Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line.
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 analogs 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 analogs also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC50values 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).
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Timothy J
TJ
Barker
Katharine K
KK
Duncan
Katerina
K
Otrubova
Dale L
DL
Boger