Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin dependent kinase (cdk) inhibitors

David A Nugiel; Anup Vidwans; Carolyn D Dzierba

doi:10.1016/j.bmcl.2004.09.023

Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin dependent kinase (cdk) inhibitors

Bioorg Med Chem Lett. 2004 Nov 15;14(22):5489-91. doi: 10.1016/j.bmcl.2004.09.023.

Authors

David A Nugiel¹, Anup Vidwans, Carolyn D Dzierba

Affiliation

¹ Dupont Pharmaceuticals, PO Box 80336, Wilmington, DE 19880-0336, USA. david.nugiel@astrazeneca.com

PMID: 15482910
DOI: 10.1016/j.bmcl.2004.09.023

Abstract

Potent cyclin dependent kinase inhibitors were prepared using parallel synthesis methodology. Treating advanced intermediate 2 with a variety of hydrazides in DMSO at 80 degrees C for 30 min gave the desired acylsemicarbazides in good to excellent yield. Several compounds were active against cdk4/D1 and cdk2/E in the low nanomolar range. The SAR indicates a wide variety of substituents are tolerated at the acylsemicarbazide moiety.

MeSH terms

CDC2-CDC28 Kinases / antagonists & inhibitors
Cell Division / drug effects
Cell Line, Tumor
Colonic Neoplasms / drug therapy
Combinatorial Chemistry Techniques / methods*
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors
Cyclin-Dependent Kinases / antagonists & inhibitors*
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Semicarbazides / chemical synthesis*
Semicarbazides / pharmacology*

Substances

Cyclin-Dependent Kinase Inhibitor p16
Semicarbazides
CDC2-CDC28 Kinases
CDK2 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases