Design and synthesis of novel isatin-based derivatives targeting cell cycle checkpoint pathways as potential anticancer agents

• Published in: Bioorganic chemistry 2020-12, Vol.105, p.104366-104366, Article 104366
• Main Authors: Yousef, Mohamed A., Ali, Ahmed M., El-Sayed, Wael M., Qayed, Wesam S., Farag, Hassan H.A., Aboul-Fadl, Tarek
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Caspase-3; Caspase-9; CDK1; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Check points; Crystallography, X-Ray; Diastereomers; Docking; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Isatin; Isatin - chemical synthesis; Isatin - chemistry; Isatin - pharmacology; Isatin-thiazolidine; Isatin-thiazolidinone; Models, Molecular; Molecular Structure; P53; Structure-Activity Relationship; X-ray
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104366

[Display omitted] •Isatin-thiazolidinone derivatives were designed and synthesized to target cell cycle checkpoint pathways.•E-and Z-diasteromeres of the synthesized molecules were identified and there structures were confirmed.•In vitro cytotoxicity of the prepared compounds was tested against three human epithelial cell lines, liver (HepG2), breast (MCF-7), and colon (HT-29) in addition to the diploid human normal cells (WI-38).•The most active compounds, 4o, 4s, 5e, 5f, 5l, 5m and 5o (IC50 3.29–9.92 mmole) were tested on the expression of CDK1, p53, caspase-3 and caspase-9.•Docking studies on CDK1 for the most active compounds were undertaken. In recent years, cell cycle and checkpoint pathways regulation are offering new therapeutic approaches against cancer. Isatin, is a well exploited scaffold in the anticancer domain. Accordingly, the current work describes the design and synthesis of two series of (Z)-3-substituted-2-(((E/Z)-5-substituted-2-oxo-1-substituted-indolin-3-ylidene)hydrazinylidene)-thiazolidin-4-ones, 4(a-s) and (E/Z)-1-substituted-3-(((Z)-3-substituted-4-methylthiazol-2(3H)-ylidene)hydrazineylidene)-5-substituted-indolin-2-ones, 5(a-s). The structures of the synthesized molecules were confirmed by spectral and elemental methods of analyses. Pure diastereomers were further identified with 1H-1H-NOESY and confirmed with X-ray crystallography. The target compounds were tested in vitro for their cytotoxicity against three human epithelial cell lines, liver (HepG2), breast (MCF-7), and colon (HT-29) in addition to the diploid human normal cells (WI-38) compared to doxorubicin as a reference drug. Variable cytotoxic effects (IC50 3.29–100 µmol) were reported on the three cancer cell lines with pronounced selectivity compared to the normal one WI-38. The potency of the most active compounds, 4o, 4s, 5e, 5f, 5l, 5m and 5o (IC50 3.29–9.92 µmol), in both series associated with the (Z) configurations of N = thiazolidin/ene or one, however, the configuration of the N = isatin moiety seemed to be of no importance to the activity. The tested compounds were grouped for their possible mechanism of action into 4 categories. Compound 4o with no apparent effect on all genes examined. Compounds 4s and 5o affected all genes investigated and seem to have multiple cellular targets; induced the expression of p53 and caspases, and downregulated that of CDK1. Compounds 5l and 5m directly elevated the expression of initiator and effector caspases without going