环戊氧基苯甲醚衍生物的合成、抗肿瘤活性及分子对接研究：酶抑制的机制研究。

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition.

机构信息

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University, New Damietta, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2020 Dec;35(1):744-758. doi: 10.1080/14756366.2020.1740695.

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold and their antitumor activity was evaluated. Compounds , , , , , and had the most potent antitumor activity (IC range: 5.13-17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives , , , and were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds and potently inhibited TNF-α (IC values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC=6.44 μM). Compounds and potently inhibited COX-2 (IC values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC=0.68 μM). Compounds , , and inhibited PDE4B (IC values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC=1.55 μM). The molecular docking of compounds and with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

基于 2-环戊氧基苯甲醚骨架合成了一系列 24 种化合物，并评估了它们的抗肿瘤活性。与对照药物塞来昔布、阿法替尼和多柔比星相比，化合物、、、、和具有最强的抗肿瘤活性（IC 范围：5.13-17.95 μM）。最活跃的衍生物、、和被评估了它们对 COX-2、PDE4B 和 TNF-α 的抑制活性。化合物和强力抑制 TNF-α（IC 值分别为 2.01 和 6.72 μM），优于塞来昔布（IC=6.44 μM）。化合物和强力抑制 COX-2（IC 值分别为 1.08 和 1.88 μM），与塞来昔布（IC=0.68 μM）相当。化合物、和抑制 PDE4B（IC 值分别为 5.62、5.65 和 3.98 μM），优于参考药物罗氟司特（IC=1.55 μM）。研究了化合物和与 COX-2 和 PDE4B 结合口袋的分子对接。

要点

评估了新合成的环戊氧基苯甲醚骨架的抗肿瘤活性。

强大的抗肿瘤化合物 4a、4b、6b、7b 和 13 被评估为 COX-2、PDE4B 和 TNF-α 抑制剂。

化合物 4a、7b 和 13 表现出 COX-2、PDE4B 和 TNF-α 抑制作用。

化合物 4b 和 13 显示在 COX-2 和 PDE4B 结合口袋处具有强相互作用。