J. Borrás

Toward the development of metal-based synthetic nucleases: DNA binding and oxidative DNA cleavage of a mixed copper(II) complex with N-(9H-purin-6-yl)benzenesulfonamide and 1,10-phenantroline. Antitumor activity in human Caco-2 cells and Jurkat T lymphocytes. Evaluation of p53 and Bcl-2 proteins in the apoptotic mechanism.

The complex [Cu(N9-ABS)(phen)2].3.6H2O, H2N9-ABS = N-(9H-purin-6-yl)benzenesulfonamide and phen = 1,10-phenanthroline, has been synthesized and then characterized with the aid of X-ray diffraction, analytical, and spectroscopic techniques. The geometry of Cu(II) is distorted square pyramidal with the equatorial positions occupied by three N atoms from two phenantroline molecules and one N atom from the adenine ring of the sulfonamide ligand. The interaction of the complex with DNA was studied by means of viscosity measurements and fluorescence spectroscopy. The results pointed to a classic intercalation of the complex between the DNA base pairs. The complex was found to be a very efficient agent of plasmid DNA cleavage in the presence of ascorbate. Both the kinetics and the mechanism of the cleavage reaction were studied. In addition, the cytotoxic properties of the complex were evaluated in human Jurkat T and Caco-2 cell lines. The cytotoxicity of the compound was higher than that of the reference ([Cu(phen)2]2+). The mechanism and type of cell death induced by the compound was determined by flow cytometry and Hoechst dye staining. The compound demonstrated a significant ability to induce cell death by apoptosis. The apoptosis induced by [Cu(N9-ABS)(phen)2].3.6H2O was associated with an increase in p53 protein levels while those of Bcl-2 were reduced.

Complexes of Ni(II) and Cu(II) with ofloxacin. Crystal structure of a new Cu(II) ofloxacin complex.

Several coordination compounds formed between Ni(II) or Cu(II) with ofloxacin have been synthesised and characterised. According to elemental chemical analysis and FT-IR spectroscopy data, direct reaction of Ni(II) and Cu(II) salts with ofloxacin leads to formation of precipitates for which mass spectrometry demonstrates their polymeric nature. However, crystalline [Cu(oflo)2(H2O)].2H2O is formed if the reaction is carried out in the presence of ammonia. This complex crystallises in the triclinic system, space group P-1 with a=9.2887(12), b=11.2376(14), c=17.874(2) A, alpha=92.12(3), beta=95.39(3), gamma=91.71(3) degrees and Z=2. The local geometry around the Cu(II) ion is a slightly distorted square base pyramid. Electronic spectra, magnetic susceptibility measurements and EPR spectra of the synthesised complexes indicate a tetragonal environment.

Carbonic anhydrase inhibitors ☆: synthesis of water-soluble, topically effective intraocular pressure lowering aromatic/heterocyclic sulfonamides containing 8-quinoline-sulfonyl moieties: is the tail more important than the ring?

Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with 8-quinoline-sulfonyl chloride afforded a series of water-soluble (as hydrochloride or triflate salts) compounds. The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes, but especially against CA II (in nanomolar range), which is the isozyme known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were topically applied as 2% water solutions onto the eye of normotensive and glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. This result prompted us to reanalyze the synthetic work done by other groups for the design of water soluble, topically effective antiglaucoma sulfonamides. According to these researchers, the IOP lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring system. In order to prove that the tail (in this case the 8-quinoline-sulfonyl moiety) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted, we also prepared a dorzolamide derivative to which the 8-quinoline-sulfonyl moiety was attached. This new compound is quite water soluble as hydrochloride salt, behaves as a strong CA II inhibitor, and fared better than the parent molecule in lowering IOP in experimental animals. Thus, the tail conferring water solubility to such an enzyme inhibitor is more important for its topical activity as antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.

Coordination behaviour of sulfanilamide derivatives.: Crystal structures of [Hg(sulfamethoxypyridazinato)2], [Cd(sulfadimidinato)2(H2O)]·2H2O and [Zn(sulfamethoxazolato)2-(pyridine)2(H2O)2]

