RESUMO
An expeditious metal free C-3 alkylation of indoles and its NIS-mediated deviation to indolo[2,3-b]quinolines is reported. This protocol, executed in aqueous HFIP has broad substrate scope and is well inclined towards the ideas of sustainable chemistry. Applications of these strategies in accessing bioactive natural products like vibrindole, norcryptotakeine, neocryptolepine and indenoindolone scaffolds has also been demonstrated.
RESUMO
In this study, we synthesized a new-generation library of colchicine derivatives via cycloaddition of colchicine utilizing position C-8 and C-12 diene system regioselectivity with aryne precursor to generate a small, focused library of derivatives. We assessed their anticancer activity against various cancer cell lines like MCF-7, MDA-MB-231, MDA-MB-453, and PC-3. Normal human embryonic kidney cell line HEK-293 was used to determine the toxicity. Among these derivatives, silicon-tethered compound B-4a demonstrated the highest potency against breast cancer cells. Subsequent mechanistic studies revealed that B-4a effectively modulates cell cycle regulatory kinases (CDK-2 and CDK-4) and their associated cyclins (cyclin-B1, cyclin-D1), inducing apoptosis. Additionally, B-4a displayed a noteworthy impact on tubulin polymerization, compared to positive control flavopiridol hydrochloride in a dose-dependent manner, and significantly disrupted the vimentin cytoskeleton, contributing to G1 arrest in breast cancer cells. Moreover, B-4a exhibited substantial anti-metastatic properties by inhibiting breast cancer cell migration and invasion. These effects are attributed to the down-regulation of major epithelial to mesenchymal transition (EMT) factors, including vimentin and Twist-1, and the upregulation of the epithelial marker E-cadherin in an apoptosis-dependent manner.
Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , Colchicina , Quinase 2 Dependente de Ciclina , Quinase 4 Dependente de Ciclina , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal , Humanos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Colchicina/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Descoberta de Drogas , Feminino , Apoptose/efeitos dos fármacos , Reação de Cicloadição , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacosRESUMO
Chemoselective oxidation of aromatic and heteroaromatic aldehydes (>45 examples) to their corresponding carboxylic acids has been developed. Potassium tert-butoxide acts as an oxygen source during this transformation that delivers the corresponding acids without chromatographic purifications. The use of bench-top reagents, operational simplicity, and high level of chemo-selectivity with respect to oxidation of the least preferred aldehyde functionality, in the presence of more susceptible functional groups, are some of the highlights of this strategy.