Synthesis of new thiazolo-pyrrolidine–(spirooxindole) tethered to 3-acylindole as anticancer agents

• Published in: Bioorganic chemistry Vol. 82; pp. 423 - 430
• Main Authors: Islam, Mohammad Shahidul, Ghawas, Hussien Mansur, El-Senduny, Fardous F., Al-Majid, Abdullah Mohammed, Elshaier, Yaseen A.M.M., Badria, Farid A., Barakat, Assem
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2019
• Subjects: 1,3-dipolar cycloaddition; Anticancer activity; Azomethine ylide; LLE; Molecular docking; Spirooxindole; Spirooxindole; LLE; Anticancer activity; LE; Molecular docking; 1,3-dipolar cycloaddition; Azomethine ylide
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.10.036

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•Spirooxindole derivatives 4a–n were synthesized and tested against anti-cancer activities.•Compounds 4b–d, 4f, 4j, and 4k showed potent cytotoxic activity and high selectivity against HCT-116 than cisplatin.•Compound 4k proved to retain a high cytotoxic activity and selectivity against HepG2 than cisplatin.•Compound 4k less active than cisplatin with greater selectivity against PC-3.•LE and Ligand LLE were calculated and showed compound 4k has acceptable value.
Anticancer therapeutics with profiles of high potency, low toxicity, and low resistance is of considerable interest. A new series of functionalized spirooxindole linked with 3-acylindole scaffold is reported, starting from chalcones derived from 3-acetyl indole with isatin, and l-4-thiazolidinecarboxylic acid. The reactions proceeded regioselectivity, stereoselectivity, without side products in high yield (71–89%). The new spirooxindole hybrids have been evaluated in vitro for their antiproliferative effects against colon cancer (HCT-116), hepatocellular carcinoma (HepG2) and prostate cancer (PC-3). The selectivity of their activity was evaluated. Some of the synthesized compounds showed considerable anticancer activities. Compound 4k proved to retain a high cytotoxic activity and selectivity against colon cancer cells HCT-116 (IC50 = 7 ± 0.27 µM, SI: 3.7), and HepG2 (IC50 = 5.5 ± 0.2 µM, SI: 4.7) in comparison to (IC50 = 12.6 ± 0.5, SI: 0.4 and 5.5 ± 0.3 µM, SI: 0.9, respectively). Compound 4k was less active (IC50 = 6 ± 0.3 µM, SI: 4.3) than cisplatin (IC50 = 5 ± 0.56 µM, SI: 1.0) but showed greater selectivity towards prostate cancer cells PC-3 in comparison to cisplatin. The details of the binding mode of the active compounds were clarified by molecular docking. Ligand Efficiency (LE) and Ligand Lipophilic Efficiency (LLE) were evaluated and revealed that compound 4k had acceptable value.