RESUMO
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity have impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and was vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug showed configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of the cis isomer compared to the trans isomer arose from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens up new avenues for G6PD-targeting cancer medicines.
Assuntos
6-Aminonicotinamida , Antineoplásicos , NADP , Oxirredução , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Humanos , 6-Aminonicotinamida/farmacologia , 6-Aminonicotinamida/química , NADP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Glucosefosfato Desidrogenase/metabolismo , Glucosefosfato Desidrogenase/antagonistas & inibidores , Hipóxia Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
A molecular networking-guided phytochemical investigation of Cruciata articulata led to the isolation of five unreported biscoumarins, four of which were characterized by a shared 6-methoxy-7,8'-dihydroxy-3,7'-biscoumarin aglycone. These were isolated alongside two known coumarin glycosides, daphnetin-8-O-ß-D-glucoside and 6'-acetoxy-daphnetin-8-O-ß-D-glucoside. Their structures were elucidated by extensive 1D and 2D NMR experiments, in combination with chemical transformation and MS/MS fragmentation analysis. Four of the biscoumarins were glycosylated at the 8' position: these are the first examples of this substitution pattern to be described in nature. All compounds were tested for cytotoxic, antimicrobial, anti-inflammatory, and α-glucosidase inhibitory properties, but did not display significant activity.
