RESUMO
A novel series of oxazole incorporated naphthyridine (21 a-j) derivatives were designed and, synthesized followed by screening of their anticancer activity profiles against human breast cancer (MCF-7), human lung cancer (A549) and human prostate (PC3 & DU-145) cancer cell lines by employing MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay using etoposide as the positive control. Of these compounds, N-(6-chloro-3-(4-(3,4,5-trimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine with 3,4,5-trimethoxy substituent on the aryl moiety attached to oxazole ring showed potent anticancer activity against PC3, A549, MCF-7, and DU-145â cell lines with IC50 values of 0.13±0.095â µM; 0.10±0.084â µM; 0.18±0.087â µM and 0.15±0.076â µM respectively. Apart from this, compounds N-(6-chloro-3-(4-(3,5-dimethoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, N-(6-chloro-3-(4-(4-methoxyphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine, and N-(6-chloro-3-(4-(3,5-dimethylphenyl)oxazol-2-yl)-1,5-naphthyridin-4-yl)oxazol-2-amine also showed better anticancer activities against four cancer cell lines screened for. These activities were also validated through the molecular docking simulations, which further indicated demonstration of better interaction energy and profile by these compounds.
Assuntos
Antineoplásicos , Neoplasias , Masculino , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Aminas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50â¯=â¯0.39⯱â¯0.13⯵M with â¼27 andâ¯>â¯250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30â¯mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30â¯mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.
Assuntos
Artrite/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Indóis/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Quinoxalinas/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Adjuvante de Freund , Índio , Indóis/síntese química , Indóis/química , Indóis/toxicidade , Estrutura Molecular , Esclerose Múltipla/induzido quimicamente , Glicoproteína Oligodendrócito-Mielina , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/toxicidade , Quinoxalinas/síntese química , Quinoxalinas/química , Quinoxalinas/toxicidade , Ratos , Relação Estrutura-Atividade , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
A series of 4ß-[4'-(1-(aryl)ureido)benzamide]podophyllotoxin congeners (11a-l) were synthesized and evaluated for their cytotoxic activity against six human cancer cell lines. Some of the compounds like 11a, 11h, 11k and 11l showed significant anti-proliferative activity in Colo-205 cells and were superior to etoposide. The flow-cytometric analysis studies indicated that these compounds show strong G1 cell cycle arrest, as well exhibited improved inhibitory activities on DNA topoisomerase I and IIα enzymes. These compounds induce apoptosis by up regulating caspase-3 protein as observed by ELISA and Western blotting analysis. In addition, a brief structure-activity relationship studies within the series along with docking results of representative compounds 11a, 11h, 11k, 11l were presented.