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

Timothy J. Barker | Zendy; Katharine K. Duncan | Zendy; Katerina Otrubova | Zendy; Dale L. Boger | Zendy

Open Access

Potent 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).

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