Synthesis of tubulysin natural product fragments and their derivatives

Abstract

Cancer is a major public health problem worldwide and is the second leading cause of death in the United States. In 2019, as per the National Centre for Health Statistics report, 606,880 cancer deaths are projected to occur in the United States. Over the years, the burden of cancer incidence has shifted to low and middle-income countries, especially India, with 11.57 million cancer cases in 2018. The disease is amenable for treatment by a few of the anticancer drugs. However, the disease develops multidrug-resistance and becomes refractory in conjunction with advancement. Therefore, there is an urgency to discover new anticancer drugs, either from natural sources such as plants, marine organisms, microorganisms, or nature-inspired molecules from a synthetic laboratory. Microtubules are decorated with several proteins and show highly dynamic behavior in a cell. They grow and shrink by addition and dissociation of α/β-tubulin heterodimers, a process that is designated as polymerization and depolymerization. This process is highly regulated and vital for a variety of functions such as migration of cells, intracellular transport of vesicles, and formation of mitotic spindle fibers or microtubules during the process of mitosis in a cell. Their significance in cell division makes microtubules an important target for anticancer drugs. Microtubule-targeted antimitotic drugs are classified into two types as per their mechanism of action: 1) microtubule stabilizing agents (eg., taxol) and epothilone) microtubule-destabilizing agents (eg., vinblastine, tubulysin). Tubulysins are antimitotic tetrapeptides and isolated from myxobacteria Archangium gephyra and Angiococcus disciformis. They show potent growth inhibition against breast, cervix, colon, leukemia, lung, melanoma, ovarian, and prostate cancers, including multidrug resistant KB-V1 cervix carcinoma cell lines. Tubulysins possesses anticancer activity with IC50 values in the range of 10 pM to 10 nM, and are more potent than other tubulin modifiers including epothilones, vinblastine, and paclitaxel by 20 to 1000-fold. A significant drawback for further applications is their limited availability from the bacterium by a fermentation process. Not surprisingly, tremendous attention has been given to the synthesis of natural tubulysins and potent simplified analogs. However, most of the methods suffer from multistep synthesis protocols requiring several isolation and purification procedures, resulting in considerable yield loss. Because of these reasons, there is an immediate need to develop efficient synthetic methods to obtain tubulysin natural products and their structurally modified analogs in the shortest possible sequence and in good yield. The main objective of the thesis work is to design new strategy and synthesize important fragments of natural tubulysins. The thesis work comprises of following chapters: 1. Synthesis of tubuphenylalanine and epi-tubuphenylalanine via regioselective aziridine ring-opening with carbon nucleophiles followed by hydroboration-oxidation of 1,1-substituted amino alkenes 2. Synthesis of the deacetoxytubuvaline fragment of pretubulysin and its lipophilic analogs for enhanced permeability in cancer cell lines 3. Synthesis of tubuvaline (Tuv) fragment of tubulysin via asymmetric dihydroxylation of homoallylamine.