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
Preprint
Repository Citation
Pavana, R., Shah, K., Gentile, T., Dybdal-Hargreaves, N., Risinger, A., Mooberry, S., Hamel, E., & Gangjee, A. (2018). Sterically induced conformational restriction: Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents. Bioorganic and Medicinal Chemistry, 26 (20), 5470-5478. https://doi.org/10.1016/j.bmc.2018.09.025