作为CDK2抑制剂的三环和四环苯并[6,7]环庚烷衍生物连接吗啉部分的合成,Drug Development Research

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作为CDK2抑制剂的三环和四环苯并[6,7]环庚烷衍生物连接吗啉部分的合成
Drug Development Research ( IF 3.5 ) Pub Date : 2023-05-12 , DOI: 10.1002/ddr.22074
Thoraya A Farghaly ₁ , Eman M H Abbas ₂ , Mariam A Al-Sheikh ₃ , Hanadi Y Medrasi ₄ , Ghada S Masaret ₁ , Rami Adel Pashameah ₁ , Jihan Qurban ₁ , Marwa F Harras ₅

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为了开发具有强抗乳腺癌功效的细胞周期蛋白依赖性激酶2（CDK2）抑制剂，合成了新的三环和四环苯并[6,7]环庚烷衍生物。新合成的三环和四环衍生物是通过4-(4-吗啉-4-基-苯基)−1,3,4,5,6,7-六氢-苯并[6,7]环庚基的反应获得的。 1,2-d]嘧啶-2-硫酮( 5 )与α-卤代酮衍生物如腙酰氯、苯甲酰溴衍生物、氯丙酮和乙基取代的乙酸酯衍生物。利用 MCF-7 和 MDA-MB-231 乳腺癌细胞系来检查抗癌特性。化合物5和8被证明是最有效的，半数最大抑制浓度(IC ₅₀ )值在5.73和9.11μM之间，与多柔比星处于水平。机制研究表明，5和8通过诱导细胞凋亡导致肿瘤细胞死亡，并且它们还在细胞周期的S期产生癌症停滞。此外，化合物5和8显示出与 roscovitine (IC ₅₀ = 0.127 µM) 相当的强抗 CDK2 作用（ IC ₅₀分别为 0.112 和 0.18 µM）。此外，对接结果表明衍生物5和8以正确的方向适合CDK2活性位点。

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Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane 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.

更新日期：2023-05-12

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