Title

Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents

DOI

10.1016/j.bmc.2018.09.025

Document Type

Journal Article

Publication Date

11-1-2018

Publication Title

Bioorganic and Medicinal Chemistry

Volume

26

Issue

20

First Page

5470

Last Page

5478

ISSN

9680896

Keywords

Microtubule depolymerizers, Microtubule targeting agents, P-glycoprotein, Preclinical agents, Pyrrolo[3, 2-d]pyrimidines, ?III tubulin

Abstract

The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and ?III tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem. 2018, 61, 1704–1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.

Open Access

Green Accepted

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