RESUMO
In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Simulação de Acoplamento Molecular , Piperazina , Piperazinas , Inibidores de Proteínas Quinases , Tiofenos , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Estrutura Molecular , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Apoptose/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Compostos Organosselênicos/síntese química , Linhagem Celular TumoralRESUMO
A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their antiproliferative activity against a panel of selected human cancer cell lines including A549 (lung cancer), HCT116 (colon cancer), MCF7 (breast cancer), and SK-MEL-28 (melanoma). Among the synthesized molecules (14a-m and 15a-d), compound 14d displayed remarkable activity against A549, HCT116 and SK-MEL-28 cells with IC50 values < 4 µM with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC50 value of 2.33 µM) over the normal rat kidney cells (NRK). Further, 14d-mediated apoptosis affected the cellular and nuclear morphology of the cancer cells in a dose-dependent manner. Wound healing and clonogenic assays inferred the inhibition of cell growth and migration. Target-based studies of compound 14d corroborated its DNA-intercalative capability and Topo I inhibitory activity which have been fortified by molecular modeling studies. Finally, the drug-likeness of the potent compound was determined by performing in silico ADME/T prediction studies.