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

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 (HL1–HL5), 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 HL1–HL5 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 HL5 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. HL5 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, HL5 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

Strong <i>in Vitro</i> Cytotoxic Potential of New Ruthenium–Cymene Complexes

Two <i>p</i>-cymenerutheniumchlorido complexes with thiourea derivative of 7-chloroquinoline (<b>C1</b>) and pyridine-3-imidazole (<b>C2</b>) were synthesized starting from [(η⁶-<i>p</i>-cymene)­RuCl₂]₂ and corresponding ligands. The structures of complexes were determined with elemental analysis and IR, ESIMS, ¹H and ¹³C­{¹H} NMR, and 2D ¹H–¹⁵N correlation NMR spectroscopy. Cytotoxic activities examined by the MTT assay were performed in five human neoplastic cell lines (HeLa, K562, A549, MDA-MB-231, EA.hy926) and one nontumor human fetal lung fibroblast cell line (MRC-5). Tested complexes exhibited low micromolar activities with IC₅₀ in the range 11.03–56.45 μM, while ligands <b>L1</b> and <b>L2</b> were significantly less active. Complex <b>C1</b> showed cytoselective activity toward the K562 cell line (IC₅₀ = 11.03 ± 1.39 μM) and was 3 times less active against the nontumor MRC-5 cell line. Flow cytometry analysis indicated that complexes <b>C1</b> and <b>C2</b> after 24 h treatment caused a concentration-dependent increase of the apoptotic sub-G1 fraction (up to 18.4%), comparable to <i>cis-</i>diamminedichloridoplatinum­(II) (cisplatin, <b>CDDP</b>), although without other substantial alterations of the cell cycle. A drug-accumulation and DNA-binding study performed by ICP-MS in the K562 cell line revealed that complex <b>C1</b> had a high intracellular uptake (1.38 μg Ru/10⁶ cells), which significantly exceeded the intracellular uptake levels of <b>CDDP </b>(0.29 μg Pt/10⁶ cells) and <b>C2 </b>(0.08 μg Ru/10⁶ cells). However, both ruthenium complexes <b>C1</b> and <b>C2</b> bind to cellular DNA less efficiently in comparison to <b>CDDP</b>. The structure–activity relationship clearly suggested that introduction of a 7-chloroquinoline moiety in the ruthenium­(II)-<i>p</i>-cymene complex significantly contributed to the intracellular uptake of <b>C1</b> and higher cytotoxicity and cytoselectivity