Synthesis of Novel Tubulin Inhibitor Candidates as Potential Anti‐Cancer Agents

Abstract

Tubulin polymerization and depolymerization are vital for cellular processes, such as cell division, making tubulin inhibition a viable target for the development of anti‐cancer agents. Previous studies have confirmed that an indole‐containing heterocycle we synthesized exhibits anti‐cancer activity through a tubulin polymerization inhibitory mechanism. The heterocycle is structurally related to combretastatin A4, and is thought to interact with tubulin at the colchicine binding site. Our goal is to build upon the existing library of indole‐containing heterocyclic analogs and synthesize novel tubulin inhibitors with increased potency. Molecular docking studies with the colchicine binding site of tubulin informed the design of PY‐391‐Das a tubulin inhibitor candidate. Thus, we are working toward synthesizing this novel compound using modular synthetic strategies. Our synthetic strategy encompasses five reactions. Three out of the five synthetic steps toward PY‐391‐Dhave been completed in high yield. Two reactions that have been previously optimized by our research group have been applied to novel compounds en route to PY‐391‐D, demonstrating the wide applicability of our synthetic strategies. The optimization of the butyl‐group addition to the indole‐nitrogen through an SN2 mechanism was investigated in this study, and has been applied to other electrophiles. Reaction success has been monitored through compound characterization facilitated by 1H NMR spectroscopy analysis. The progress towards completing the streamlined synthesis to produce tubulin inhibition candidates, including PY‐391‐Dand structurally related analogs, are detailed in this study.