Synthesis and evaluation of antitumor activity of 9-methoxy-1H-benzo[f]chromene derivatives

• Published in: Bioorganic chemistry 2021-11, Vol.116, p.105402-105402, Article 105402
• Main Authors: El Gaafary, Menna, Lehner, Julia, Fouda, Ahmed M., Hamed, Abdelaaty, Ulrich, Judith, Simmet, Thomas, Syrovets, Tatiana, El-Agrody, Ahmed M.
• Format: Article
• Language: English
• Subjects: 1H-benzo[f]chromene; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzopyrans - chemical synthesis; Benzopyrans - chemistry; Benzopyrans - pharmacology; CAM; Cancer xenografts; Caspase 3/7; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; In vitro cytotoxicity; Mitochondrial membrane potential; Molecular Structure; Structure-Activity Relationship; Structure-activity relationships; Triple-negative breast cancer
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105402

[Display omitted] •Naturally occurring chromene and benzochromene scaffolds are biologically active.•Synthesized benzochromenes induce cancer cell apoptosis in vitro and in vivo.•Halogens at meta or para positions of the phenyl ring enhance chromene cytotoxicity. Herein, a series of aryl-substituted derivatives of 3-amino-1-aryl-9-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a-4q) were designed and synthesized via reaction of 7-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. Among the tested benzochromene, the known compound 4e and four novel compounds 4f, 4j, 4k, 4m exhibited the highest cytotoxicity towards a panel of six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, RPMI 7951, and PC-3. Compound 4j with 2,4-dichloro substitution on the pendant phenyl ring exhibited the highest broad-spectrum cytotoxicity towards all tested cancer cell lines. Compounds 4e, 4f, 4j, 4k, 4m were further selected to study the mechanism of cellular toxicity using the triple-negative breast cancer cells MDA-MB-231. Compounds 4e, 4f, 4j, 4k, 4m induced accumulation of the treated MDA-MB-231 cells in the S phase and 4k additionally in the G2/M phase of the cell cycle. Compounds 4e, 4f, 4j, 4k, 4m induced dissipation of mitochondrial transmembrane potential and activation of caspase 3/7 in MDA-MB-231 cells with 4j being one of the most active. In an in vivo model, compound 4j and less efficiently 4e and 4f inhibited growth and proliferation and triggered DNA fragmentation in MDA-MB-231 xenografts grown on chick chorioallantoic membranes. SAR study confirmed that the 2,4-dichloro substitution pattern on the pendant phenyl ring enhanced the cytotoxic activity of benzochromene.