Synthesis and Evaluation of Novel Tri-Aryl Phosphonium Derivatives as Potential Anti-Cancer Agents

Abstract

The metabolic properties of cancer cells differ significantly from those of normal cells due to their high demand for energy for rapid proliferation and the need to produce anabolic building blocks for increasing cell mass. In fact, 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. Several recent studies have revealed additional levels of complexity and also recognized the importance of mitochondrial OxPhos to generate a large portion of ATP in cancer cells. OxPhos also plays an important role in cancer cell survival, drug resistance, relapse, and metastasis. OxPhos intermediates are utilized in the Kreb’s cycle and many of which are shuttled into numerous biosynthetic pathways including fatty acids, amino acids, and nucleotides. Selective inhibition of OxPhos will lead to severe ATP depletion and dysfunction of the TCA cycle, starving cancer cells of critical components for cell survival and proliferation. In this regard, we designed, synthesized and evaluated mitochondrial OxPhos inhibitors with therapeutically relevant features. We undertook a structure-activity study using triphenylphosphine as a structural template. For this purpose, several modified phosphonium salts conjugated to α-halomethylacrylate template with high potential for reactivity within the mitochondria were synthesized. In this thesis, the design, synthesis, in vitro cell proliferation inhibition, mitochondrial activity, systemic toxicity in mice and in vitro fluorescence microscopy studies will be presented.