ABSTRACT
A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O)2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)](2+) (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.
Subject(s)
Antineoplastic Agents/chemistry , Cobalt/chemistry , Coordination Complexes/chemistry , Heterocyclic Compounds/chemistry , Prodrugs/chemistry , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Hypoxia , Cell Line, Tumor , Cobalt/pharmacology , Cobalt/therapeutic use , Coordination Complexes/pharmacology , Coordination Complexes/therapeutic use , Crystallography, X-Ray , Cyclams , Heterocyclic Compounds/pharmacology , Heterocyclic Compounds/therapeutic use , Humans , Ligands , Mice , Models, Molecular , Neoplasms/drug therapy , Prodrugs/pharmacology , Prodrugs/therapeutic useABSTRACT
A series of cobalt complexes of the potent DNA minor groove alkylator 1-(chloromethyl)-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinolin-5-ol (seco-6-azaCBI-TMI) were prepared from a series of N-substituted cyclen ligands. The final N-substituted complexes carried formal overall charges ranging from +2 to -2 and showed limited improvements in solubility. They showed similar stabilities to that of the complex with the unsubstituted cyclen ligand, and large but variable attenuation of the cytotoxicity of the free alkylator (2-30-fold), compared to 150-fold for the unsubstituted ligand. However, they had oxic/hypoxic ratios (2-22-fold) comparable to that of the unsubstituted cyclen complex (5).
Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Prodrugs/chemical synthesis , Alkylation , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Azo Compounds/chemistry , Cell Hypoxia/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cobalt/chemistry , Cyclams , DNA/chemistry , DNA/metabolism , Drug Screening Assays, Antitumor , Drug Stability , Female , Heterocyclic Compounds/chemistry , Humans , Hypoxia/metabolism , Indoles/chemistry , Prodrugs/chemistry , Prodrugs/pharmacology , Solubility , Trace Elements/chemistryABSTRACT
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.