Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.
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| Abstract |
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.
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| Authors | Thoraya A Farghaly, Eman M H Abbas, Mariam A Al-Sheikh, Hanadi Y Medrasi, Ghada S Masaret, Rami Adel Pashameah, Jihan Qurban, Marwa F Harras |
| Journal | Drug development research (Drug Dev Res) Vol. 84 Issue 6 Pg. 1127-1141 (09 2023) ISSN: 1098-2299 [Electronic] United States |
| PMID | 37170788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2023 Wiley Periodicals LLC. |
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