Abstract Hg(II), Cd(II) and Zn(II) complexes with the ligands sulfadimethoxine, sulfamethoxypyridazine, sulfadiazine, sulfamerazine, sulfadimidine and sulfamethoxazole have been prepared and characterised by spectral data. 1H and 13C NMR have been used to interpret the structural characteristics of the complexes in solution. The X-ray crystal structures of [Hg(sulfamethoxypyridazinato)2] (2a), [Cd(sulfadimidinato)2(H2O)]·2H2O (4b) and [Zn(sulfamethoxazolato)2(py)2(H2O)2] (6d) have been determined. In complex 2a the Hg(II) ion lies on an inversion centre and exhibits linear coordination by two sulfonamidic nitrogen atoms [Hg–N(1)=2.071(4) A] of the two deprotonated sulfamethoxypyridazinato ligands. The polymeric Cd(II) complex (4b) exhibits a high distorted-octahedral geometry, involving the sulfonamidic nitrogen [Cd–N(1)=2.328(6); Cd–N(1′)=2.326(6) A] and the heterocyclic N(3)/N(2′) [Cd–N(3)=2.307(6) A; Cd–N(2′)=2.426(6) A] of two bidentate sulfadimidine ligands, the terminal amino N(4′b) [Cd–N(4′b)=2.379(7) A] of a third sulfadimidine which is bonded to an adjacent Cd(II), and the O(3) atom of a coordinated water molecule [Cd–O(3)=2.334(6) A]. In complex 6d the geometry around the Zn(II) ion can be described as a slightly distorted compressed octahedron. Two pyridine [Zn–N(16)=2.1841(17) A] and two isoxazole N atoms [Zn–N(2)=2.1736(15) A] are located in the equatorial plane and two oxygen atoms of two water molecules [Zn–O(4)=2.0984(14) A] are placed in the apical positions. IR and NMR spectral studies suggest a similar behaviour of the Cd(II) and Zn(II) complexes, both in solid state and solution, and different to the corresponding Hg(II) complexes. Thus 1H and 13C NMR spectra, in DMSO-d6, of Cd(II) and Zn(II) compounds show coordination mainly through the heterocyclic nitrogen while the corresponding Hg(II) derivatives seem to be coordinated through the sulfonamidic nitrogen.

COORDINATION BEHAVIOR OF SULFATHIAZOLE. CRYSTAL STRUCTURE OF CU(SULFATHIAZOLE) (PY)3CL SUPEROXIDE DISMUTASE ACTIVITY

Abstract The preparation, spectroscopic, magnetic properties, and crystal structure of [Cu(stzxpy) 3 Cl] (stz − stands for the deprotonated form of sulfathiazole, 4-amino-N-2-thiazolylbencenosulfonamide) are reported. Crystals are orthorhombic, space group Pbca, with cell constants a = 15.834(2), b = 17.512(4), and c = 18.79(2) A, and Z = 8. The structure was solved and refined to R = 0.041 (R W = 0.040). The structure consists of mononuclear units linked via hydrogen bonds to form the tridimensional pyramid. The geometry of CuN3N*NCl chromophore is distorted square-pyramid. The superoxide-dismutase mimetic activity of the compound is measured and compared with those of the SOD enzyme, the free drug, and other related sulfathiazole complexes.

Oxidative DNA damage of mixed copper(II) complexes with sulfonamides and 1,10-phenanthroline: Crystal structure of [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)2(1,10-phenanthroline)]

Mixed coordination compounds of Cu(II) with sulfonamides and 1,10-phenanthroline as ligands have been prepared and characterised. Single crystal structural determination of the complex [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)(2)(phen)] shows Cu(II) ions are located in a highly distorted octahedral environment, probably as a consequence of the Jahn-Teller effect. The FT-IR and electronic paramagnetic resonance (EPR) spectra are also discussed. The mixed complexes prepared undergo an extensive DNA cleavage in the presence of ascorbate and hydrogen peroxide. Two of the complexes have higher nucleolytic efficiency than the bis(o-phenanthroline)copper(II) complex.

Superoxide dismutase activity of ternary copper complexes of sulfathiazole and imidazole derivatives. Synthesis and properties of [CuL2(R-Him)2] [HL=4-amino-N-(thiazol-2-yl)benzenesulfonamide, R-Him=4-methylimidazole, 4,4-dimethylimidazoline or 1,2-dimethylimidazole]. Crystal structure of [CuL2(4,4-dimethylimidazoline)2]

