Potent Vinblastine C20′ Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line

Abstract

A series of disubstituted C20′-urea derivatives of vinblastine were prepared from 20′-aminovinblastine that was made accessible through a unique Fe­(III)/NaBH₄-mediated alkene functionalization reaction of anhydrovinblastine. Three analogues were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC₅₀ = 200–300 pM), being 10–200-fold more potent than vinblastine (avg. IC₅₀ = 6.1 nM). Significantly, the analogues also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC₅₀ values on par with that of vinblastine against the sensitive HCT116 cell line, 100–200-fold greater than the activity of vinblastine against the resistant HCT116/VM46 cell line, and display a reduced 10–20-fold activity differential between the matched sensitive and resistant cell lines (vs 100-fold for vinblastine)