Open AccessPotent Vinblastine C20′ Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line
Author(s) -
Timothy J. Barker,
Katharine K. Duncan,
Katerina Otrubova,
Dale L. Boger
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400281w
Subject(s) - vinblastine , cell culture , ic50 , urea , cancer cell lines , pharmacology , chemistry , cell , in vitro , biochemistry , cancer research , biology , medicine , cancer cell , cancer , chemotherapy , genetics
A series of disubstituted C20'-urea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH 4 - mediated alkene functionalization reaction of anhydrovinblastine. Three analogs were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC 50 = 200-300 pM), being 10-200-fold more potent than vinblastine (avg. IC 50 = 6.1 nM). Significantly, the analogs also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC 50 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).