title: Bis(dialkyl)dithiocarbamato cobalt(III) complexes of bidentate nitrogen mustards: synthesis, reduction chemistry and biological evaluation as hypoxia-selective cytotoxins.
abstract: Cobalt(III) complexes [Co(R2dtc)2(L)]+ containing two dithiocarbamate ligands (R = Me, Et, pyrrolidine) and a bidentate nitrogen mustard ligand (L) have been prepared as potential hypoxia-selective cytotoxins. The complexes were synthesized by treatment of the binuclear precursor [Co2(R2dtc)5]+ with the diamine mustards N,N'-bis(2-chloroethyl)ethylenediamine (BCE) and N,N-bis(2-chloroethyl)ethylenediamine (DCE), or their non-alkylating analogues [N,N-diethylethylenediamine (DEE) and N,N'-diethylethylenediamine (BEE)]. Cyclic voltammetry of the complexes in MeCN reveals quasi-reversible behaviour for the Co(III)/Co(II) couple, with E1/2 increasing in the order DCE < DEE approximately BCE < BEE. In MeCN/H2O electrochemical reduction is irreversible, indicating rapid substitution of H2O into the coordination sphere of the Co(II) intermediate. This fast ligand loss was confirmed by pulse radiolysis of [Co(Me2dtc)2(DEE)]+, while steady-state radiolysis showed that the initial intermediate disproportionates to [CoII(H2O)6]2+ + 2[CoII(Me2dtc)3]. The latter species reduces additional parent complex to give an overall stoichiometry of 3 mol parent complex/mol reductant. [Co(Me2dtc)2(DCE)]+ decays rapidly by an analogous mechanism in hypoxic culture medium. This reaction is not inhibited by O2, indicating that reoxidation of the Co(II) intermediate by O2 is not rapid enough to compete with ligand dissociation. The resulting free R2dtc-ligands, rather than the released mustards, are primarily responsible for growth inhibition by [Co(R2dtc)2(L)]+ complexes, although DCE release does contribute to clonogenic cell killing. Clonogenic cell killing is not appreciably enhanced under hypoxic conditions for any of the dithiocarbamato complexes. This finding, coupled with their instability in culture medium, suggests that [Co(R2dtc)2(L)]+ complexes are probably not suited for further development as bioreductive anticancer drugs.
authors.affiliation: Cancer Society Research Laboratory, University of Auckland, New Zealand.
authors.forename: D C
authors.initials: DC
authors.lastname: Ware
authors.forename: H R
authors.initials: HR
authors.lastname: Palmer
authors.forename: F B
authors.initials: FB
authors.lastname: Pruijn
authors.forename: R F
authors.initials: RF
authors.lastname: Anderson
authors.forename: P J
authors.initials: PJ
authors.lastname: Brothers
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D003035:Cobalt / Q000737:chemistry* / Q000494:pharmacology; D006224:Cricetinae; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D009588:Nitrogen Mustard Compounds; D003035:Cobalt