Francesco Abbate

Carbonic anhydrase inhibitors: SAR and x-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with Isozymes I, II and IV

A series of sugar sulfamate/sulfamide derivatives were prepared and assayed as inhibitors of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV. Best inhibitory properties were observed for the clinically used antiepileptic drug topiramate, which is a low nanomolar CA II inhibitor, and possesses good inhibitory properties against the other two isozymes investigated here, similarly with acetazolamide, methazolamide or dichlorophenamide. The X-ray structure of the complex of topiramate with hCA II has been solved and it revealed a very tight association of the inhibitor, with a network of seven strong hydrogen bonds fixing topiramate within the active site, in addition to the Zn(II) coordination through the ionized sulfamate moiety. Structural changes in this series of sugar derivatives led to compounds with diminished CA inhibitory properties as compared to topiramate.

Crystal structure and solution chemistry of the cytotoxic complex 1,2-dichloro(o-phenanthroline)gold(III) chloride

Abstract The crystal structure of the cytotoxic complex 1,2-dichloro(o-phenanthroline)gold(III) chloride ([AuphenCl2]Cl) has been solved through single crystal X-ray diffraction methods. The complex is square planar and exhibits a quite regular geometry. Crystals of the compound belong to the space group P21/n with a=12.632(5), b=16.916(3), c=12.902(6) A, β=91.31(3)° and Z=8. The coordination of the two gold(III) ions in the asymmetric unit is completed by two chloride ions at 2.972(3) and 3.043(3) A, respectively, forming a distorted square pyramid. The behavior in solution of [AuphenCl2]Cl was further analyzed through 1H NMR spectroscopy. Results point out that the [Au(III)phen]3+ molecular fragment is stable in solution for several hours, even under physiological conditions, whereas the two chloride ligands are released within approximately 30 min after dissolution in the buffer, at 25°C. The gold(III) chromophore is easily and quickly reduced by addition of stoichiometric amounts of sodium ascorbate; metallic gold is formed and free phenanthroline liberates. The implications of these findings for the biological properties of the [Au(III)phen]3+ species are discussed.

Role of internal conversion on the excited state properties of trans-styrylpyridines

Abstract A theoretical and photophysical study of the three isomeric trans- n -styrylpyridines ( n = 2,3,4) has been carried out to evaluate the role of internal conversion (IC) on their deactivation pathways from the singlet manifold. Calculations by the QCFF/PI and CNDO/S methods and application of current theories of radiationless transitions allowed the rate constants for IC to be evaluated. The fluorescence lifetimes measured in the picosecond region and the fluorescence and trans → cis photoisomerization quantum yields from previous works allowed the rate constants for the non-radiative and non-reactive deactivation processes to be calculated. The experimental results were in a reasonable agreement with the theoretical predictions on the role of IC (markedly more important for the 2 and 4 derivatives) and confirmed that intersystem crossing is a low efficiency process for these azastilbenes. On the basis of the temperature and the solvent viscosity effects on the electronic spectra, an interpretation of the excitation energy effect on the quantum yields of the 3 isomer was attempted.

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with the perfluorobenzoyl analogue of methazolamide. Implications for the drug design of fluorinated inhibitors.

The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with 4-methyl-5-perfluorophenylcarboximido-δ2-1,3,4-thiadiazoline-2-sulfonamide (PFMZ), a topically acting antiglaucoma sulfonamide, has been resolved at a resolution of 1.8 Å. This compound is almost 10 times more effective as a hCA II inhibitor (KI of 1.5 nM) compared to the lead molecule, methazolamide, a clinically used drug (KI of 14 nM). Its binding to the enzyme active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group and thiadiazoline ring contacts, but differs considerably when the perfluorobenzoylimino fragment of the molecule is analyzed. Indeed, several unprecedented strong hydrogen bonds involving the imino nitrogen, carbonyl oxygen, a fluorine atom in the ortho position of the inhibitor, and two water molecules, as well as Gln 92 of the enzyme active site were seen. A stacking interaction of the perfluorophenyl ring of the inhibitor and the aromatic ring of Phe 131 was also observed for the first time in a CA–sulfonamide adduct. All these findings prove that more potent CA inhibitors incorporating perfluoroaryl/alkyl tails may be designed, with potentially improved antiglaucoma properties, in view of the new types of interactions seen here between the enzyme and the perfluorobenzoylated analogue of methazolamide.

