Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent

Abstract

A key series of vinblastine analogs 7–13, which contain modifications to the C20′ ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20′ side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R = F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R = F (equipotent with H) > N3, CN (10-fold) > Me (50 fold) > Et (100-fold) > OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20′/C15′-fused six-membered ring.

Inverse Electron Demand Diels–Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-Butadienes, Cyclopropenone Ketals, and Related Systems. A Retrospective

“…In the course of these efforts, we comprehensively defined the importance and role of nearly every atom and substituent in vinblastine and vincristine, including the vindoline C4 acetate, C5 ethyl substituent, C6–C7 double bond, and the vindoline core structure itself, and have systematically explored the upper catharanthine-derived C20′ ethyl substituent, C16′ methyl ester, added C10′ or C12′ indole substitutions, and, most recently, the C20′ alcohol . We have shown that the latter is remarkably tolerant to replacement, resulting in the discovery of both ultrapotent analogues of the natural products as well as those that match the potency of the natural products but do not suffer from overexpressed Pgp-derived resistance (Figure ).…”

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

“…Thus, a powerful oxadiazole tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade was introduced − that not only assembled the full pentacyclic skeleton in a single step, but also incorporated each substituent, functional group, embedded heteroatom, and all necessary stereochemistry for direct conversion of the cascade cycloadduct to vindoline. , Combined with the use of a single-step Fe­(III)-promoted coupling of catharanthine with vindoline and a newly developed in situ Fe­(III)/NaBH 4 -promoted hydrogen atom transfer free radical C20′ oxidation, ,,, the approach provides vinblastine and its analogues in 8–13 steps. This was used to provide vinblastine analogues not previously accessible by semisynthetic modification of the natural products themselves that contain changes within either the lower vindoline-derived − or upper catharanthine-derived subunits − with the late stage divergent introduction of new functionality. In addition to the examination of C10′ substituents, we have prepared more than 400 analogues of vinblastine, defining the role of individual structural features and substituents.…”

Metabolites of Vinca Alkaloid Vinblastine: Tubulin Binding and Activation of Nausea-Associated Receptors

“…Its conformation adaption shows the major role of CT moiety in VLB binding and agrees with the previously published data in this regard. 2b,30 VLB makes H-bonds with Asn329 and Lys336 of α-tubulin along with Lys176 and Val177 of β-tubulin (Tables 2, S7 and Figure S2).…”