Coculture‐Based Screening Revealed Selective Cytostatic Effects of Pyrazol–Azepinoindoles

• Published in: ChemMedChem Vol. 20; no. 12; pp. e202500052 - n/a
• Main Authors: Skvortsov, Dmitry A., Zhirkina, Irina V., Ipatova, Daria A., Vasilyeva, Lilya A., Ivanenkov, Yan A., Rubtsova, Maria P., Kartsev, Victor G., Sergiev, Petr V., Dontsova, Olga A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.06.2025
• Subjects: anticancers; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor agents; Azepines - chemistry; Azepines - pharmacology; breast cancer models; Cancer; Caprolactam; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Coculture Techniques; cocultures; Colchicine; Coumarin; Cytostatic Agents - chemistry; Cytostatic Agents - pharmacology; cytotoxicities; Cytotoxicity; Dose-Response Relationship, Drug; Drug development; Drug Screening Assays, Antitumor; Fluorescence; Humans; Indoles - chemistry; Indoles - pharmacology; lung cancer models; Molecular Structure; phenotypic screening; Pyrazole; Pyrazoles; Pyrazoles - chemistry; Pyrazoles - pharmacology; Structure-Activity Relationship; cytotoxicities; phenotypic screening; cocultures; breast cancer models; anticancers; lung cancer models
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202500052

This work focuses on the search for new small molecules for anticancer therapy using the fluorescent cells cocultivation test (FCCT). This method allows the control of the specificity of the action of compounds from the earliest stages of drug development. For the FCCT, labeled MCF7′ breast cancer cells and noncancerous breast MCF10A cells are cocultured. Screening of 2025 compounds in the above system and previously developed coculture of A549 with VA13 yields 16 selectively cytotoxic molecules. The results are confirmed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay for seven of these molecules. Few are known as potential antitumor agents: angelicin, coumarin, and colchicine derivatives. However, the structures of macrocycle 1, pyrazole–azepinoindole derivative 2, and complex heterocyclic derivative 3 are not described as anticancer compounds according to the PubChem and SciFinder databases. Structure–activity relationships are investigated for 2 and its derivatives. The indole with a caprolactam ring (tetrahydro‐azepinoindolone core) together with the pyrazolyl at the third position is the key element of the pharmacophore. The optimized pyrazole–azepinoindole derivative 23 shows SI = 18 for HCT116 versus VA‐13 on the expanded array of cell lines. Its effect is mainly mediated by the G1 arrest of the cell cycle. Breast cancer cells MCF7′ and noncancerous MCF10A are cocultured for cytotoxicity test. Screening of 2025 compounds in the above system and the previously developed coculture of A549′ with VA‐13 yields novel potential anticancer compounds macrocycle 1, pyrazole–azepinoindole derivative 2, and heterocyclic derivative 3. The optimized pyrazole–azepinoindole derivative 23 is mainly mediated by G1 arrest of the cell cycle.