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Statements

Subject Item
n2:RIV%2F61388963%3A_____%2F13%3A00396979%21RIV14-MSM-61388963
rdf:type
n8:Vysledek skos:Concept
dcterms:description
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. 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.
dcterms:title
Synthesis and biological evaluation of guanidino analogues of roscovitine Synthesis and biological evaluation of guanidino analogues of roscovitine
skos:prefLabel
Synthesis and biological evaluation of guanidino analogues of roscovitine Synthesis and biological evaluation of guanidino analogues of roscovitine
skos:notation
RIV/61388963:_____/13:00396979!RIV14-MSM-61388963
n8:predkladatel
n9:ico%3A61388963
n4:aktivita
n11:P n11:Z
n4:aktivity
P(1M0508), P(ED0007/01/01), P(GAP305/12/0783), Z(AV0Z40550506), Z(AV0Z50380511)
n4:cisloPeriodika
April 2013
n4:dodaniDat
n19:2014
n4:domaciTvurceVysledku
n10:1570889 n10:8519544 n10:1675877 n10:7774729
n4:druhVysledku
n12:J
n4:duvernostUdaju
n17:S
n4:entitaPredkladatele
n7:predkladatel
n4:idSjednocenehoVysledku
109463
n4:idVysledku
RIV/61388963:_____/13:00396979
n4:jazykVysledku
n20:eng
n4:klicovaSlova
6-Guanidinopurine; Olomoucine; Roscovitine
n4:klicoveSlovo
n13:Olomoucine n13:6-Guanidinopurine n13:Roscovitine
n4:kodStatuVydavatele
FR - Francouzská republika
n4:kontrolniKodProRIV
[C3672ED6493D]
n4:nazevZdroje
European Journal of Medicinal Chemistry
n4:obor
n15:CE
n4:pocetDomacichTvurcuVysledku
4
n4:pocetTvurcuVysledku
7
n4:projekt
n5:1M0508 n5:GAP305%2F12%2F0783 n5:ED0007%2F01%2F01
n4:rokUplatneniVysledku
n19:2013
n4:svazekPeriodika
62
n4:tvurceVysledku
Voller, J. Brynda, Jiří Janeba, Zlatko Dračínský, Martin Dolečková, Iva Kryštof, Vladimír Česnek, Michal
n4:wos
000318577500046
n4:zamer
n6:AV0Z50380511 n6:AV0Z40550506
s:issn
0223-5234
s:numberOfPages
10
n16:doi
10.1016/j.ejmech.2013.01.021