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New platinum-oxicam complexes as anti-cancer drugs. Synthesis, characterization, release studies from smart hydrogels, evaluation of reactivity with selected proteins and cytotoxic activity in vitro |
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| Authors: | Gabriella Tamasi Agnese Magnani Luisa Chiasserini Chiara Gabbiani Michael A. Jakupec Michael B. Hursthouse |
| Affiliation: | a Department of Chemistry, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy b Department of Medicinal Chemistry, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy c Laboratory of Metals in Medicine METMED, Department of Chemistry, University of Florence, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy d Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, A-1090 Vienna, Austria e School of Chemistry, University of Southampton, Southampton, SO17 1BJ, United Kingdom |
| Abstract: | The reaction of aqueous cis-[Pt(NH3)2(H2O)2](NO3)2 with Na+HMEL− (H2MEL, meloxicam, 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide), and Na+HISO− (H2ISO, isoxicam, 4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) at pH 7 produced micro-crystalline cis-[Pt(NH3)2(N1′-HMEL)2], 5 and cis-[Pt(NH3)2(N1′-HISO)2], 6. The X-ray diffraction structure of 5 shows two HMEL− anions donating through the thiazole nitrogen atoms and adopting a head-to-tail (HT) conformation. The 1H NMR spectrum for 5 from DMSO-d6 shows inertness of the complex up to at least 24 h. Delivery studies for 5 and 6 from vinyl hydrogel based on l-phenylalanine (pH 6.5, 25 °C) show that concentrations of complexes ranging between 2.5 and 5 μM can be reached after a day. Compounds 5 and 6 show strong anti-proliferative effects on CH1 cells (ovarian carcinoma, human) in vitro, IC50 values being 0.60 and 0.37 μM, respectively (0.16 μM for reference, cis-diamminodichloridoplatinum(II), cisplatin). ESI-MS measurements clearly documented that both 5 and 6 form adducts with the three model proteins ubiquitin (UBI), cytochrome c (CYT C) and superoxide dismutase (SOD), the HISO− complex being significantly more effective than the HMEL− one. Density functional methods help in finding rationale for the easiest dissociation of Pt-H2ISO/HISO bonds when compared to the Pt-N1′-H2MEL/N1′-HMEL linkages. |
| Keywords: | Platinum Cancer Oxicam Hydrogel Density functional |
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