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.
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(1')-HMEL)(2)], 5 and cis-[Pt(NH(3))(2)(N(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 24h. 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 microM 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 microM, respectively (0.16 microM 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(1)(')-H(2)MEL/N(1)(')-HMEL linkages.
Tamasi
Gabriella
G
Department of Chemistry, Università di Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
Casolaro
Mario
M
Magnani
Agnese
A
Sega
Alessandro
A
Chiasserini
Luisa
L
Messori
Luigi
L
Gabbiani
Chiara
C
Valiahdi
Seied Mojtaba
SM
Jakupec
Michael A
MA
Keppler
Bernhard K
BK
Hursthouse
Michael B
MB
Cini
Renzo
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D000077239:Meloxicam; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010984:Platinum; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D020100:Hydrogels; D009363:Neoplasm Proteins; D013843:Thiazines; D013844:Thiazoles; D010984:Platinum; D000077239:Meloxicam