Structure-based Design,Synthesis,and Antitumor Activity Of Cyclin-dependent Kinases Inhibitors

The cell cycle is one of the basic processes of life activities.The growth,development and all activities of the body are inseparable from the regulation of the cell cycle.Indeed,cell cycle disorder is an important feature of cancer cells.The mammalian cell cycle is regulated by cyclin-dependent kinases(CDKs).Since the imbalances of CDKs has been linked to cause uncontrolled cells proliferation and cancer eventually.Cyclin-dependent kinases(CDKs),therefore,represent a promising target that can block cancer proliferation by inhibiting the enzymatic activity of CDK.In the past decades,great progress has been made in the discovery and development of CDK inhibitors,and many CDK pan-inhibitors have entered the clinical research,such as Flavopiridol,Seliciclib and Dinaciclib.However,the clinical developments of CDK pan-inhibitors was hindered by the poor selectivity and safety.Therefore,the development of novel selective CDK inhibitors is still a hotspot area of research in medicinal chemistry scope.In this study,we aim to design and synthesize novel series of CDK2 and CDK7 isoform selective inhibitors to avoid the toxicity and severe side effects caused by CDKs pan-inhibitors.Design,Synthesis and Preliminary Biological Activity Evaluation of CDK2 Inhibitors.we used AlphaSpace software to analyze CDK2-IN-4 and CDK2 crystal structure.And we found an unoccupied polar pocket of CDK2.On this basis,we designed series Ⅰ target compounds,aminomethyl group is introduced in para-or orthoposition of C6-benzene ring.Alicyclic group,aromatic ring,and benzyl substituents are introduced in C2-NH2 of purine.From series Ⅰ target compounds,the amino group was further modified to obtain Ⅱ series of target compounds.In the process of synthesizing the target compounds,we used 2,6-dichloropurine and 4-bromobenzylamine as the starting material,and then followed by the reaction of borylation,Suzuki coupling,Buchwald-Hartwig coupling,amide condensation,and deprotection of Boc group.Then twenty-one new compounds were obtained,including fifteen target compounds and six intermediates.For CDK2 inhibition screening,ZHUY-2 and ZHUY-4 have shown good inhibitory activity against CDK2.Among them,ZHUY-4 exhibited the best inhibitory with three times high in relative to the positive control drug Roscovitine.However,ZHUY-4 showed poor antiproliferative activities against MDA-MB-231 cell line.We assume this is because of the poor physicochemical properties of ZHUY-4 in in vitro study.In our on-going research,compound ZHUY-4 can utilized as lead compound to develop more potent CDK2 Inhibitor with focus to enhance its Drug-likeness properites.Design,Synthesis and Preliminary Biological Activity Evaluation of CDK7 covalent Inhibitors.Based on our previous research,we designed two series compounds based on THZ1,CDK7-Wang and YKL-5-124 with 4-thiazolonepyrimidine structure as the basic skeleton.Then we designed a series of CDK7 inhibitors based on THZ1 by optimizing the indole ring and pyrimidine ring in the original structure to other heterocycles respectively.In the process of synthesizing the target compound,we used 4-methylthiazole as starting material,and then followed by the reaction of bromination,nucleophilic substitution,borylation,Suzuki coupling,deprotection,N-methylation,Buchwald coupling,amide condensation,hydrodebenzylation,reduction of nitro groups,protection and removal of amino groups.We synthesized thirty new compounds,including fourteen target compounds and sixteen intermediates.For CDK7 inhibition screening,two target compounds,ZZ-10 and ZZ-14,possess good inhibition rates.Among them,ZZ-14 showed the best inhibitory activities against CDK7 and in vitro anti-tumor activity.Yet further structural modification is needed to develop novel selective CDK7 inhibitors armed with good in vitro and in vivo activities.