Novel ruthenium (ll/lll) complexes with multidentate Schiff base chelates containing biologically relevant moieties.

Abstract

The discovery of novel ruthenium metallopharmaceuticals is highly dependent on its coordination chemistry. As emphasized in Chapter 1, the biodistribution pathway of a potential ruthenium metallopharmaceutical depends on its oxidation state, aqueous solubility and the size of its metallic core. Recent developments are geared towards the utilization of biocompatible ligands which may facilitate biodistribution and finetune solubility in the blood stream of the formulated ruthenium anticancer agents. This design approach has motivated us to explore the coordination behaviour of multidentate N-donor ligands incorporating various biologically active components (viz. uracil, antipyrine, chromone or benz(imidazole/othiazole) moieties) towards the diamagnetic ruthenium(II) core. The resultant ruthenium compounds were characterized via various spectroscopic techniques and structural elucidations were confirmed using single X-ray analysis. The structural elucidations were complemented with electro-analytical and DFT studies. In Chapter 3, the coordination reactions of trans-[Ruᴵ̍ᴵCl₂(PPh₃)₃] with Schiff bases derived from 5,6-diamino-1,3-dimethyl uracil (H₂ddd) are reported. In the diamagnetic ruthenium(II) complexes, trans-[RuCl(PPh₃)₂(Htdp)](1) {H₂tdp = 5- ((thiophen-3-yl)methyleneamino)-6-amino-1,3-dimethyluracil} and trans- [RuCl(PPh₃)₂(Hsdp)](2) {H₂sdp = 5-(2-(methylthio)benzylideneamino)-6-amino-1,3- dimethyluracil}, the Schiff base ligands (i.e. Htdp and Hsdp) act as monoanionic tridentate chelators. Similarly, the diimine H₃ucp chelator coordinated as a monoanionic tridentate moiety in complex 3, [Ru̍ᴵ̍ᴵCl(PPh₃)(H₃ucp)] (H₄ucp = 2,6-bis- ((6-amino-1,3-dimethyluracilimino)methylene)pyridine). Upon reacting 5-(2- hydroxybenzylideneamino)-6-amino-1,3-dimethyluracil (H₃hdp) with the metal precursor, the paramagnetic complex, trans-[Ru̍ᴵᵛCl₂(ddd)(PPh₃)₂](4) was isolated, in which the bidentate dianionic ddd co-ligand was formed by hydrolysis. The presence of the paramagnetic metal centre for 4 was confirmed by ESR spectroscopy. DFT studies of complex 3 were conducted to provide insight into its intrinsic solid state structural features. The redox properties were probed via cyclic voltammetry: complexes 1, 2 and 4 exhibited comparable electrochemical behaviour with half-wave potentials (E½) at 0.70 V (for 1), 0.725 V (for 2) and 0.68 V (for 4) vs Ag|AgCl respectively while the attained half-wave potential (0.37 V vs Ag|AgCl) of 3 was significantly lower. Chapter 4 focuses on the isolation of novel ruthenium(II/III) compounds from the respective reactions of the metal precursor, trans-[RuCl₂(PPh₃)₃] with multidentate Schiff base ligands bearing the chromone and antipyrine moieties. From these coordination reactions of trans-[RuCl₂(PPh₃)₃] with 4-((pyridine-2- ylimino)methylene)-chromone (pch) and 2,6-bis-((antipyrineimino) methylene)pyridine (bpap); the ruthenium(II/III) complexes: trans-P, cis-Cl- [Ru̍ᴵ̍ᴵ̍ᴵ(pch)Cl₂(PPh₃)₂] (1) and cis-[RuCl₂(bpap)(PPh₃)] (2) were formed, respectively. The presence of the paramagnetic metal centre of 1 was confirmed via room temperature solution ESR spectroscopy. The more delocalized nature of the diimine chelator of 2 promotes faster electron transfer resulting in a lower redox potential in contrast to the mono-imine chelator of 1. The electronic spectra of the metallic compounds exhibited common intraligand Л-Л* and red-shifted Metal-to-Ligand- Charge-Transfer electronic transitions whilst a d-d electronic transition was only observed for the paramagnetic compound 1. In Chapter 5, the analogous chelating behaviour of bidentate N,O-donor heterocyclic ligands which coordinated in a ‘2+2’ coordination mode, is described. The 1:2 molar ratio reactions of trans-[RuCl₂(PPh₃)₃] with 2-hydroxyphenylbenzimidazole (Hobz) and 2-hydroxyphenylbenzothiazole (Hobs), respectively led to the formation of the diamagnetic ruthenium(II) complex salt, [RuCl(Hobz)₂(PPh₃)]Cl (1) as well as the paramagnetic ruthenium complex, [Ru̍ᴵ̍ᴵ̍ᴵCl(obs)₂(PPh₃)] (2). The X-ray crystal structures of both metallic compounds confers a distorted octahedral geometry imposed by the mutual ’2+2’ coordination modes of the chelators. DFT studies indicated that the complex cation of 1 was more energetically favourable than the neutral complex 2. Solid state ESR analysis of the paramagnetic complex 2 gave rise to a distorted rhombic spectra whilst the liquid state ESR afforded an isotropic singlet (at 298 K) and three distinctive signals (at 77 K).