Design, synthesis, and biological evaluation of third-generation tubulin inhibitors as anti-cancer agents

Abstract

Tubulysins are the most active tetrapeptides against cancer found in nature. Tubulysin was extracted from Myxobacterium by Höfle and his coworkers in 2000. Tubulysin inhibits cancer growth by disrupting microtubules. It binds to the vinca domain of β-tubulin of alpha-beta heterodimer which finally results in the depolymerization of the microtubule, and consequently, the cytoskeleton has been disrupted. Due to this disruption, cell death occurs through apoptosis. Due to its strong ability to kill cancer cells, tubulysin has been used to treat various types of cancer. Tubulysins are effective against multidrug-resistant cancer cells. Although tubulysin has anticancer properties against cancer cells, there is a need for derivatives that have better serum stability, shelf life, and reduced toxicity to normal cells. In this study, we synthesized new tubulysin derivatives by structural modifications to improve their protease stability and biological activities. Tubulysin derivatives were synthesized by modifying tubuvaline and tubuphenylalanine subunits. The synthesis involves optimizing side chain functionalization, followed by purification using RP-HPLC and characterization using spectroscopic techniques such as 1H and 13C NMR and mass spectrometry.