Synthesis of potent oxindole CDK2 inhibitors.

Bioorg Med Chem

Hoffmann-La Roche Inc., 340 Kingsland str., Nutley, NJ 07110-1199, USA.

Published: April 2003

A series of oxindole CDK2 inhibitors was synthesized. These novel analogues have a saturated monosubstituted cyclic moiety at their C-4 position that mimics the ribofuranoside of ATP. This substitution afforded agents with increased potency relative to the parent indolinone and nanomolar range IC(50) against the CDK2 enzyme and two cancer cell lines.

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0968-0896(03)00036-1DOI Listing

Publication Analysis

Top Keywords

oxindole cdk2
8
cdk2 inhibitors
8
synthesis potent
4
potent oxindole
4
inhibitors series
4
series oxindole
4
inhibitors synthesized
4
synthesized novel
4
novel analogues
4
analogues saturated
4

Similar Publications

Oxindole-benzothiazole hybrids as CDK2 inhibitors and anticancer agents: design, synthesis and biological evaluation.

BMC Chem

September 2024

Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, P.O. 12622, Cairo, Egypt.

In the current study, molecular hybridization between the oxindole core and benzothiazole system through an acetohydrazide moiety was accomplished for the design of a new series of oxindole-benzothiazole hybrids 9a-r targeting CDK2 for cancer therapy. The afforded hybrids displayed promising growth inhibitory activity on NCI cancer cell lines at 10 µM. Compound 9o displayed mean GI% = 55.

View Article and Find Full Text PDF

A new series of benzimidazole-oxindole hybrids 8a-x was discovered as dual cyclin-dependent kinase (CDK2) and glycogen synthase kinase-3-beta (GSK-3β) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single-dose and five-dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC-1 cells with IC = 1.

View Article and Find Full Text PDF

Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC = 2.

View Article and Find Full Text PDF

Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach.

Phys Chem Chem Phys

June 2024

Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation.

View Article and Find Full Text PDF

A series of 16 novel spirooxindole analogs 8a-p were designed and constructed via cost-effective single-step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a-d) with suitable amino acids (7a-c) and ethylene-engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF-7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF-7 and HepG2 cell lines, with IC values of 0.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!