Adriana G. Bakalova*, Rossen T. Buyukliev, Rositsa P. Nikolova, Boris L. Shivachev, Rositsa A. Mihaylova and Spiro M. Konstantinov Pages 1243 - 1252 ( 10 )
Background: The accidental discovery of Cisplatin’s growth-inhibiting properties a few decades ago led to the resurgence of interest in metal-based chemotherapeutics. A number of well-discussed factors such as severe systemic toxicity and unfavourable physicochemical properties further limit the clinical application of the platinating agents. Great efforts have been undertaken in the development of alternative platinum derivatives with an extended antitumor spectrum and amended toxicity profile as compared to the reference drug cisplatin. The rational design of conventional platinum analogues and the re-evaluation of the empirically derived “structure- activity” relationships allowed for the synthesis of platinum complexes with great diversity in structural characteristics, biochemical stability and antitumor properties.
Methods: The new compounds have been studied by elemental analyses, IR, NMR and mass spectral analyses. The structures of the organic compound and one of the new mixed/ammine Pt(II) complexes were studied by X-ray diffraction analysis. The cytotoxic effects of the compounds were studied vs. the referent antineoplastic agent cisplatin against four human tumour cell lines using the standard MTT-dye reduction assay for cell viability. The most promising complex 3 was investigated for acute toxicity in male and female H-albino-mice models.
Results: A new organic compound (5-methyl-5-(2-thiomethyl)ethyl hydantoin) L bearing both S- and Ncoordinating sites and three novel platinum complexes, 1, 2 and 3 were synthesized and studied. Spectral and structural characterization concluded monodentate S-driven coordination of the ligand L to the metal center in complexes 1 and 2, whereas the same was acted as a bidentate N,S-chelator in complex 3. Ligand L crystallizes in the tetragonal space group I41/a (No 88) with one molecule per asymmetric unit. While complex 3 crystallizes in the monoclinic space group P21/c (No 14) with one molecule per asymmetric unit. In the same complex 3, the platinum ion coordinates an L ligand, a chloride ion and an ammonia molecule. In the in vitro experiments, the tested L and complexes 1 and 2 exhibited negligible cytotoxic activity in all tumor models. Accordingly, complex 3 is twice as potent as cisplatin in the HT-29 cells and is at least as active as cisplatin on the MDA-MB-231 breast cancer cell line. In the in vivo toxicity estimation of complex 3 no signs of common toxicity were observed.
Conclusion: The Pt(II)-bidentate complex 3 exhibited significant cytotoxic potential equaling or surpassing that of the reference drug cisplatin in all the tested tumor models. Negligible anticancer activity on the screened tumor types has been shown by the ligand L and its Pt(II) and Pt(IV) complexes 1 and 2, respectively. Our study on the acute toxicity of the most active complex 3 proved it to be non-toxic in mice models.
Pt(II) and Pt(IV) complexes, hydantoins, S-containing ligands, X-ray analysis, mixed ammine/amine complexes, cytotoxicity.
Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Dunav -2 Street, 1000 Sofia, Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, Dunav -2 Street, 1000 Sofia, Institute of Mineralogy and Crystallography, Bulgarian Academy of Science, Acad. G. Bonchev Street, 107 bl, 1113 Sofia, Institute of Mineralogy and Crystallography, Bulgarian Academy of Science, Acad. G. Bonchev Street, 107 bl, 1113 Sofia, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav-2 Street, 1000 Sofia, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav-2 Street, 1000 Sofia