). 1a also display a high level of cytotoxicity against four other human cancer cells and inhibited tubulin assembly at a micromolar level. Moreover, at a concentration of 5â¯nM, 1a arrested the cellular cycle in G2/M phase of the cellular cycle and induced apoptosis of HCT116â¯cells. It was also showed that after few hours 1a at a concentration of 10â¯nM totally disrupted endothelial network formation on Matrigel.
Assuntos
Antineoplásicos/farmacologia , Citotoxinas/farmacologia , Metilaminas/farmacologia , Mitose/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Metilaminas/síntese química , Metilaminas/química , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure-activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.
Assuntos
Carbazóis/farmacologia , Quinaldinas/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Carbazóis/síntese química , Carbazóis/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Ligação Proteica , Quinaldinas/síntese química , Quinaldinas/metabolismo , Ratos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismoRESUMO
An unexpected ring opening of 3-aminobenzofurans promoted by NaO tBu in hot toluene, leading to a variety of α-ketoimines, is described. In the presence of 3-iodobenzofurans, NaO tBu mediates the 3-aminobenzofurans ring opening via a possible radical pathway without the help of any external radical sources.
RESUMO
The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50 < 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.
Assuntos
Desenho de Fármacos , Multimerização Proteica/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Quaternária de Proteína , Quinazolinas/química , Quinazolinas/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismoRESUMO
For the first time, the combination of chlorotrimethylsilane with NaI is used as a selective reducting system toward 1,2-diketones. This combination is successfully evaluated with several unsymmetrically benzil derivatives, which are reduced in good yields and with a total α-regioselectivity at room temperature. Identification of benzoin intermediates is achieved, and a mechanistic radical process is proposed.