Issue 25, 2019

Discovery, biological evaluation, structure–activity relationships and mechanism of action of pyrazolo[3,4-b]pyridin-6-one derivatives as a new class of anticancer agents

Abstract

We have recently reported computational models for prediction of cell-based anticancer activity using machine learning methods. Herein, we have developed an integrated strategy to discover new anticancer agents using a cascade of the established screening models. Application of this strategy identified 17 compounds with antitumor activity. Among these compounds, h2 (containing a pyrazolo[3,4-b]pyridin-6-one scaffold) exhibited anticancer activity against six tumor cell lines, including MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116, with IC50 values of 13.37, 13.04, 15.45, 7.05, 9.30 and 8.93 μM. Subsequently, a total of 61 h2 analogues were obtained by similarity searching and tested for their anticancer activities. I2 was identified as a novel anticancer agent having activity against MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116 tumor cell lines with IC50 values of 3.30, 5.04, 5.08, 3.71, 2.99 and 5.72 μM. I2 also showed potent cytotoxicity against adriamycin-resistant human breast and hepatocarcinoma cells. Further investigation revealed that I2 inhibited the microtubule polymerization by binding to the colchicine site, resulting in inhibition of cell migration, cell cycle arrest in the G2/M phase and apoptosis of cancer cells. Finally, molecular docking and molecular dynamics provided insights into the binding interactions of I2 with tubulin. This study identified I2 as a novel starting point for further development of anticancer agents that target tubulin.

Graphical abstract: Discovery, biological evaluation, structure–activity relationships and mechanism of action of pyrazolo[3,4-b]pyridin-6-one derivatives as a new class of anticancer agents

Supplementary files

Article information

Article type
Paper
Submitted
15 Mar 2019
Accepted
04 Jun 2019
First published
04 Jun 2019

Org. Biomol. Chem., 2019,17, 6201-6214

Discovery, biological evaluation, structure–activity relationships and mechanism of action of pyrazolo[3,4-b]pyridin-6-one derivatives as a new class of anticancer agents

Q. Guo, Y. Luo, S. Zhai, Z. Jiang, C. Zhao, J. Xu and L. Wang, Org. Biomol. Chem., 2019, 17, 6201 DOI: 10.1039/C9OB00616H

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements