Design,Synthesis And Antitumor Activity Evaluation Of CDK7 Selective Inhibitors

Cyclin-dependent kinase(CDK)is a key kinase in cell cycle regulation and is involved in cell proliferation,transcription,survival and other physiological processes.CDK belongs to the silk/threonine protein kinase family.CDK is abnormally activated in a variety of tumors and is one of the important targets for antitumor drug development.Cyclin-dependent kinase 7(CDK7)plays a dual role in activating several other cyclin-dependent kinases involved in transcription initiation,and is overexpressed in a variety of tumors.So far,there have been relatively few studies on selective CDK7 inhibitors.Most inhibitors belong to two chemical families:pyrazole and pyrazole triazine on one side and pyrimidine on the other.They also have different molecular mechanisms.Some are competitive inhibitors,some are covalent inhibitors.With these basic studies,awareness of the potential therapeutic role of CDK7 inhibitors in cancer is growing rapidly.They have antiproliferative activity against various types of tumors and leukemias,and synergistic effects have been demonstrated.Two inhibitors are in clinical trials.The most effective compounds inhibit a large number of IC50<200 nm cell lines.On the basis of previous studies,the three parts of Roscovitine were replaced and modified.Using cheap and readily available 2,6-dichloroprine,iodide isopropane or bromocyclopentane as raw materials,13 Roscovitine derivatives were obtained through multi-step reaction,and the biological activities of some compounds were evaluated at the cellular level.Through in vitro bioactivity tests on two normal cell lines,HUVEC and 293-t,and four tumor cell lines,K562,HepG2,hct-116 and McF-7,it was found that compound 1-9 had less toxicity to normal cell lines and higher inhibition rate to tumor cell lines.At the level of kinases,by comparing Roscovitine and some compounds on CDK7,CLK2,CLK4,CLK1,CK1 and DYRK1A,we found that compounds E and H had better selective inhibition of CDK7.Through in vitro bioactivity tests on some of the compounds,it was found that compounds with 2 nitrogen substituents and 6 dipiperidine side chains had the best bioactivity.