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

Abstract

Cytotoxic tests recently performed at National Cancer Institute, NCI (USA), on [Cu(HPIR) 2(DMF) 2], 1, (H 2PIR = piroxicam, 4-hydroxy-2-methyl- N-pyridin-2-yl-2 H-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 μM against several cancer lines, with an average value 54.4 μM. The activity of 1 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 μM. The reactions of copper(II)–acetate with other NSAIDs from the oxicam family were tested and crystalline complexes were obtained and characterized. Isoxicam (H 2ISO = 4-hydroxy-2-methyl- N-(5-methylisoxazol-3-yl)-2 H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HISO) 2] · 0.5DMF, 2 · 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 (H 2MEL = 4-hydroxy-2-methyl- N-(5-methyl-1,3-thiazol-2-yl)-2 H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HMEL) 2(DMF)] · 0.25H 2O, 3 · 0.25H 2O. The coordination arrangement is square-pyramidal, the equatorial donors being O(amide),N(thiazole) from two HMEL − anions and the apical donor being O(DMF). Unexpectedly, cinnoxicam (HCIN = 2-methyl-1,1-dioxido-3-[(pyridin-2-ylamino)carbonyl]-2 H-1,2-benzothiazin-4-yl-(3-phenylacrylate)) produced [Cu(MBT) 2(PPA) 2] (MBT = 3-(methoxycarbonyl)-2-methyl-2 H-1,2-benzothiazin-4-olate 1,1-dioxide, PPA = 3-phenyl- N-pyridin-2-ylacrylamide).