The coordination chemistry and anticancer activity of organo-ruthenium(II), -iridium(III) and -rhodium(III) complexes with sulfonyl-substituted thiourea ligands

Abstract

Some half-sandwich compounds with a variety of ligands and metal centres have shown promising anticancer activity. Herein we report a series of reactions between the sulfonylthiourea ligands p-TolSO₂NHC(S)NHPh, EtSO₂NHC(S)NHPh and CH₃SO₂NHC(S)NHPh and [(η⁶-p-cymene)RuCl₂]₂, [(η⁶-arene)RuCl₂(PR₃)] (arene = benzene or p-cymene), [Cp*MCl₂(PR₃)] or [Cp*RhCl₂]₂ (M = Ir(III), Rh(III)), Cp* = η⁵-pentamethylcyclopentadienyl, PR₃ = triphenylphosphine (PPh₃), tris(2-cyanoethyl)phosphine (tcep) and 1,3,5-triaza-7-phosphaadamantane (pta) and their corresponding piano stool complexes. Single crystal X-ray diffraction structure determinations indicated that the resulting linkage isomer of the complex, i.e., proximal (coordination via S,N_(sulfonated) placing the sulfonyl group near the coordination sphere) or distal (coordination via S,N_{(non-sulfonated)}, placing the sulfonyl group away from the coordination sphere), is directly related to the steric bulk around the metal centre. Proximal to distal isomerisation of the complex [(η⁶-p-cymene)Ru{p-TolSO₂NC(S)N(PPh₃)}] (1aL1) was observed by ¹H and ³¹P{¹H} NMR spectroscopy. DFT calculations suggested this to be the result of the conversion from the initially formed kinetically favourable to the thermodynamically favourable isomer. Computational investigation of non-covalent interactions using the reduced density gradient also revealed a chalcogen bond present between the thiourea sulfur and sulfonyl oxygen atoms of complex 1aLa. The in vitro antiproliferative activity of several complexes was determined against human cancer cells, which revealed a correlation between potency and lipophilic properties of the ancillary ligands for a series of Ru(II) p-cymene complexes.