Discovery of Novel Antitumor Antimitotic Agents That Also Reverse Tumor Resistance

Abstract

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-dimethylpro-panamide 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 NH 3 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.

Overview of P-glycoprotein inhibitors: a rational outlook

“…Novel 7-benzyl-4-methyl-5-[(2-substituted phenyl) ethyl] -7H-pyrrolo [2, 3-d] -pyrimidine-2-amine series showed remarkable P-gp mediated MDR reversal potential by binding to a unique site on tubulin which was distinct from other antineoplastic drug binding sites (Gangjee et al, 2007). KP772 (FFC24), a new anticancer lanthanum compound was reported to block P-gp expression especially in MDR cancerous cells (Heffeter et al, 2007).…”

The design, synthesis and biological evaluation of conformationally restricted 4-substituted-2,6-dimethylfuro[2,3-d]pyrimidines as multi-targeted receptor tyrosine kinase and microtubule inhibitors as potential antitumor agents

“…The conversion of 8 to 9 under different oxidation conditions including the use of MnO 2 , 34 Pd/C, 35 SeO 2 36–38 and DDQ 36–38 were unfruitful. This inability to convert 8 to 9 attests to the stability of 8 to aromatization.…”

Dihydrofolate reductase inhibitors: developments in antiparasitic chemotherapy

“…Because of the central role that DHFR plays in the folate pathway, inhibitors of DHFR are called antifolates. Recently, an excellent comprehensive review of DHFR as a target in antimicrobial therapy has appeared [5] .…”

“…Structurally unique C4-alkyl DHFR inhibitors (structure O ) substituted the C4 pyrimidine amino group with a methyl group [5,76] . Several analogs of this series were tested against T. gondii DHFR using in vitro biological assays.…”

“…In all cases, activity against T. gondii DHFR diminished significantly with the addition of a benzyl group to the pyrrole nitrogen (R 1 = Bn). Interestingly, these N -benzyl methoxyaryl compounds have recently been demonstrated as promising antitumor/antimitotic agents [5] . Two classic folate inhibitors (R 2 = p-benzoyl-L-glutamate, For personal use only.…”