Bonding and structure trends of thiosemicarbazone derivatives of metals—An overview

Neutral and cationic copper bis(thiosemicarbazone) complexes bearing methyl, phenyl, and hydrogen, on the diketo-backbone of the ligand have been synthesized. All of them were characterized by spectroscopic methods and in three cases by X-ray crystallography. In vitro cytotoxicity studies revealed that they are cytotoxic unlike the corresponding zinc complexes. Copper complexes Cu(GTSC) and Cu(GTSCHCl) derived from glyoxal-bis(4-methyl-4-phenyl-3-thiosemicarbazone) (GTSCH(2)) are the most cytotoxic complexes against various human cancer cell lines, with a potency similar to that of the anticancer drug adriamycin and up to 1000 fold higher than that of the corresponding zinc complex. Tritiated thymidine incorporation assay revealed that Cu(GTSC) and Cu(GTSCHCl) inhibit DNA synthesis substantially. Cell cycle analyses showed that Cu(GTSC) and Cu(GTSCHCl) induce apoptosis in HCT116 cells. The Cu(GTSCHCl) complex caused distinct DNA cleavage and Topo II alpha inhibition unlike that for Cu(GTSC). In vivo administration of Cu(GTSC) significantly inhibits tumor growth in HCT116 xenografts in nude mice.

In Vitro and in Vivo Anticancer Activity of Copper Bis(thiosemicarbazone) Complexes

Spectral and structural studies of iron(III), cobalt(II,III) and nickel(II) complexes of 2-pyridineformamide N(4)-methylthiosemicarbazone

Palladium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones: spectral characterization, structural studies and cytotoxic activity.

Anticancer metal compounds in NCI's tumor-screening database: putative mode of action

Copper(II) complexes of 2-benzoylpyridine 4N-substituted thiosemicarbazones

Copper(II) and nickel(II) complexes of 2,3-butanedione bis(N(3)-substituted thiosemicarbazones)

2-Benzoylpyridine piperidinyl- and hexamethyleneiminylthiosemicarbazones, HBzpip and HBzhexim, respectively, crystallize in a hydrogen bonded Z isomeric conformation with respect to the C7-N2 bond. The intramolecular hydrogen bond is between N3-H...N1, but the S atom is E to the azomethine nitrogen, N2, for HBzpip and Z for HBzhexim. HBzpip is the second ZE isomer known, but the first that does not have a formal hydrogen bond to N2.

Different structures for two very similar 2-benzoylpyridine azacyclothiosemicarbazones

A number of thiosemicarbazones have been tested previously and herein are included three bis(thiosemicarbazones) for comparison to the previous derivatives. In general the uncomplexed thiosemicarbazones were more potent in the cytotoxic screens than the bis(thiosemicarbazone) except in the murine L1210 and the human colon SW480 screens. Mode of action studies have only demonstrated slight differences in the effects of the two types of compounds on nucleic acid metabolism. The symmetrical and unsymmetrical bis(thiosemicarbazones) complexes of copper, nickel, zinc, and cadmium have been examined to compare them to the heterocyclic N(4)-substituted thiosemicarbazones metal complexes. These new derivatives demonstrated excellent activity against the growth of suspended lymphomas and leukemias although it should be pointed out that generally they were not as active as the copper complexes of N(4)-substituted thiosemicarbazones. Nevertheless, selected bis(thiosemicarbazones) complexes were active against the growth of human lung MB9812, KB nasopharynx, epidermoid A431, glioma UM-86, colon SW480, ovary 1-A9, breast MCK-7, and osteosarcoma Saos-2. In human HL-60 promyelocytic leukemia cells the complexes preferentially inhibited DNA and purine syntheses over 60 min. The regulatory enzyme of the de novo purine pathway, IMP dehydrogenase, appeared to be a major target of the complexes. However, minor inhibition of the activities of DNA polymerase alpha, PRPP-amido transferase, ribonucleotide reductase, and nucleoside kinases occurred over the same time period. No doubt these effects of the complexes on nucleic acid metabolism were additive since the d[NTP] pool levels were reduced after 60 min as was DNA synthesis. The symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes did not cause as severe DNA fragmentation as the heterocyclic N(4)-substituted thiosemicarbazone metal complexes; furthermore, their metabolic effects in the tumor cell were more focused on a single synthetic pathway.

The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells.

Copper(II) and nickel(II) complexes of phenylglyoxal and phenylpropane-1,2-dione bis{N(3)-methyl-, bis{N(3)-dimethyl-, bis{piperidylthiosemicarbazone} have been prepared and studied spectroscopically. The six bis(thiosemicarbazones) have been characterized by their melting points, as well as i.r., electronic and 1H-n.m.r. spectra. The four-coordinate copper(II) complexes have been studied by e.s.r. spectroscopy, and the copper(II) and nickel(II) complexes by spectroscopic techniques mentioned above. Upon formation of these complexes, the loss of protons from each thiosemicarbazone moiety occurs, and the bis(thiosemicarbazones) coordinate to the metal centres as dianionic, tetradentate N2S2 ligands.

Janeice S. Ives

Papers

Copper(II) complexes of 2-benzoylpyridine 4N-substituted thiosemicarbazones

Copper(II) and nickel(II) complexes of 2,3-butanedione bis(N(3)-substituted thiosemicarbazones)

Different structures for two very similar 2-benzoylpyridine azacyclothiosemicarbazones

The cytotoxicity of symmetrical and unsymmetrical bis(thiosemicarbazones) and their metal complexes in murine and human tumor cells.

Copper(II) and nickel(II) complexes of the bis{N(3)-substituted thiosemicarbazones} of phenylglyoxal and 1-phenylpropane-1,2-dione