Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors.

作者: Young-Tae Chang , Nathanael S Gray , Gustavo R Rosania , Daniel P Sutherlin , Soojin Kwon

DOI: 10.1016/S1074-5521(99)80048-9

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摘要: Background Purines constitute a structural class of protein ligands involved in mediating an astonishing array metabolic processes and signal pathways all living organisms. Synthesis purine derivatives targeting specific purinebinding proteins vivo could lead to versatile compounds for use as biological probes or drug candidates. Results We synthesized several libraries 2,6,9-trisubstituted purines using both solution- solid-phase chemistry, screened the inhibition cyclin-dependent kinase (CDK) activity human leukemic cell growth. Lead were optimized by iterative synthesis based on structure-activity relationships (SARs), well analysis CDK-inhibitor cocrystal structures, afford interesting including one most potent CDK inhibitors known date. Unexpectedly, some with similar inhibitory arrested cellular proliferation at distinctly different phases cycle, another inhibitor directly induced apoptosis, bypassing cell-cycle arrest. Some these selectively inhibited growth cells derived from tumors. Conclusions 2,6,9-Trisubstituted have various activities, despite high concentrations competing endogenous cells. Purine source small molecules that affect distinct biochemical functions.

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