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Synthesis and biological evaluation of guanidino analogues of roscovitine
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SYSNO ASEP 0396979 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Synthesis and biological evaluation of guanidino analogues of roscovitine Author(s) Dolečková, Iva (UEB-Q)
Česnek, Michal (UOCHB-X) RID, ORCID
Dračínský, Martin (UOCHB-X) RID, ORCID
Brynda, Jiří (UOCHB-X) RID, ORCID
Voller, J. (CZ)
Janeba, Zlatko (UOCHB-X) RID, ORCID
Kryštof, Vladimír (UEB-Q) RID, ORCIDSource Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 62, April 2013 (2013), s. 443-452Number of pages 10 s. Language eng - English Country FR - France Keywords 6-Guanidinopurine ; Olomoucine ; Roscovitine Subject RIV CE - Biochemistry R&D Projects 1M0508 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GAP305/12/0783 GA ČR - Czech Science Foundation (CSF) CEZ AV0Z50380511 - UEB-Q (2005-2011) AV0Z40550506 - UOCHB-X (2005-2011) UT WOS 000318577500046 DOI 10.1016/j.ejmech.2013.01.021 Annotation 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. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2014
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