Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.

2024-03-19·Proceedings of the National Academy of Sciences of the United States of America1区 · 综合性期刊

H ₂ S preconditioning induces long-lived perturbations in O ₂ metabolism

1区 · 综合性期刊

Article

作者: Banerjee, Ruma ; Diessl, Jutta ; Guha, Arkajit ; Hanna, David A. ; Lyssiotis, Costas ; Andren, Anthony ; Kumar, Roshan

Hydrogen sulfide exposure in moderate doses can induce profound but reversible hypometabolism in mammals. At a cellular level, H 2 S inhibits the electron transport chain (ETC), augments aerobic glycolysis, and glutamine-dependent carbon utilization via reductive carboxylation; however, the durability of these changes is unknown. We report that despite its volatility, H 2 S preconditioning increases P50(O2) , the O 2 pressure for half-maximal cellular respiration, and has pleiotropic effects on oxidative metabolism that persist up to 24 to 48 h later. Notably, cyanide, another complex IV inhibitor, does not induce this type of metabolic memory. Sulfide-mediated prolonged fractional inhibition of complex IV by H 2 S is modulated by sulfide quinone oxidoreductase, which commits sulfide to oxidative catabolism. Since induced hypometabolism can be beneficial in disease settings that involve insufficient or interrupted blood flow, our study has important implications for attenuating reperfusion-induced ischemic injury and/or prolonging the shelf life of biologics like platelets.

2023-10-21·bioRxiv : the preprint server for biology

H ₂ S preconditioning induces long-lived perturbations in O ₂ metabolism.

作者: Banerjee, Ruma ; Diessl, Jutta ; Guha, Arkajit ; Lyssiotis, Costas ; Andren, Anthony ; Hanna, David A ; Kumar, Roshan

Hydrogen sulfide exposure in moderate doses can induce profound but reversible hypometabolism in mammals. At a cellular level, H ₂ S inhibits the electron transport chain (ETC), augments aerobic glycolysis, and glutamine-dependent carbon utilization via reductive carboxylation; however, the durability of these changes is unknown. We report that despite its volatility, H ₂ S preconditioning increases P _50(O2) , the O ₂ pressure for half maximal cellular respiration, and has pleiotropic effects on oxidative metabolism that persist up to 24-48 h later. Notably, cyanide, another complex IV inhibitor, does not induce this type of metabolic memory. Sulfide-mediated prolonged fractional inhibition of complex IV by H ₂ S is modulated by sulfide quinone oxidoreductase, which commits sulfide to oxidative catabolism. Since induced hypometabolism can be beneficial in disease settings that involve insufficient or interrupted blood flow, our study has important implications for attenuating reperfusion-induced ischemic injury, and/or prolonging shelf life of biologics like platelets.

100 项与 GYR-777 series (Biota) 相关的药物交易

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