Chemotherapeutic Evaluation of a Synthetic Tubulysin Analogue-Dendrimer Conjugate in C26 Tumor Bearing Mice

摘要

The tubulysins, first isolated from myxobacterial cultures by the Hofle-Reichenbach group,are exceptionally potent cell-growth inhibitors that act by inhibiting tubulin polymerization and thereby inducing apoptosis. For this reason, the biosynthesis,mechanism,and anticancer activity of the tubulysins have been intensively investigated. Tubulysin D (Figure 1), the most potent of the tubulysins, has activity that exceeds virtually all known tubulin modifiers, and in particular is 20- to 10000-fold more cytotoxic than the important, clinically approved anticancer drugs, the epothilones, vinblastine, and pa-clitaxel. Unfortunately, the extraordinary activity of the most potent tubulysins poses considerable complications for chemotherapeutic applications due to toxicity against healthy cells and tissues. Moreover, the tubulysins are difficult to obtain in large quantities from the myxobacteria from which they are isolated, and total synthesis routes are prohibitively difficult due to the fragile and complex nature of the most potent of the naturally occurring tubulysins, which incorporate the labile N,O-acetal functionality. Consequently, both academia and the pharmaceutical industry have focused on the synthesis and evaluation of simpler and more stable tubulysin analogues.Similarly, significant efforts have been directed to prodrug strategies for selective tumor delivery of tubulysin and its analogues in order to minimize toxicity.