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

Tamasi, Gabriella, Casolaro, Mario, Magnani, Agnese, Sega, Alessandro, Chiasserini, Luisa, Messori, Luigi, Gabbiani, Chiara, Valiahdi, Seied Mojtaba, Jakupec, Michael A., Keppler, Bernhard K., Hursthouse, Michael B. and Cini, Renzo (2010) 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. Journal of Inorganic Biochemistry, 104 (8), 799-814. (doi:10.1016/j.jinorgbio.2010.03.010). (PMID:20447694)

Abstract

The reaction of aqueous cis-[Pt(NH(3))(2)(H(2)O)(2)](NO(3))(2) with Na(+)HMEL(-) (H(2)MEL, 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(-)(H(2)ISO, 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(NH(3))(2)((N) under bar (1)'-HMEL)(2)], 5 and cis-[Pt(NH(3))(2)((N) under bar (1)'-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 (1)H NMR spectrum for 5 from DMSO-d(6) 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 degrees C) show that concentrations of complexes ranging between 2.5 and 5 mu M can be reached after a day. Compounds 5 and 6 show strong anti-proliferative effects on CH1 cells (ovarian carcinoma, human) in vitro. IC(50) values being 0.60 and 0.37 mu M, respectively (0.16 mu M 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-H(2)ISO/HISO bonds when compared to the Pt-(N) under bar (1)'-H(2)MEL/(N) under bar (1)'-HMEL linkages.

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