Synthesis of tricyclic and tetracyclic benzocycloheptane derivatives linked morpholine moiety as CDK2 inhibitors

With the aim of developing cyclin‐dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri‐ and tetracyclic derivatives were achieved from the reaction of 4‐(4‐morpholin‐4‐yl‐phenyl)−1,3,4,5,6,7‐hexahydro‐benzo[6,7]cyclohepta[1,2‐d]pyrimidine‐2‐thione (5) with α‐haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF‐7 and MDA‐MB‐231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half‐maximal inhibitory concentration (IC50) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti‐CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.