Abstract New ternary copper(II) complexes of sulfathiazole (4-amino-N-(thiazol-2-yl)benzenesulfonamide)(HL) and methyl imidazole derivatives have been synthesised and characterised. The crystal structure of the complex [CuL2(4,4-dmHim)2] (1) [4,4-dmHim=4,4-dimethylimidazoline] has been determined. The copper centre has a quasi regular square planar environment with Cu-nitrogen bond lengths ranging from 1.952 to 2.010 A. From the spectroscopic properties of the complexes [CuL2(1,2-dmHim)2] (2) [1,2-dmHim=1,2-dimethylimidazole] and [CuL2(4-mHim)2] (3) [4-mHim=4-methylimidazole] a distorted tetragonal octahedral geometry is deduced. The compounds showed SOD mimetic activity in fact, a low concentration of the complexes catalyses the dismutation of superoxide at biological pH. This SOD activity is correlated with their structural properties. Using Extended Huckel Molecular Orbital Calculations the one-electron energy levels of the CuN4 chromophore in complex 1 are reported and correlated with the data of the CuN6 and CuN5 chromophores of the previously reported [CuL2(Him)2]·MeOH and [CuL2(mim)2]·H2O compounds. In addition, the influence of the geometry distortion on the composition and energy of the molecular orbitals is described using idealised models.

Oxidative nuclease activity of ferromagnetically coupled μ-hydroxo-μ-propionato copper(II) complexes [Cu3(L)2(μ-OH)2(μ-propionato)2] (L = N-(pyrid-2-ylmethyl)R-sulfonamidato, R = benzene, toluene, naphthalene)

Three doubly-bridged, trinuclear copper(II) compounds with hydroxo and carboxylato bridges, (infinity)(1)[Cu(3)(L1)(2)(mu-OH)(2)(mu-propionato)(2)](1), [Cu(3)(L2)(2)(mu-OH)(2)(mu-propionato)(2)(DMF)(2)] (2) and (infinity)(1){[Cu(3)(L3)(2)(mu-OH)(2)(mu-propionato)(2)]} [Cu(3)(L3)(2)(mu-OH)(2)(mu-propionato)(2)(DMF)(2)]} (3) [HL1=N-(pyrid-2-ylmethyl)benzenesulfonylamide, HL2=N-(pyrid-2-ylmethyl)toluenesulfonylamide, HL3=N-(pyrid-2-ylmethyl)naphthalenesulfonylamide], have been synthesized and characterized. 1 is built from [Cu(3)(L1)(2)(mu-OH)(2)(mu-propionato)(2)] clusters. Each unit contains three copper(II) with two different coordination environments: the terminal centers are square-base pyramidal whereas the central copper is square planar. 2 presents a similar square-base pyramidal geometry in the terminal centers, but the central copper is six-coordinate. 3 shows an unusual 1D coordination polymer comprised of two distinct building blocks: one similar to that found in 1 and the other similar to that found in 2. The magnetic susceptibility measurements (2-300K) reveal a ferromagnetic interaction between the Cu(II) ions with J values of 76.0, 55.0, and 48.0cm(-1) for 1, 2, and 3, respectively. Emission spectroscopy, thermal denaturation, viscosimetry and cyclic voltammetry show an interaction of the complexes with DNA through the sugar-phosphate backbone. All three Cu(II) complexes were found to be very efficient agents of plasmid DNA cleavage in the presence of ascorbato or mercaptopropionic acid. Both the kinetics and the mechanism of the cleavage reaction have also been examined.

Spectroscopic behaviour of metal–drug complexes. Infrared spectra of Cu(II) complexes with 5-amino-1,3,4-thiadiazole-2-thiol (Hatm)

Abstract The infrared spectra of the drug Hatm and its copper (II) complexes with stoichiometry [Cu(atm) 2 (H 2 O)] and [Cu(Hatm)(HIm) 2 (SO 4 )] are reported and discussed. The Raman spectrum of Hatm is also reported. An assignment of Hatm, HIm, H 2 O and SO 4 modes in the complexes is proposed in comparison with the modes of the free ligands. Important information about the metal–ligand vibrations has been obtained.

Metal complexes of sulfanilamide derivatives. Crystal structure of [Zn(sulfathiazole)2]·H2O

Abstract The crystal structure of the Zn(sulfathiazole) 2 ·H 2 O complex is reported. The complex crystallizes in the monoclinic space group C 2/ c . The cell dimensions are a = 9.098(3) A, b = 17.871(5) A, c = 14.61(1) A, β = 99.44(6)°, V = 2343(2) A 3 , Z = 4, and D x = 1.68 g/cm 3 . The final conventional R-factor = 0.027 for 2669 “observed” reflections and 191 variables. The Zn ion is surrounded in a regular tetrahedral arrangement by two N amino and two N thiazole atoms pertaining to four sulfathiazole (Hstz) ligands. Each stz anion, acting as a bidentate ligand, chelates to two Zn ions as a bridge through the N thiazole and the N amino atoms. The IR, 13 C NMR in solid state, 1 H NMR, and 13 C NMR in DMSO d6 solutions spectra are discussed in detail with regard to the crystal structure.