Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-04-29 DOI:10.1002/ddr.22193
Dana M. Odeh, Heba Abdelrasheed Allam, Fady Baselious, Walaa R. Mahmoud, Mohanad M. Odeh, Hany S. Ibrahim, Hatem A. Abdel-Aziz, Eman R. Mohammed
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Abstract

The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02–99.13 against 15 cancer cell lines at 10 μM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib.

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作为 CDK 抑制剂的 dinaciclib 和 CAN508 杂交化合物的设计、合成和生物学评价
以两种已知 CDK 抑制剂(CAN508 和 dinaciclib)的支架为起点,合成了两个系列的哒唑并[1,5-a]嘧啶类化合物,以获得具有适当选择性的强效抑制剂。根据细胞毒性研究,该研究提出了四种有前景的化合物:10d、10e、16a 和 16c。化合物 16a 在初步抗癌筛选中显示出卓越的活性,在 10 μM 的浓度下对 15 种癌细胞株具有 79.02-99.13 的 GI %,这些癌细胞株来自美国国立癌症研究所(NCI)的 60 种全系列癌细胞株。此外,这四种化合物对正常细胞株 WI-38 具有良好的安全性。这四种化合物针对四种不同的同工酶抑制活性进行了研究。所有化合物都对 CDK5/P25 和 CDK9/CYCLINT 有很强的抑制作用。化合物 10d 对 CDK5/P25 的活性最好(IC50 = 0.063 µM),对 CDK1 和 CDK2 具有适当的选择性。化合物 16c 对 CDK9/CYCLINT 的抑制活性最高(IC50 = 0.074 µM),对其他同工酶具有良好的选择性。最后,对化合物 10e 和 16c 进行了对接模拟,并进行了分子动力学模拟,以了解它们在两个 CDK 的活性位点上相对于 CAN508 和地那西利(dinaciclib)的行为。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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