In Vitro and In Silico Study to Assess Toxic Mechanisms of Hybrid Molecules of Quinone-Benzocaine as Plastoquinone Analogues in Breast Cancer Cells

Abstract

We managed to obtain three different series of 2,3-dimethyl-1,4-benzoquinones, named nonhalogenated and halogenated (brominated and chlorinated) PQ analogues, via the molecular hybridization strategy. Sixteen of eighteen hybrid molecules were selected by the National Cancer Institute (NCI) of Bethesda for their in vitro antiproliferative potential against the full NCI 60 cell line panel. The hybrid molecules ( BrPQ5 , CIPQ1 , and CIPQ3 ) showed good growth inhibition at 10 μM concentration, particularly against breast cancer cell lines. As per the results obtained from in vitro antiproliferative evaluation, cytotoxic activities of the hybrid molecules ( BrPQ5 , CIPQ1 , and CIPQ3 ) were evaluated with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in T47D and MCF7 breast cancer and human umbilical vein endothelial (HUVEC) cells. Molecules exhibited cytotoxic activity, and especially, CIPQ1 showed remarkable cytotoxic activity and good selectivity on T47D and MCF7 cells. Furthermore, CIPQ1 could inhibit cell proliferation, cause apoptotic cell death and disturb the cell cycle in T47D and MCF7 cells. Additionally, CIPQ1 caused oxidative stress induction in both cells, more so in T47D. In vitro study results indicated that the anticancer activity of CIPQ1 was more prominent in T47D cells than in MCF7 cells. The compound CIPQ1 showed a prominent binding with JNK3 in silico . Thus, the obtained hybrid molecules via the molecular hybridization strategy of two important pharmacophores could be useful in the discovery of novel antiproliferative agents, and CIPQ1 could be considered a promising drug candidate.

In Vitro Cytotoxicity Evaluation of Plastoquinone Analogues against Colorectal and Breast Cancers along with In Silico Insights

“…These findings indicated that meta trifluoromethyl substitution of AQ-12 played an important role in its significant anti-CRC and anti-breast cancer activity when compared with the para methyl substitution of AQ-15 and non-substitution of AQ-11 . Moreover, AQ-12 exerted similar cytotoxic effects against both cell lines in comparison with our aforementioned studies [ 28 , 42 , 55 ]. Current results once more confirmed that the presence of PQ moiety played an important role in anti-CRC and anti-breast cancer activity.…”

“…In the first study [ 42 ], the most significant cytotoxic effects were observed with PQ2 , amino-1,4-benzoquinone ( Figure 8 ), against HCT-116 CRC cells with an IC 50 value of 4.97 ± 1.93 μM. In the latter one [ 55 ], compound ClPQ1 , quinone-benzocaine hybrid molecule, ( Figure 8 ) was found as the most effective anti-breast cancer agent against T47D and MCF-7 breast cancer cells, with IC 50 values of 2.35 ± 0.30 and 6.53 ± 0.71 μM, respectively.…”

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

“…Our research group followed the 1,4‐quinone moiety as a main part condensed with pyridine, named quinolinequinones, for cancer research, including its potential in the drug discovery field, and, last but not least, its potential impact in the field of monitoring response and toxicity to different cancer cell lines. The freshly obtained results for MCF7 and T‐47D cells from luminal type A breast tumors were clearly meaningful; in both cell lines, quinolinequinone promoted ROS generation and apoptosis and dose‐dependently decreased colony formation (Yilmaz Goler et al, 2022). Herein, testing the nine aminated QQs against the NCI panel of 60 cell lines will provide comprehensive information on the growth inhibitory effects of QQ analogs.…”

“…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.…”

Synthesis of Oleanolic Acid-Dithiocarbamate Conjugates and Evaluation of Their Broad-Spectrum Antitumor Activities

“…In recent years, the pharmacophore hybrid strategy has emerged as an essential method for the discovery and modification of lead compounds [ 28 , 29 , 30 , 31 ]. Covalently combining two known pharmacophores yields a novel hybrid molecule, which can possess integrated advantages for optimizing certain biological activities and overcoming the deficiencies of a single drug [ 32 , 33 , 34 , 35 ]. In view of the high performance of dithiocarbamate derivatives in structural modification, the synthesis of OA-dithiocarbamate conjugates may enhance the polarities and antitumor properties of the reaction products in a readily accessible manner [ 7 , 23 , 24 , 25 , 26 , 27 ].…”