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Rev Electron Biomed / Electron J Biomed 2012;1:11-15.
Editorial:
THIOSEMICARBAZONES AS NEW ANTITUMOR COMPOUNDS
Javier García Tojal, PhD
Profesor Titular de Química Inorgánica. Facultad de Ciencias. Universidad de Burgos.
Burgos. España
qipgatoj @ ubu.es
The search of new compounds with medicinal applications is promoting important therapeutic advances and generates a new scientific multidisciplinary field where chemistry, pharmacy and biomedicine overlap together with other specialities. Thiosemicarbazones are some of the studied compounds. These sulfur-containing organic substances exhibit an interesting biological activity, which has been studied for more than fifty years1. In this sense, it is worth mentioning the efforts carried out in the cancer research. During the middle 1960s some of these derivatives showed high antitumor activity in different assays2-3. This fact encouraged to perform the first clinical trials, early stopped due to the unexpected low activity in humans4.
In addition, cellular targets of these substances were identified, mainly redox cellular processes and several enzymatic systems as topoisomerases, dehydrogenases, polymerases and nucleoside kinases5-8. Among the last ones, it is remarkable the inhibition of ribonucleotide reductases (RNRs), enzymes that transform ribonucleoside diphosphates into deoxyribonucleoside diphospates to give the basic constituents of DNA9.
The synthesis of new more selective and less toxic compounds led to the attainment of a novel drug (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, ATSC), which is currently involved in phase I and II clinical trials10-13. In parallel, other compounds exhibiting even better biological activity than ATSC have been developed14. Among them, there are some metal-organic derivatives. Binding of such organic molecules to metal ions gives rise to very stable coordination compounds. It also allows to modify the physicochemical properties of the thiosemicarbazones. Thus, their usually low water solubility drastically increases upon coordination. Moreover, a fine selection of the metal ion leads to a control of the stability of these substances against decomposition reactions.
Finally, the coordination induces changes in the acid-base behavior and the redox properties as in the metal ions as in the thiosemicarbazones. These physicochemical transformations affect the biological activity. For instance, it has recently been suggested that inhibition of RNRs is actually carried out by thiosemicarbazoneiron complexes15, it has also been demonstrated that copper derivatives activate lysosomal apoptosis pathway16 and, finally, both ions-containing compounds are responsible for the redox activity shown by thiosemicarbazones inside the cell17.
On the other hand, thiosemicarbazonecopper compounds are yielding quite promising findings in diagnosis. In this regard, 64Cu-based thiosemicarbazone radiopharmaceuticals are being explored to be used in PET (positron emission tomography) because of the hypoxia-selective tissue uptake, and they have been approved for use in clinical trials in patients with cervical cancer18.
In summary, the interesting results obtained in therapy and diagnosis become the thiosemicarbazones and their metal complexes into very attractive systems to be studied with a great applicative prospect. However, it is necessary a deeper research of these compounds in order to diminish their toxicity and increase the effectiveness in humans.
To achieve these goals, the preparation of new compounds, studies on structure-properties relationships and the reactivity against biomolecules, which are in an early stage, should be carried out. The advances in this field could be very useful to interpret the biological properties, as the interactions and bonding of thiosemicarbazone compounds to biological targets, and virtually to increase their therapeutic possibilities.
REFERENCES
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8.- Miller III MC, Bastow KF, Stineman CN, Vance JR, Song SC, West DX, Hall IH. The cytotoxicity of 2-formyl and 2-acetyl-(6-picolyl)-N-4-substituted thiosemicarbazones and their copper(II) complexes. Arch Pharm Pharm Med Chem. 1998, 331: 121-127.
9.- Moore EC, Zedeck MS, Agrawal KC, Sartorelli AC. Inhibition of ribonucleoside diphosphate reductase by 1-formylisoquinoline thiosemicarbazone and related compounds. Biochemistry. 1970, 9: 4492-4498.
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12.- Karp JE, Giles FJ, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M, Low J. A Phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders. Leuk Res. 2008, 32: 71-77.
13.- Traynor AM, Lee JW, Bayer GK, Tate JM, Thomas SP, Mazurczak M, Graham DL, Kolesar JM, Schiller JH. A phase II trial of Triapine® (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503. Invest. New Drugs. 2010, 28: 91-97.
14.- Yuan J, Lovejoy DB, Richardson DR. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood. 2004, 104: 1450-1458.
15.- Shao J, Zhou B, Di Bilio AJ, Zhu L, Wang T, Qi C, Shih J, Yen Y. A ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol Cancer Ther. 2006, 5: 586-592.
16.- Lovejoy DB, Janson PJ, Brunk UT, Wong J, Ponka P, Richardson DR. Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes. Cancer Res. 2011, 71: 5871-5780.
17.- Yu Y, Rahmanto YS, Hawkins CL, Richardson DR. The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity. Mol Pharmacol. 2011, 79: 921-931.
18.- Holland JP, Barnard, PJ, Collison D, Dilworth JR, Edge R, Green JC, McInnes EJL. Spectroelectrochemical and computational studies on the mechanism of hypoxia selectivity of copper rediopharmaceuticals. Chem Eur J. 2008; 14: 5890-5907.
CORRESPONDENCE:
Prof. Javier García Tojal
Profesor Titular de Química Inorgánica.
Facultad de Ciencias.
Universidad de Burgos
Plaza Misael Bañuelos s/n
09001. Burgos. España
Mail: qipgatoj @ ubu.es