Vinblastine 20′ Amides: Synthetic Analogues That Maintain or Improve Potency and Simultaneously Overcome Pgp-Derived Efflux and Resistance

A series of 180 vinblastine
20′ amides were prepared in
three steps from commercially available starting materials, systematically
exploring a typically inaccessible site in the molecule enlisting
a powerful functionalization strategy. Clear structure–activity
relationships and a structural model were developed in the studies
which provided many such 20′ amides that exhibit substantial
and some even remarkable enhancements in potency, many that exhibit
further improvements in activity against a Pgp overexpressing resistant
cancer cell line, and an important subset of the vinblastine analogues
that display little or no differential in activity against a matched
pair of vinblastine sensitive and resistant (Pgp overexpressing) cell
lines. The improvements in potency directly correlated with target
tubulin binding affinity, and the reduction in differential functional
activity against the sensitive and Pgp overexpressing resistant cell
lines was found to correlate directly with an impact on Pgp-derived
efflux.