2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d] pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance

DOI

10.1016/j.bmc.2011.05.030

Document Type

Journal Article

Publication Date

7-15-2011

Publication Title

Bioorganic and Medicinal Chemistry

Volume

19

Issue

14

First Page

4355

Last Page

4365

ISSN

9680896

Keywords

Antimitotic, Cytotoxic, Sonogashira coupling, Tumor resistance reversal

Abstract

Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5- phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P-glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF-7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration. © 2011 Elsevier Ltd. All rights reserved.

Open Access

Green Accepted

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