Syntheses of 8-quinolinolatocobalt(iii) complexes containing cyclen based auxiliary ligands as models for hypoxia-activated prodrugs

Abstract

New ligands H₂L2–H₂L6 comprise the cyclen macrocycle which is N,N′-dialkylated at the 1,7-nitrogen atoms by three- and four-carbon alkyl chains bearing terminal sulfonic (C₃ H₂L2), phosphonic (C₃ H₂L3, C₄ H₂L4) or carboxylic acid (C₃ H₂L5, C₄ H₂L6) groups, and HL7 is N-monoalkylated by a four-carbon sulfonic acid group. The ligands were prepared by alkylation of a bridged bisaminal intermediate. The syntheses of cobalt(III) complexes containing a tetradentate cyclen, N,N′-1,7-Me₂cyclen, cyclam or L2–L7 ligand together with the bidentate 8-quinolinato (8QO⁻) ligand, of interest as it is a model for a more potent cytotoxic analogue, were investigated. Coordination of ligands (L) cyclen, N,N′-1,7-Me₂cyclen or cyclam to cobalt(III) was achieved using Na₃[Co(NO₆)] to form [Co(L)(NO₂)₂]⁺. HOTf (trifluoromethansulfonic acid) was used to prepare the triflato complexes [Co(L)(OTf)₂]⁺, followed by substitution of the labile triflato ligands to yield [Co(L)(8QO)](ClO₄)₂ isolated as the perchlorate salts. One further example containing cyclam and the 5-hydroxymethyl-8-quinolinato ligand was also prepared by this method. Complexes containing the pendant arm ligands L2–L6 were prepared from the cobalt precursor trans-[Co(py)₄Cl₂]⁺. Reaction of this complex with H₂L2·4HCl and 8QOH produced [Co(L2)(8QO)] in one step and contains two deprotonated sulfonato pendant arms. The reaction of H₂L3·4HBr with [Co(py)₄Cl₂]⁺ gave [Co(L3)]Cl in which L3 acts as a hexadenate ligand with the three-carbon phosphonato side chains coordinated to cobalt. H₂L5·4HCl bearing three-carbon carboxylic acid pendant arms gave a similar result. The four-carbon ligands were coordinated to cobalt by reaction of [Co(py)₄Cl₂]⁺ with H₂L4·4HBr or H₂L6·4HCl to give [Co(HL4)Cl₂] or [Co(H₂L6)Cl₂]Cl, which in turn with 8QOH gave the 8QO⁻ complexes [Co(L4)(8QO)] bearing anionic phosphate pendant arms or [Co(H₂L6)(8QO)]Cl₂ containing neutral carboxylic acid side chains. The reaction of Na₃[Co(CO₃)₃] with the mono-N-alkylated ligand HL7·4HCl and then HOTf gave [Co(L7)(CO₃)] and then in turn [Co(L7)(OTf)₂]. The carbonato complex [Co(L7)(CO₃)] with [8QO]₂[SO₄] produced [Co(L7)(CO₃)]. All complexes containing L7 bear an anionic sulfonato group on the side chain. The synthesis and characterisation of the six new ligands based on N-alkylated cylen ligand and the cobalt complexes outlined above are described, along with cyclic voltammograms of the 8QO⁻ complexes and the molecular structures determined by X-ray crystallography of [Co(cyclen)(H₂O)₂](OTf)₃ (formed by aquation of the triflato complex), [Co(cyclen)(8QO)](ClO₄)₂, Co(L2)(8QO)·2H₂O, Co(L4)(8QO)·6H₂O and [Co(H₂L6)Cl₂]Cl·H₂O. These demonstrate the coordination of the cyclen ligand in the folded anti-O,syn-N configuration with the N-alkylated nitrogens occupying apical positions.