Discovery of novel antitumor antimitotic agents that also reverse tumor resistance.
We have discovered a novel series of 7-benzyl-4-methyl-5-[(2-substituted phenyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amines, which possess antimitotic and antitumor activities against antimitotic-sensitive as well as resistant tumor cells. These agents bind to a site on tubulin that is distinct from the colchicine, vinca alkaloid, and paclitaxel binding sites and some, in addition to their antitumor activity, remarkably also reverse tumor resistance to antimitotic agents mediated via the P-glycoprotein efflux pump. The compounds were synthesized from N-(7-benzyl-5-ethynyl-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide 11 or the corresponding 5-iodo analog 14 via Sonogashira couplings with appropriate iodobenzenes or phenylacetylene followed by reduction and deprotection to afford the target analogs. Sodium and liquid NH3 afforded the debenzylated analogs. The most potent analog 1 was one to three digit nanomolar against the growth of both sensitive and resistant tumor cells in culture. Compounds of this series are promising novel antimitotic agents that have the potential for treating both sensitive and resistant tumors.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA. gangjee@duq.edu
Yu
Jianming
J
Copper
Jean E
JE
Smith
Charles D
CD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008938:Mitosis / Q000187:drug effects*; D014404:Tubulin / Q000378:metabolism; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014404:Tubulin; D014747:Vinblastine; D003078:Colchicine