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 H 2L2), phosphonic (C3 H2L3, C4 H 2L4) 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)4Cl 2]+. 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 H 2L4·4HBr 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(CO 3)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)·2H 2O, 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. Show more