Seliciclib is a cyclin-dependent kinase (CDK) inhibitor that has been assayed in phase II clinical trials as an anticancer agent. This paper describes the synthesis of novel derivatives of seliciclib with improved potency, metabolic stability, aqueous solubility, and anti-proliferative activity. The new derivatives showed a novel CDKs selectivity profile. Replacement of ethyl alcohol at position 2 of purine with dimethylaminopropyl and fluorination of benzyl at position 6 of purine of seliciclib resulted in the formation of a derivative that potently and selectively inhibited CDK9 (26 nM vs. CDK9 and > 60-fold selectivity vs. CDK2/5/7). In comparison to seliciclib, this derivative shows lower metabolic clearance (25% lower in Cl_int), higher aqueous solubility and is more cytotoxic in androgen-independent prostate cancer cells.

Graphic abstract

中文翻译：

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seliciclib衍生物作为前列腺癌有效和选择性CDK9抑制剂的合成和生物学评估

Seliciclib是一种细胞周期蛋白依赖性激酶（CDK）抑制剂，已在II期临床试验中作为抗癌剂进行了分析。本文描述了具有增强的效力，代谢稳定性，水溶性和抗增殖活性的塞塞利比布新型衍生物的合成。新的衍生物显示出新颖的CDK选择性。用二甲基氨基丙基取代嘌呤2位上的乙醇，并在seliciclib嘌呤6位上取代苄基的氟化，导致形成了一种衍生物，该衍生物有效地和选择性地抑制了CDK9（对CDK9为26 nM，对CDK2为60倍以上的选择性） / 5/7）。与seliciclib相比，该衍生物的代谢清除率较低（Cl _int降低25％），在非雄激素依赖性前列腺癌细胞中具有更高的水溶性，并且具有更高的细胞毒性。

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