A Novel Series of Highly Potent 2,6,9-Trisubstituted Purine Cyclin-Dependent Kinase Inhibitors
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- 作者：Tom谩拧 Guck媒 ; Radek Jorda ; Marek Zatloukal ; V谩clav Bazgier ; Karel Berka ; Eva 艠ezn铆膷kov谩 ; Tibor B茅res ; Miroslav Strnad ; Vladim铆r Kry拧tof
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：August 8, 2013
- 年：2013
- 卷：56
- 期：15
- 页码：6234-6247
- 全文大小：537K
- 年卷期：v.56,no.15(August 8, 2013)
- ISSN：1520-4804
文摘
The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.