Synthesis and Evaluation of Indenopyrazoles as Cyclin-Dependent Kinase Inhibitors. 2. Probing the Indeno Ring Substituent Pattern

Abstract

We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmacophores led us to a series of semicarbazide-based inhibitors that are highly potent against CDK2 and CDK4 while maintaining selectivity against other relevant serine/threonine kinases. These compounds were active against a transformed human colon cancer cell line (HCT116) while maintaining an acceptable margin of activity against a normal fibroblast cell line. The compounds were found to be highly protein bound in our cell-based assay with the exception of 11k, which maintained a reasonable level of activity in the presence of human plasma proteins.

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

“…A variety of chemical classes, which include purine analogues (21 -25), pyrimidine analogues (26)(27)(28), indenopyrazoles (29,30), pyridopyrimidines (31)(32)(33), pyrazolopyridines (34,35), indolocarbazoles (36), pyrrolocarbazoles (37,38), oxindoles (39,40), and aminothiozoles (41) have been developed as Cdk inhibitors. Several compounds that inhibit Cdk activity are currently in clinical trials, including flavopiridol, R-roscovitine (CYC-202), UCN-01 (7-hydroxystaurosporine), and BMS-387032 either as single agents or in combination.…”

A Systematic Review on Antitumor Agents with 1, 3, 5-triazines

“…However, CDK7, CDK8, and CDK9 have been invovled in the regulation of RNA elongation [84]. It is a common feature for uncontrolled CDK activity with increasing evidence interrelated to proliferative diseases such as psoriasis, cancer and restenosis, and many CDK inhibitors have been investigated over the past decade [85][86][87][88][89][90][91].…”

Computational evaluation of some indenopyrazole derivatives as anticancer compounds; application of QSAR and docking methodologies

“…In vitro biological activity data used in this study were CDK2 inhibitory activity (in terms of-log IC 50 ), of a set of ninety four indenopyrazole derivatives selected from literature [16][17][18][19][20] . General chemical structures and the structural details of these compounds and also their activities are reported in Table 1.…”