Unusual coordinating behavior by three non-steroidal anti-inflammatory drugs from the oxicam family towards copper(II). Synthesis, X-ray structure for copper(II)-isoxicam, -meloxicam and -cinnoxicam-derivative complexes, and cytotoxic activity for a copper(II)-piroxicam complex

Cytotoxic tests recently performed at National Cancer Institute, NCI (USA), on [Cu(HPIR)(2)(DMF)(2)], 1, (H2PIR = piroxicam, 4-4hydroxy-2-methyl-N-pyridin-2-yl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) a widely used non-steroidal anti-inflammatory drug, NSAID [see R. Cini, G. Giorgi, A. Cinquantini, C. Rossi, M. Sabat. Inorg. Chem. 29 (1990) 5197-5200, for synthesis and structural characterization, DMF = dimethylformamide] (NSC #624662) by using a panel of ca. 50 human cancer cells, showed growth inhibition factor GI(50) values as low as 20 mu M against several cancer lines, with an average value 54.4 mu M. The activity of is larger against ovarian cancer cells, non-small lung cancer cells, melanoma cancer cells, and central nervous system cancer cells. The widely used anticancer drug carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)) (NSC #241240) has average GI(50) value of 102 mu M. The reactions of copper(II)-acetate with other NSAIDs from the oxicarn family were tested and crystalline complexes were obtained and characterized. Isoxicam (H2ISO = 4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HI-SO)center dot 0.5DMF, 2 center dot 0.5DMF (DMF = dimethylfomamide). The coordination arrangement is square-planar and the HISO- anions behave as ambi-dentate chelators via O(amide),N(isoxazole) and O(enolate),O(amide) donors. Meloxicam (H2MEL = 4-hydroxy-2methyl-N-(5-methyl-1,3-thiazol-2-yi)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HMEL)(2)(DMF)]center dot 0.25H(2)O, 3 center dot 0.25H(2)O. The coordination arrangement is square-pyramidal, the equatorial donors being O(amide),N(thiazole) from two HMELanions and the apical donor being O(DMF). Unexpectedly, cinnoxicam (HCIN = 2-methyl-1, 1-dioxido-3-[(pyridin-2-ylamino)carbonyl]2H-1,2-benzothiazin-4-yl-(3-phenylacrylate)) produced [Cu(MBT)(2)(PPA)(2)] (MBT = 3-(methoxycarbonyl)-2-methyl-2H-1,2-benzothiazin-4-olate 1, 1-dioxide, PPA = 3-phenyl-N-pyridin-2-ylacrylamide). (c) 2007 Elsevier Inc. All rights reserved.