Carbonic anhydrase inhibitors: X-ray crystallographic structure of the adduct of human isozyme II with a bis-sulfonamide - Two heads are better than one?

The X-ray crystal structure for the adduct of human carbonic anhydrase II (hCA II) with 4-(4-sulfamoylphenylcarboxamidoethyl)benzenesulfonamide, a topically acting antiglaucoma sulfonamide has been resolved at a resolution of 1.8 A. Its binding to the enzyme is similar with that of other sulfonamides, considering the interactions of the sulfonamide zinc anchoring group, but differs considerably when the organic part of the inhibitor is analyzed. This part of the inhibitor interacts only within the hydrophobic half of the CA active site, leaving the hydrophilic half able to accomodate several water molecules not present in the uncomplexed enzyme. Furthermore, the second head (sulfonamide moiety) participates in two strong hydrogen bonds with amino acid residues (Gly 132 and Gln 136) situated on the rim of the entrance to the active site cleft. Thus, the answer to the question in the title of this paper is that two heads are better than one, since the two sulfamoyl moieties of the inhibitor allow its proper orientation within the active site, with only one head binding in ionized form to the zinc ion, the organic part lying within the hydrophobic half of the active site, and the terminal, carboxamido containing phenylsulfamoyl head participating in strong hydrogen bonds with amino acid residues located at the entrance of it. All these findings are important for the design of better carboxamido CA inhibitors with applications in clinical medicine.

Carbonic Anhydrase Inhibitors, Interaction of Boron Derivatives with Isozymes I and II: A New Binding Site for Hydrophobic Inhibitors at the Entrance of the Active Site as shown by Docking Studies

The interaction of human carbonic anhydrase (hCA) isozymes I and II with boron derivatives was investigated by kinetic and spectroscopic studies. These derivatives, tested as new inhibitors of carbonic anhydrase, are sulfonamide and non-sulfonamide boron derivatives and some of them proved to be moderately efficient inhibitors of hCA I and hCA II, their activities being comparable to those of the un-substituted sulfonamides, the classical inhibitors of these zinc enzymes. Ph2BOH, one of the compounds with the highest affinity for hCA II in the present study, has been docked within the active site. After minimisation it was found situated at 7.9 Å from zinc, within the hydrophobic half of the active site, in Van der Waals contacts with the amino acid residues: Val 121, Phe 130, Val 135, Leu 141, Val 143, Val 207 and Pro 201. This is the first time that a CA inhibitor has been found to bind at the edge of the active site cavity, similarly to the CA activator histamine, which binds on the hydrophilic half. This finding may be of importance also for the design of novel types of inhibitors with increased affinity for the different CA isozymes.

A theoretical and experimental study of the excited state relaxation properties of mono‐aza‐ and di‐aza‐trans‐stilbenes

A theoretical and photophysical study of the three isomeric trans‐n‐styryl‐pyridines (n‐StP with n=2,3,4) and the three symmetrical 1,2‐dipyridyl‐ethylenes (n,n′‐DPE with n,n′=2,2′, 3,3′ and 4,4′) has been carried out to evaluate the role of internal conversion (IC) on their deactivation pathways from the singlet manifold. The rate constants for IC have been obtained by quantum mechanical calculations. The fluorescence lifetimes measured in the picosecond time range and the fluorescence and trans→cis photoisomerization quantum yields from the present and previous works allowed the rate constants for the relaxation processes to be calculated. The experimental results were in a reasonable agreement with the theoretical predictions on the role of IC (markedly more important for the ortho and para aza‐derivatives). The study of the effects of temperature and solvent on the spectral properties and the photophysical and photochemical parameters allowed a better understanding of the excited state behavior of the...

Au2trien: a dinuclear gold(III) complex with unprecedented structural features

The X-ray structure of a dinuclear gold(III) complex, Au2trien, shows the presence of two square planar gold(III) centers bridged by a nitrogen donor, in a very unusual fashion.