M. Alexandra Esteves

New hydroxypyrimidinone-containing sulfonamides as carbonic anhydrase inhibitors also acting as MMP inhibitors.

A set of benzenesulfonamide (BSA) derivatives bearing a hydroxypyrimidinone (HPM) moiety were synthesized and investigated for their inhibitory activity against several carbonic anhydrase (CA, EC 4.2.1.1) isozymes. They all revealed to be very potent inhibitors (nanomolar order) of the cytosolic CA I and II isozymes, but especially of the transmembrane, tumor-associated CA IX isozyme, a beneficial feature for a potential antitumor effect of these compounds. Further structure optimization aimed at improving the specificity of CA inhibition and enhancing their matrix metalloproteinase (MMP) inhibitory activity may also lead to new compounds with an attractive dual mechanism of action as antitumor agents.

Siderophore analogues. Chelating properties of a new cyclic diazadihydroxamic acid

Abstract A new cyclic diaza-dihydroxamic acid, 1,4-diazacycloheptane- N, N ′-bis( N -methyl-acetohydroxamic acid) (DACHDMAHA) has been synthesized and studied. This paper is the second one devoted to finding synthetic ferric sequestering agents suitable for mimicking chemical and biological properties of the naturally occurring rhodotorulic acid. This ligand, having the hydroxamate arms bound to a seven-membered ring diamine, presents some biological activity, as was previously found for the corresponding six-membered compound (PIPDMAHA). Stability constants with iron(III) and iron(II) as well as with copper(II) and copper(I) have been determined by potentiometry, spectrophotometry and cyclic voltammetpy, this latter technique being also useful for the interpretation of the electrochemical reaction and the determination of the rate constant of dissociation of iron(II) complexes. Comparing the complexes obtained with DACHDMAHA and PIPDMAHA it has been noticed that the complexes with the first ligand are more stable and that the rate constant of dissociation of the iron(II) complex is higher, showing that this ligand has more of the characteristics of a siderophore.

Siderophore analogues. Synthesis and chelating properties of a new macrocyclic trishydroxamate ligand

A new iron(III)-specific ligand, 1,5,9-triazacyclododecane-N,N′,N″-tris(N-methylacetohydroxamic acid) H3L, containing three hydroxamic acid groups as pendant arms on a macrocyclic triamine backbone, has been synthesized and characterized. Its acid–base and chelating properties with iron(III) and copper(II) ions have been studied by potentiometric and spectrophotometric techniques. The mechanism of electron transfer as well as the kinetics of dissociation and stability constants of reduced species, which are thought to be important in the biological activity of this siderophore analogue, have been studied by voltammetric methods. This ligand has proved to be biologically active and its properties were compared with ferrichrome and ferrioxamine B.

MICROSCOPIC ACID-BASE EQUILIBRIA OF A SYNTHETIC HYDROXAMATE SIDEROPHORE ANALOG, PIPERAZINE-1,4-BIS(N-METHYLACETOHYDROXAMIC ACID)

The protonation behavior of the cyclic diaminodihydroxamate ligand, piperazine-1,4-bis(N-methylacetohydroxamic acid) (H2L1), has been studied at both the macroscopic and the microscopic level. Potentiometric and 1H NMR techniques have been used for the study of this ligand as well as several model compounds: N-methylchloroacetohydroxamic acid, glycinehydroxamic acid and piperidino(N-methylacetohydroxamic acid). Molecular modeling calculations have also been performed to predict the most stable conformations and to estimate relevant contributions to the overall protonation process. The results of the protonation microconstants show that the N-donors in H2L1 are much less basic than the O-donors. The protonated amine moieties release most of their protons in the acid region while the deprotonation of the hydroxamate moieties starts only above pH 5. The theoretical modeling calculations show the effect of electrostatic interactions and internal hydrogen bonds on the interactivity of the basic sites throughout the protonation process.

A new iron(III) ion sequestering ligand: synthesis, solution chemistry and electrochemistry

A new cyclic diaminodihydroxamic ligand, piperazine-1,4-bis(N-methylacetohydroxamic acid)(H2L2), presenting a reasonable analogy with the naturally occurring siderophore rhodotorulic acid (H2L1), has been prepared through an easy two-step process. This ligand, which has proved to be biologically active, forms a very stable complex [Fe2L23]. The ligand and its iron and copper complexes have been characterized by potentiometric and spectrophotometric techniques. The mechanism of electron transfer in the complexes has been studied by voltammetric methods, and the kinetics of dissociation of the iron(II) complex, which might be of crucial importance in the biological activity of this siderophore analogue, was also investigated.

Molecular recognition of guanosine and 2-acetylaminofluorene-modified guanosine. A comparative study

Abstract The ability of an abiotic receptor, 7-acetylamino-2-methyl–1,8-naphthyridine, to bind to guanosine was analysed by a combination of NMR determinations and molecular modeling studies. The results indicate that this receptor simulates the base-pairing properties of cytidine in its Watson-Crick interaction with guanosine. Binding of the same receptor to N-(guanosin-8-yl)-2-acetylaminofluorene, the guanosine adduct containing the carcinogen 2-acetylaminofluorene, was found to occur in a similar manner. The calculated binding energies show that the molecular recognition of the adduct is lower than that of the unmodified guanosine. The theoretical studies suggest that the predominance of an abnormal low energy syn conformation for the adduct is the main structural feature accounting for the observed decrease of the host-guest interaction.

Kinetics and mechanism of iron exchange in a hydroxamate siderophore analogue complex

The kinetics of iron release from the dinuclear iron(III) complex of piperazine-1,4-bis(N-methylaceto-hydroxamic acid), upon treatment with ethylenediaminetetraacetate (edta) has been studied using UV/VIS absorption spectrophotometry. The absorbance vs. time evolution of the complex is well described by a consecutive two-step reaction mechanism. The rate constants for removal of the first and the second iron(III) ions have different dependences on the edta concentration. This is attributed to different conformations of the ligand involved in the co-ordination of di-and mono-iron(III) complexes. The increase in the rate constants with the acidity of the medium probably results from changes in conformation and the degree of co-ordination of the complexes. The results are compared with published studies for iron release from transferrins.