Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

Abstract

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI50, TGI, and LC50 parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI50 values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC50 values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents.

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling

“…The versatility of quinone chemistry in drug development is extensive (Borba‐Santos et al, 2022; Di Marco et al, 2021; Dos Santos et al, 2022; Mahalapbutr et al, 2022). Our recent studies have demonstrated the in vitro and in silico anticancer activities of brominated PQ analogs against MCF7 breast cancer cells via cell cycle arrest and oxidative stress induction (Jannuzzi et al, 2022). This was followed by another report claiming the anticancer potential of chlorinated PQ analogs against the MCF7 cell line via oxidative stress, apoptosis, and the suppression of cell proliferation (Jannuzzi et al, 2021).…”

“…Reactions between 1,4‐quinones and amines that address biologically important lead molecules have been extensively reported (Lima et al, 2021; Lopez‐Lira et al, 2021; Pauli et al, 2023; Uysal et al, 2021; Varricchio et al, 2020; Yildirim et al, 2022). In line with these studies, we investigated halogenated (brominated and chlorinated) and non‐halogenated plastoquinone (PQ) analogs to understand their antiproliferative profiles against breast cancer cell lines (Jannuzzi et al, 2021, 2022; Yilmaz Goler et al, 2022). Earlier studies motivated us to use the quinolinequinone moiety as the main framework for our new molecules.…”

“…Earlier studies motivated us to use the quinolinequinone moiety as the main framework for our new molecules. Encouraged by previous results with PQ analogs, especially in breast cancer cell lines (Jannuzzi et al, 2021(Jannuzzi et al, , 2022Yildirim et al, 2022), we introduced aryl amines containing different ester groups at different positions into the quinolinequinone moiety. The process of converting commercially available hydroxyquinoline (HQ) into quinolinequinone (QQ) in one step using sodium chlorate in concentrated HCl solution was the first step in the synthesis of aminated QQs (AQQ1-9), as described in Scheme 1 (Shaikh et al, 1986).…”

“…Previously, we focused on discovering novel anticancer prototypes for the treatment of breast cancer and discovered a new family of chemicals called substituted 1,4-quinones as members of plastoquinone analogs (Jannuzzi et al, 2021(Jannuzzi et al, , 2022Yilmaz Goler et al, 2022). This study aimed to further this inquiry using a structure-based drug design strategy to identify new inhibitors for breast cancer treatment.…”