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

被引：48

作者：

Tamasi, Gabriella ^{[1
]}

Casolaro, Mario ^{[2
]}

Magnani, Agnese ^{[2
]}

Sega, Alessandro ^{[2
]}

Chiasserini, Luisa ^{[2
]}

Messori, Luigi ^{[3
]}

Gabbiani, Chiara ^{[3
]}

Valiahdi, Seied Mojtaba ^{[4
]}

Jakupec, Michael A. ^{[4
]}

Keppler, Bernhard K. ^{[4
]}

Hursthouse, Michael B. ^{[5
]}

Cini, Renzo ^{[1
]}

机构：

[1] Univ Siena, Dept Chem, I-53100 Siena, Italy

[2] Univ Siena, Dept Med Chem, I-53100 Siena, Italy

[3] Univ Florence, Dept Chem, Lab Met Med METMED, I-50019 Florence, Italy

[4] Univ Vienna, Inst Inorgan Chem, A-1090 Vienna, Austria

[5] Univ Southampton, Sch Chem, Southampton SO17 1BJ, Hants, England

来源：

JOURNAL OF INORGANIC BIOCHEMISTRY | 2010年 / 104卷 / 08期

关键词：

Platinum; Cancer; Oxicam; Hydrogel; Density functional; DENSITY-FUNCTIONAL THEORY; X-RAY STRUCTURES; CRYSTAL-STRUCTURE; METAL-COMPLEXES; STRUCTURAL-CHARACTERIZATION; PROTONATION THERMODYNAMICS; ANTIINFLAMMATORY DRUGS; BIOLOGICAL-ACTIVITY; PT-II; LIGANDS;

D O I：

10.1016/j.jinorgbio.2010.03.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)((N) under bar (1)'-HMEL)(2)], 5 and cis-[Pt(NH3)(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 H-1 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. IC50 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-H2ISO/HISO bonds when compared to the Pt-(N) under bar (1)'-H2MEL/(N) under bar (1)'-HMEL linkages. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：799 / 814

页数：16

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