Synthesis, solution equilibria and antiproliferative activity of copper(II) aminomethyltriazole and aminomethylthioxotriazoline complexes.
The aim of the present study was the synthesis, the determination of formation constants, and the evaluation of the antiproliferative activity of two copper(II) complexes formed with triazole-type ligands. The synthesis of the unsymmetrical triazole ligand 4-amino-3-aminomethyl-5-methyl-1,2,4-triazole (L1), and its copper(II) complex is reported. The ligand was prepared by functionalization of the carboxylate function of tert-butyloxycarbonyl (BOC) protected glycine O-methyl ester. All intermediates and final products were isolated and characterized with IR, 1H NMR, and elemental analysis. X-ray structures of the ligand as a sulfate salt ((H2L1)2SO4.H2O) and the copper(II) complex [CuCl2(L1)(2)] are described. The ligand forms a (N,N) bidentate chelate with the amino group and one triazole nitrogen atom. The tetragonally distorted octahedral coordination of Cu(II) results from two axially coordinated chloride ions. Protonation constants for L1 and speciation of the Cu(II)/L1 system were determined in 0.1 M aqueous KCl solution at 25 degrees C. Complexes formed in solution were also characterized by visible spectrophotometry. Ligand substitution competition between L1 and glycine has also been studied using potentiometric titrations. Antiproliferative activities of ([CuCl2(L1)2]) and [CuCl2(H2L2)]Cl, where HL2 is the 5-thioxo analog of L1, against human tumor cell lines HT1080 and HT29 as well as normal human fibroblasts (HF) are presented along with the antiproliferative activities of L1, CuCl2, and cisplatin. Activity of these two complexes are discussed and compared with the activity of analogous compounds reported in the literature which contain pyridyl groups in place of the aminomethyl group. In particular, it is suggested that a lypophilic residue such as a pyridyl group is important for antiproliferative activity of this class of compounds.
Gaccioli
Francesca
F
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università degli Studi di Parma, Parco Area delle Scienze 17A, I-43100 Parma, Italy.
Franchi-Gazzola
Renata
R
Lanfranchi
Maurizio
M
Marchiò
Luciano
L
Metta
Giuseppe
G
Pellinghelli
Maria Angela
MA
Tardito
Saverio
S
Tegoni
Matteo
M
D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000737:chemistry; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D002712:Chlorides; D007783:Lactones; D009942:Organometallic Compounds; D014230:Triazoles; C504114:aminomethylthioxotriazoline; C504113:copper(II) aminomethyltriazole; D005998:Glycine