Design and Synthesis of Novel Heterocyclic-Based 4H-benzo[h]chromene Moieties: Targeting Antitumor Caspase 3/7 Activities and Cell Cycle Analysis

Abstract

Novel fused chromenes (4,7–11) and pyrimidines (12–16) were designed, synthesized, and evaluated for their mammary gland breast cancer (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2) activities. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR, and mass spectroscopy. The preliminary results of the bioassay disclosed that some of the target compounds were proven to have a significant antiproliferative effect against the three cell lines, as compared to Doxorubicin, Vinblastine, and Colchicine, used as reference drugs. Particularly, compounds 7 and 14 exerted promising anticancer activity towards all cell lines and were chosen for further studies, such as cell cycle analysis, cell apoptosis, caspase 3/7 activity, DNA fragmentation, cell invasion, and migration. We found that these potent cytotoxic compounds induced cell cycle arrest at the S and G2/M phases, prompting apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. The structure-activity relationship (SAR) survey highlights that the antitumor activity of the desired compounds was affected by the hydrophobic or hydrophilic nature of the substituent at different positions.

Synthesis, Cytotoxic Activity, Crystal Structure, DFT Studies and Molecular Docking of 3-Amino-1-(2,5-dichlorophenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile

“…In addition, 4H-benzo[h]chromene derivatives are a very successful choice in the treatment of several human diseases. For instance, some derivatives of 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitrile and 2-amino-4-aryl-6-methoxy-4H-benzo[h]chromene-3-carbonitrile act as potential tumor vascular-disrupting agents and induce cell cycle arrest at G2/M and apoptosis [11,12], thus they have emerged as a new class of cytotoxic agents [13][14][15][16][17][18][19][20][21]. In addition, a range of studies has revealed the potential anticancer effect of 1H-benzo[f]chromene derivatives [22][23][24][25][26][27].…”

2H/4H-Chromenes—A Versatile Biologically Attractive Scaffold

“…A series of novel heterocyclic incorporated 4H-benzo[h] chromenes were designed and synthesized and evaluated for their anticancer specific potency against targeted cancer cell lines (Alblewi et al, 2019a ). As a result, compounds 59 and 60 showed higher anticancer activity toward the all targeted cancer cell lines with IC 50 ranges of 0.7 to 3.0 μg/mL and 0.8 to 1.4 μg/mL, respectively.…”

“…Therefore, compounds 59 and 60 trigger cell apoptosis by the activation of caspse3/7 and executioner DNA fragmentation in cancer cells. Additionally, these compounds also exhibited a substantial reduction in cell invasion and cell migration parentage (Alblewi et al, 2019a ). These compounds are potent lead molecules for the development of anticancer drug molecules.…”

“…Therefore, these molecules target and interrupt tumor vasculature (Anthony et al, 2007 ). Some analogs of 2H/4H-ch triggered the cell apoptosis by the caspse3/7 activation and executioner of DNA fragmentation and also caused a substantial reduction in the cell invasion and cell migration percentage (Alblewi et al, 2019a ; Luque-Agudo et al, 2019 ). Additionally, the potency of substituted-1H-benzimidazol-2-yl fused with 4H-chromen-4-ones analogs was reported, which revealed that 4H-ch analogs were selective inhibitors of formyl peptide receptor-1 (FPR-1), led to blocking the Ca 2+ flux and inhibited chemotaxis in human neutrophils (Schepetkin et al, 2014 ).…”

A New Family of Benzo[h]Chromene Based Azo Dye: Synthesis, In-Silico and DFT Studies with In Vitro Antimicrobial and Antiproliferative Assessment

“…Mccarroll and co-workers also reported that tephrosin, a viable anti-lung carcinoma drug, as well as Acronycine, a drug targeting colon, lung, and ovary tumors, obstruct the cell proliferation through their binding to the β-tubulin specific site, which subsequently induces apoptosis through microtubule polymerization [ 11 ]. Furthermore, chromene molecules are deemed ‘privileged medicinal scaffolds’ due to their unique pharmacological and biological activities [ 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”