Novel Heterocyclic Compounds as Tumor Metabolism Inhibitors

Abstract

Altered metabolism has been recognized as one of the critical hallmarks of cancer, and tumors characteristically exhibit aggressive glycolysis even in the presence of sufficient amounts of oxygen.1–3 Several recent studies also recognize the importance of mitochondrial OxPhos to generate a large portion of ATP in cancer cells. In this regard, inhibition of OxPhos will lead to severe ATP depletion and dysfunction of the TCA cycle, again starving cancer cells of critical components for cell survival and proliferation. In fact, as glycolysis and OxPhos are highly interdependent, inhibition of glycolysis or OxPhos has been shown to reduce the tumor growth and overcome drug resistance in multiple cancer cells. Combined inhibition of glycolysis and OxPhos should be highly effective in disrupting energetic and biosynthetic pathways in cancers leading to an efficient elimination of tumor and prevent cancer recurrence and metastasis. There are several drug candidates that inhibit tumor glycolysis efficiently, but there are very few reports on the development of mitochondrial OxPhos inhibitors without causing significant toxicity issues. In this regard, we have carried out extensive synthetic studies and developed various classes of novel heterocyclic compounds as mitochondrial OxPhos inhibitors. Some of our biological targets include monocarboxylate transporters 1 & 4 and mitochondrial pyruvate carrier and potentially electron transport chain. In this thesis, design, synthesis, spectral characterization, in vitro studies, lead identification and in vivo toxicology and anticancer efficacy studies will be presented.