RESUMEN
Aim: Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1-18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31 µm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and â¼ two/â¼fourfold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.
Asunto(s)
Antineoplásicos/síntesis química , Cromanos/química , Diseño de Fármacos , Compuestos de Espiro/química , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Cromanos/metabolismo , Cromanos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
The spiro[chromane-2,4'-piperidine]-4(3H)-one is an important pharmacophore. It is a structural component in many drugs, drug candidates (or lead compounds) and various biochemical reagents. This review demonstrated an impressive progress in syntheses of spiro[chromane-2,4'-piperidine]-4(3H)-one-derived compoundsin the recent years and focuses on features of their biological relevance's. The prospects for the development of new biologically active substances containing a spiro[chromane-2,4'-piperidine]-4(3H)-one pharmacophore are analyzed and briefly discussed in terms of its structure, reaction, mechanism, scope and potential utility.
Asunto(s)
Química Farmacéutica , Cromanos/química , Piperidinas/química , Compuestos de Espiro/química , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Antioxidantes/química , Anhidrasas Carbónicas/química , Anhidrasas Carbónicas/metabolismo , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Compuestos de Espiro/metabolismo , Relación Estructura-ActividadRESUMEN
Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4'-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC50â¯=â¯369â¯nM, Emaxâ¯=â¯82%). An extensive structure-activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC50â¯=â¯54â¯nM, Emaxâ¯=â¯181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3â¯mg/kg in a dose-dependent manner.