Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs

• Published in: Inorganic chemistry 2022-12, Vol.61 (50), p.20445-20460
• Main Authors: Kuznetcova, Irina, Ostojić, Marija, Gligorijević, Nevenka, Aranđelović, Sandra, Arion, Vladimir B.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation; Cisplatin - pharmacology; Colonic Neoplasms; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Glycogen Synthase Kinase 3 beta - pharmacology; Heterocyclic Compounds - pharmacology; Humans
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.2c03134

The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization (1H and 13C NMR, UV–vis, IR), ESI-mass spectrometry, and single-crystal X-ray diffraction analysis of a new ring system of medicinal significance, 5,6,7,9-tetrahydro-8H-indolo­[3,2-e]­benzazocin-8-one, and a series of derived potential ligands (HL 1 –HL 5 ), as well as ruthenium­(II), osmium­(II), and copper­(II) complexes (1a, 1b, and 2–5). The stability of compounds in 1% DMSO aqueous solutions has been confirmed by 1H NMR and UV–vis spectroscopy measurements. The antiproliferative activity of HL 1 –HL 5 and 1a, 1b, and 2–5 was evaluated by in vitro cytotoxicity tests against four cancer cell lines (LS-174, HCT116, MDA-MB-361, and A549) and one non-cancer cell line (MRC-5). The lead compounds HL 5 and its copper­(II) complex 5 were 15× and 17×, respectively, more cytotoxic than cisplatin against human colon cancer cell line HCT116. Annexin V-FITC apoptosis assay showed dominant apoptosis inducing potential of both compounds after prolonged treatment (48 h) in HCT116 cells. HL 5 and 5 were found to induce a concentration- and time-dependent arrest of cell cycle in colon cancer cell lines. Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL 5 and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC50 = 1.4–6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs.