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

New ligands H(2)L2-H(2)L6 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 (C(3) H(2)L2), phosphonic (C(3) H(2)L3, C(4) H(2)L4) or carboxylic acid (C(3) H(2)L5, C(4) H(2)L6) 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-Me(2)cyclen, 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-Me(2)cyclen or cyclam to cobalt(III) was achieved using Na(3)Co(NO(6))] to form Co(L)(NO(2))(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)](ClO(4))(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)(4)Cl(2)](+). Reaction of this complex with H(2)L2·4HCl and 8QOH produced Co(L2)(8QO)] in one step and contains two deprotonated sulfonato pendant arms. The reaction of H(2)L3·4HBr with Co(py)(4)Cl(2)](+) gave Co(L3)]Cl in which L3 acts as a hexadenate ligand with the three-carbon phosphonato side chains coordinated to cobalt. H(2)L5·4HCl bearing three-carbon carboxylic acid pendant arms gave a similar result. The four-carbon ligands were coordinated to cobalt by reaction of Co(py)(4)Cl(2)](+) with H(2)L4·4HBr or H(2)L6·4HCl to give Co(HL4)Cl(2)] or Co(H(2)L6)Cl(2)]Cl, which in turn with 8QOH gave the 8QO(-) complexes Co(L4)(8QO)] bearing anionic phosphate pendant arms or Co(H(2)L6)(8QO)]Cl(2) containing neutral carboxylic acid side chains. The reaction of Na(3)Co(CO(3))(3)] with the mono-N-alkylated ligand HL7·4HCl and then HOTf gave Co(L7)(CO(3))] and then in turn Co(L7)(OTf)(2)]. The carbonato complex Co(L7)(CO(3))] with 8QO](2)SO(4)] produced Co(L7)(CO(3))]. 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)(H(2)O)(2)](OTf)(3) (formed by aquation of the triflato complex), Co(cyclen)(8QO)](ClO(4))(2), Co(L2)(8QO)·2H(2)O, Co(L4)(8QO)·6H(2)O and Co(H(2)L6)Cl(2)]Cl·H(2)O. These demonstrate the coordination of the cyclen ligand in the folded anti-O,syn-N configuration with the N-alkylated nitrogens occupying apical positions.