Water-Soluble Mono- and Binuclear Ru(η⁶-p-cymene) Complexes Containing Indole Thiosemicarbazones: Synthesis, DFT Modeling, Biomolecular Interactions, and In Vitro Anticancer Activity through Apoptosis

Abstract

Indole thiosemicarbazone ligands were prepared from indole-3-carboxaldehyde and N-(un)substituted thiosemicarbazide. The Ru(η 6 -p-cymene) complexes [Ru(η 6 -pcymene)(HL1)Cl]Cl (1) and [Ru(η 6 -p-cymene)(L2)] 2 Cl 2 (2*) were exclusively synthesized from thiosemicarbazone (TSC) ligands HL1 and HL2, and [RuCl 2 (p-cymene)] 2 . The compounds were characterized by analytical and various spectroscopic (electronic, FT-IR, 1D/2D NMR, and mass) tools. The exact structures of the compounds (HL1, HL2, 1, and 2*) were confirmed by single-crystal X-ray diffraction technique. In complexes 1 and 2*, the ligand coordinated in a bidentate neutral (1)/monobasic (2*) fashion to form a fivemembered ring. The complexes showed a piano-stool geometry around the Ru ion. While 2* existed as a dimer, 1 existed as a monomer, and this was well explained through free energy, bond parameter, and charge values computed at the B3LYP/SDD level. The intercalative binding mode of the complexes with calf thymus DNA (CT DNA) was revealed by spectroscopic and viscometric studies. The DNA (pUC19 and pBR322 DNA) cleavage ability of these complexes evaluated by an agarose gel electrophoresis method confirmed significant DNA cleavage activity. Further, the interaction of the complexes with bovine serum albumin (BSA) was investigated using spectroscopic methods, which disclosed that the complexes could bind strongly with BSA. A hemolysis study with human erythrocytes revealed blood biocompatibility of the complexes. The in vitro anticancer activity of the compounds (HL1, HL2, 1, and 2*) was screened against two cancer cell lines (A549 and HepG-2) and one normal cell line (L929). Interestingly, the binuclear complex 2* showed superior activity with IC 50 = 11.5 μM, which was lower than that of cisplatin against the A549 cancer cell line. The activity of the same complex (IC 50 = 35.3 μM) was inferior to that of cisplatin in the HepG-2 cancer cell line. Further, the apoptosis mode of cell death in the cancer cell line was confirmed by using confocal microscopy and DNA fragmentation analysis.

Design, Synthesis, DNA/HSA Binding, and Cytotoxic Activity of Half-Sandwich Ru(II)-Arene Complexes Containing Triarylamine–Thiosemicarbazone Hybrids

“…34,52 The activity of complexes 2 and 3 was also comparable with reported ruthenium-arene complexes against HeLa S3 and A549 cell lines. 53 It is evident from the comparison that our complexes showed good cytotoxic property with the earlier reported ruthenium-arene complexes (Figure 5). Cytotoxicity results indicate higher activity of complexes because of the nature of the chelating TSC/TAA ligand and arene moiety.…”

Tunable Anticancer Activity of Furoylthiourea‐Based RuII–Arene Complexes and Their Mechanism of Action

“…They demonstrate a wide range of oxidation states, lipophilic character, redox properties, structural diversity, kinetic stability, an ability to bind to biomolecules and the opportunity to tune ligands to control the kinetic properties. In this regard, ligand selection needs to be carefully planned for the development of organometallic drugs [11–14] . Aroylthioureas are known to exhibit antibacterial, antifungal, and anticancer properties.…”

Unusual coordination mode of aroyl/acyl thiourea ligands and their π‐arene ruthenium (II) piano‐stool complexes: Synthesis, molecular geometry, theoretical studies and biological applications

“…Eventually, we have found that the thiourea ligand and its Ru‐ p ‐cymene complex displayed a rather unusual coordination mode where they form a strained four‐membered ring. This type of coordination mode was also known for some thiosemicarbazones . The new coordination mode of aroyl/acyllthiourea ligands along with the five different coordination modes was shown in Figure .…”