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1.
Molecules ; 27(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36364427

RESUMO

A series of novel neocryptolepine-rhodanine hybrids (9a,b, 11a-d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC50 values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values.


Assuntos
Antineoplásicos , Rodanina , Humanos , Ensaios de Seleção de Medicamentos Antitumorais , Rodanina/farmacologia , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Proliferação de Células , Antineoplásicos/química , Estrutura Molecular , Desenho de Fármacos
2.
Molecules ; 26(3)2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33535575

RESUMO

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Produtos Biológicos/farmacologia , Carcinoma de Ehrlich/tratamento farmacológico , Indóis/farmacologia , Quinolinas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Carcinoma de Ehrlich/enzimologia , Carcinoma de Ehrlich/patologia , Catalase/antagonistas & inibidores , Feminino , Técnicas In Vitro , Indóis/química , Camundongos , Quinolinas/química , Superóxido Dismutase/antagonistas & inibidores , Inibidores da Topoisomerase II/farmacologia , Células Tumorais Cultivadas
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