Pharmaceutical Toxicology Department, Pharmacy Faculty, Istanbul University, Beyazit, 34116, Istanbul, Turkey.
Chemistry Department, Gebze Technical University, Gebze, 41400, Kocaeli, Turkey.
Chem Biol Interact. 2021 Nov 1;349:109673. doi: 10.1016/j.cbi.2021.109673. Epub 2021 Sep 22.
2,3-Dimethyl-1,4-benzoquinones named as Plastoquinone (PQ) analogs have antiproliferative activity and are promising new members of molecules that can be used to cope with cancer. In an attempt to develop effective and potentially safe antiproliferative agents, previously reported twelve Plastoquinone analogs (PQ1-12) have been obtained to understand their antiproliferative profile. All PQ analogs have been selected by the National Cancer Institute (NCI) of Bethesda based on the NCI Developmental Therapeutics Program and tested against the panel of 60 cancer cell lines. Based on those studies, the cytotoxicity of the selected PQ analogs (PQ8, PQ9, PQ11, and PQ12) was determined using four breast cancer cell lines (MCF7, UACC-2087, MDA-MB-231, and MDA-MB-435) and a normal cell line (HaCaT). For better understanding, apoptosis induction, changes in cell proliferation, cell migration, and reactive oxygen species (ROS) generation were investigated for the selected PQ analog (PQ11) on MCF7 and UACC-2087 cell lines. According to the study results, PQ11 showed the most promising anticancer activity against MCF7 cell line through increased oxidative stress and apoptosis and suppression of cell proliferation. Based on the biological activity profile, we hypothesize that PQ11 could be a modulator of the cannabinoid 2 (CB2) receptor. Accordingly, we analyzed molecular level interaction of PQ11 with CB2 receptor through molecular docking simulation and it was also predicted to have a favorable ADMET profile. Overall, our findings suggest that integration of the N-phenylpiperazine moiety can be a good strategy for the structural optimization of PQ analogs as anticancer agents, especially in breast cancer.
2,3-二甲基-1,4-苯醌类被称为植物醌（PQ）类似物，具有抗增殖活性，是可用于应对癌症的有前途的新型分子。为了开发有效且具有潜在安全性的抗增殖剂，我们获得了先前报道的十二种植物醌类似物（PQ1-12），以了解它们的抗增殖特征。所有 PQ 类似物都是由位于贝塞斯达的美国国立癌症研究所（NCI）根据 NCI 发展治疗计划选择的，并针对 60 种癌细胞系进行了测试。基于这些研究，使用四种乳腺癌细胞系（MCF7、UACC-2087、MDA-MB-231 和 MDA-MB-435）和一种正常细胞系（HaCaT）测定了选定的 PQ 类似物（PQ8、PQ9、PQ11 和 PQ12）的细胞毒性。为了更好地理解，在 MCF7 和 UACC-2087 细胞系上研究了选定的 PQ 类似物（PQ11）诱导细胞凋亡、改变细胞增殖、细胞迁移和活性氧（ROS）生成的情况。根据研究结果，PQ11 通过增加氧化应激和细胞凋亡以及抑制细胞增殖，对 MCF7 细胞系表现出最有希望的抗癌活性。根据生物学活性谱，我们假设 PQ11 可能是大麻素 2（CB2）受体的调节剂。因此，我们通过分子对接模拟分析了 PQ11 与 CB2 受体的分子水平相互作用，并且还预测它具有有利的 ADMET 特征。总的来说，我们的研究结果表明，整合 N-苯基哌嗪部分可以成为植物醌类似物作为抗癌剂的结构优化的良好策略，特别是在乳腺癌中。
