Discovery of novel rigid analogs of 2-naphthol with potent anticancer activity through multi-target topoisomerase I & II and tyrosine kinase receptor EGFR & VEGFR-2 inhibition mechanism

• Published in: Chemico-biological interactions 2022-03, Vol.355, p.109838-109838, Article 109838
• Main Authors: El-Mawgoud, Heba K.A., Fouda, Ahmed M., El-Nassag, Mohammed A.A., Elhenawy, Ahmed A., Alshahrani, Mohammed Y., El-Agrody, Ahmed M.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis - drug effects; Benzochromene; Binding Sites; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - chemistry; DNA Topoisomerases, Type II - metabolism; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Molecular docking; Molecular Docking Simulation; Naphthols - chemistry; Naphthols - metabolism; Naphthols - pharmacology; Structure-Activity Relationship; Thermodynamics; Topoisomerase; Tyrosine kinase receptors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2022.109838

A novel oxygen-containing heterocyclic linked 1H-benzo[f]chromene moieties (4a-g) and (6a-g) with anti-proliferative activity against cancer cell lines was designed, synthesized, and established on the basis of spectral data. All the prepared compounds were evaluated in vitro for their anti-proliferative activity against MCF-7, HCT-116, HepG-2 cell lines and normal cell lines HFL-1, WI-38. Compounds 4a, 4b, and 6e exhibited good activity against MCF-7, HCT-116, and HepG-2 cell lines, comparable to that of Vinblastine and Doxorubicin, and weak active against normal cell lines. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds 4a, 4b, and 6e on the more sensitive cell line MCF-7 were studied. We found that compounds 4a, 4b, and 6e induce cell cycle arrest at G2/M phases for MCF-7 treated cells compared to untreated cells, which causes apoptosis and inhibits both the topoisomerase I and II enzymes. In addition, compounds 4a and 4b exhibited comparable inhibitory activity on tyrosine kinase receptors EGFR and VEGFR-2 kinases to that of the reference protein kinases inhibitor Sorafenib. The in silico molecular docking of the most active compounds into the active sites of EGFR kinase and Topo I & II enzymes provides us with a reasonable clarification of the interpreted biological data. •Tricyclic 1H-benzo[f]chromenes were synthesized as potential anticancer agents.•The cytotoxic activity was tested against (MCF-7), (HCT-116) and (HepG-2) cell lines.•4a,b and 6e displayed the highest activity with ability to induce cell cycle arrest at G2/M phase.•4a,b &6e induced apoptosis in cells by inhibiting the f TOPO I and II, and EGFR and VEGFR-2.