Synthesis of Camphor-Derived Bis(pyrazolylpyridine) Rhodium(III) Complexes: Structure−Reactivity Relationships and Biological Activity Angelina Petrovic ́ , † Milan M. Milutinovic ́ , †,∇ Edward T. Petri, # Marko Z ̌ ivanovic ́ , † Nevena Milivojevic ́ , † Ralph Puchta, ‡,§,∥ Andreas Scheurer, ‡ Jana Korzekwa, ‡ Olivera R. Klisuric ́ , ⊥ and Jovana Bogojeski* ,† † Faculty of Science, University of Kragujevac, Radoja Domanović a 12, 34000 Kragujevac, Serbia ‡ Inorganic Chemistry, Department of Chemistry and Pharmacy, § Computer Chemistry Center, Department of Chemistry and Pharmacy, and ∥ Zentralinstitut fü r Scientific Computing, University of Erlangen-Nü rnberg, 91058 Erlangen, Germany ⊥ Faculty of Science, Department of Physics and # Faculty of Science, Department of Biology and Ecology, University of Novi Sad, Trg Dositeja Obradovic ́ a 4, 21000 Novi Sad, Serbia ∇ Department of Organic Chemistry, University of Paderborn, Warburgerstraße 100, 33098 Paderborn, Germany * S Supporting Information ABSTRACT: Two novel rhodium(III) complexes, namely, [Rh III (X)Cl 3 ] (X = 2 2,6-bis((4S,7R)- 7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine or 2,6-bis((4S,7R)-1,7,8,8-tet- ramethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine), were synthesized from camphor derivatives of a bis(pyrazolylpyridine), tridentate nitrogen-donor chelate system, giving [Rh III (H 2 L*)- Cl 3 ] (1a) and [Rh III (Me 2 L*)Cl 3 ] (1b). A rhodium(III) terpyridine (terpy) ligand complex, [Rh III (terpy)Cl 3 ](1c), was also synthesized. By single-crystal X-ray analysis, 1b crystallizes in an orthorhombic P2 1 2 1 2 1 system, with two molecules in the asymmetric unit. Tridentate coordination by the N,N,N-donor localizes the central nitrogen atom close to the rhodium(III) center. Compounds 1a and 1b were reactive toward L-methionine (L-Met), guanosine-5′-monophosphate (5′-GMP), and glutathione (GSH), with an order of reactivity of 5′-GMP > GSH > L-Met. The order of reactivity of the Rh III complexes was: 1b> 1a > 1c. The Rh III complexes showed affinity for calf thymus DNA and bovine serum albumin by UV−vis and emission spectral studies. Furthermore, 1b showed significant in vitro cytotoxicity against human epithelial colorectal carcinoma cells. Since the Rh III complexes have similar coordination modes, stability differences were evaluated by density functional theory (DFT) calculations (B3LYP(CPCM)/LANL2DZp). With (H 2 L*) and (terpy) as model ligands, DFT calculations suggest that both tridentate ligand systems have similar stability. In addition, molecular docking suggests that all test compounds have affinity for the minor groove of DNA, while 1b and 1c have potential for DNA intercalation. ■ INTRODUCTION Transition-metal complexes have a range of applications in supramolecular chemistry, 1 catalytic chemistry, 2 and as medicinal agents. 3 In chemical biology, transition-metal complexes were investigated as inhibitors, 4−9 imaging agents, 10−12 biological probes, 13,14 or catalysts with unique properties. Over the last century, platinum-based complexes have been used as anticancer drugs. 15,16 However, side effects, such as cell-acquired resistance and high toxicity, 17 have prompted investigation of other metal complexes. 18,19 Despite their variable oxidation states, the anticancer properties of rhodium complexes have not been extensively explored. 20,21 However, kinetically inert transition-metal complexes could serve as scaffolds for pharmacological agents due to their inertness, stability, unique geometries, and structural diver- sity. 22 Recently, such metal complexes were shown to have affinity both for DNA, their primary target, as well as various proteins, 23−27 suggesting potential use in the design of anticancer agents. Transition-metal complexes have been synthesized with pyridine-containing tridentate triamine ligands, for use in catalytic reactions or as potential antitumor agents, etc. Tridentate triamine ligands have advantages, including ready availability, relatively low cost, and low toxicity. 28 Various metal complexes with camphor-based pyridine ligands have also been used for asymmetric catalytsis 29 and tested for biomolecular interactions or antitumor activity. 30−33 Previously, we synthesized a Rh III complex with a tridentate nitrogen-donor pincer-type ligand that displayed promising properties and biomolecular reactivity. 20 Thus, we sought to expand our investigation of Rh III complexes to pincer-type ligands with diverse substituent patterns on the pyrazolyl moiety, creating differences in space configuration and electron density distribution that could influence biomolecular interaction potential or cytotoxicity. Received: August 24, 2018 Article pubs.acs.org/IC Cite This: Inorg. Chem. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.inorgchem.8b02390 Inorg. Chem. XXXX, XXX, XXX−XXX Inorg. Chem. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 12/20/18. For personal use only.