The primary focus of this thesis is to design, synthesize, characterize and evaluate novel small molecules as potential anti-cancer agents for the treatment of solid tumors. In this regard, we carried out three projects and synthesized numerous molecules with distinct mechanisms of actions. In project one, we synthesized indazole appended diphenyl urea molecules as multi-tyrosine kinase targeted anti-cancer agents. The lead candidate compounds exhibited excellent cell proliferation inhibition against various solid tumor cell lines including, murine metastatic breast cancer 4T1, murine glioblastoma Gl261-Luc2, human triple negative breast cancer MDA-MB-231, human pancreatic MIAPaCa-2, and human colorectal adenocarcinoma WiDr. The lead candidate compounds were found to be well tolerated in healthy mice and exhibited significant tumor growth reduction in WiDr xenograft and 4T1 syngraft flank models in mice. In the second project, we have introduced a novel cytotoxicity enhancing pharmacophore with SN2 /SN2’ isomerization with nucleophilic cellular components. As an application of this pharmacophore, we appended to piperazinyl curcuminoids and synthesized several highly soluble quaternary ammonium derivatives. All of the synthesized compounds were evaluated for their cell proliferation inhibition against three cancer cell lines, MIAPaCa-2, WiDr, and MDA-MB-231. The lead candidate compound was tested in a MIAPaCa-2 xenograft in mice and it exhibited significant tumor growth inhibition. In project three, we designed and synthesized chalcone appended cyanocinnnamic acids as potential glycolysis and mitochondrial oxidative phosphorylation inhibitors for the treatment of cancers. Chalcone acts as an irreversible covalent linker and the doubly activated cyanoacrylic acid unit as a potential reversible inhibitor of monocarboxylate transports and mitochondrial pyruvate carriers. The synthesized compounds have been evaluated for cell proliferation, glycolysis, and mitochondrial inhibition properties.
University of Minnesota Ph.D. dissertation. May 2019. Major: Integrated Biosciences. Advisor: Venkatram Mereddy. 1 computer file (PDF); xxiv, 221 pages.
Synthesis and Evaluation of Novel Small Molecules as Potential Anti-Cancer Agents for The Treatment of Solid Tumors.
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