Synthesis and biological evaluation of guanidino analogues of roscovitine

0396979 - ÚEB 2014 RIV FR eng J - Journal Article
Dolečková, Iva - Česnek, Michal - Dračínský, Martin - Brynda, Jiří - Voller, J. - Janeba, Zlatko - Kryštof, Vladimír
Synthesis and biological evaluation of guanidino analogues of roscovitine.
European Journal of Medicinal Chemistry. Roč. 62, April 2013 (2013), s. 443-452. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA MŠMT 1M0508; GA ČR GAP305/12/0783
Grant - others:GA MŠk(CZ) ED0007/01/01
Program: ED
Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z40550506
Keywords : 6-Guanidinopurine * Olomoucine * Roscovitine
Subject RIV: CE - Biochemistry
Impact factor: 3.432, year: 2013

A series of 2,9-substituted 6-guanidinopurines, structurally related to the cyclin-dependent kinase (CDK) inhibitors olomoucine and roscovitine, has been synthesized and characterized. A new copper-catalyzed method for the synthesis of 2-substituted 6-guanidino-9-isopropylpurines under mild reaction conditions has been developed. All prepared compounds were screened for their CDK1 and CDK2 inhibitory activities, cytotoxicity and antiproliferative effects in the breast cancer-derived cell line MCF7. The most active derivative 16g possessed an identical side chain in the C2 position to roscovitine; this compound displayed approximately five fold higher inhibitory activity towards CDK2/cyclin E and more than ten fold increase in cytotoxicity in MCF7 cells. Interestingly and in contrast to previously described findings, (S)-6-guanidinopurine derivatives were generally more active than their (R)-counterparts. Kinase selectivity profiling of (R)- and (S)-enantiomers 16e and 16g, respectively, revealed that introduction of a guanidino group at the C6 position of the purine moiety decreased selectivity towards protein kinases compared to roscovitine. Nevertheless, increased inhibitory activity and decreased selectivity offer a good starting point for further development of new protein kinase inhibitors.
Permanent Link: http://hdl.handle.net/11104/0224681