RESUMEN
Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.
Asunto(s)
Alcaloides , Antineoplásicos , Benzodioxoles , Proliferación Celular , Dihidroorotato Deshidrogenasa , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos , Ferroptosis , Piperidinas , Alcamidas Poliinsaturadas , Humanos , Alcaloides/farmacología , Alcaloides/química , Alcaloides/síntesis química , Dihidroorotato Deshidrogenasa/antagonistas & inhibidores , Piperidinas/farmacología , Piperidinas/química , Piperidinas/síntesis química , Benzodioxoles/farmacología , Benzodioxoles/síntesis química , Benzodioxoles/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Ferroptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Alcamidas Poliinsaturadas/química , Alcamidas Poliinsaturadas/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Línea Celular TumoralRESUMEN
In this research, five new indolequinazoline alkaloids (1-5), along with six known indolequinazoline alkaloids (6-11) were obtained from the fruits of Tetradium ruticarpum. Their structures were elucidated through comprehensive spectroscopic data of 1D and 2D NMR, HRESIMS and ECD spectra. Additionally, all isolates were assayed for their SIRT1 inhibitory activities in vitro and compounds 2, 7, 10 and 11 exhibited activities with IC50 values ranged from 43.16 to 118.35 µM.
Asunto(s)
Alcaloides , Evodia , Evodia/química , Frutas/química , Estructura Molecular , Alcaloides/análisis , Espectroscopía de Resonancia MagnéticaRESUMEN
Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).
