Anticancer agents based on Plastoquinone analogs with N-phenylpiperazine: Structure-activity relationship and mechanism of action in breast cancer cells. (1st November 2021)

• Record Type: Journal Article
• Authors: Jannuzzi, Ayse Tarbin; Yıldız, Mahmut; Bayrak, Nilüfer; Yıldırım, Hatice; Shilkar, Deepak; Jayaprakash, Venkatesan; TuYuN, Amaç Fatih
• Is Part Of: Chemico-biological interactions. Volume 349(2021)
• Publication Date: 2021-11-01
• Subjects: Aminoquinone -- Plastoquinones -- Breast cancer -- ROS generation -- Oxidative stress -- Anticancer activity -- Cytotoxicity -- Molecular docking; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109673
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: PQ analogs have been selected and tested against the panel of cancer cell lines. The cytotoxicity of the PQ8, PQ9, PQ11, and PQ12 was determined. Apoptosis induction, cell migration, and ROS generation were investigated. PQ11 showed the most promising anticancer activity against MCF7 cell line. Molecular level interaction of PQ11 with CB2 receptor has been analyzed.