Synthesis and biological evaluation of guanidino analogues of roscovitine.

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Doleckova I, Cesnek M, Dracinsky M, Brynda J, Voller J, Janeba Z, Krystof V

Synthesis and biological evaluation of guanidino analogues of roscovitine.

Eur J Med Chem. 2013 Apr;62:443-52. doi: 10.1016/j.ejmech.2013.01.021. Epub 2013 Jan 22.

PubMed ID

23399722 [ View in PubMed

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Abstract

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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Seliciclib	Cyclin-dependent kinase 1	IC 50 (nM)	2400	N/A	N/A	Details