Arturo Silvestri

Structure validation of natural products by quantum-mechanical GIAO calculations of 13C NMR chemical shifts.

Geometry optimization and GIAO (gauge including atomic orbitals) (13)C NMR chemical shift calculations at Hartree-Fock level, using the 6-31G(d) basis set, are proposed as a tool to be applied in the structural characterization of new organic compounds, thus providing useful support in the interpretation of experimental NMR data. Parameters related to linear correlation plots of computed versus experimental (13)C NMR chemical shifts for fourteen low-polar natural products, containing 10-20 carbon atoms, were employed to assess the reliability of the proposed structures. A comparison with the hybrid B3LYP method was carried out to evaluate electron correlation contributions to the calculation of (13)C NMR chemical shifts and, eventually, to extend the applicability of such computational methods to the interpretation of NMR spectra in apolar solutions. The method was tested by studying three examples of revised structure assignments, analyzing how the theoretical (13)C chemical shifts of both correct and incorrect structures matched the experimental data.

Determination of the relative stereochemistry of flexible organic compounds by Ab initio methods: conformational analysis and Boltzmann-averaged GIAO 13C NMR chemical shifts.

Ab initio calculations at the Hartree-Fock level with full-geometry optimization using the 6-31G(d) basis set, and GIAO (gauge including atomic orbitals) (13)C NMR chemical shifts, are presented here as a support in the study of the stereochemistry of low-polar organic compounds having an open-chain structure. Four linear stereoisomers, fragments of a natural product previously characterized by experimental (13)C NMR spectra, which possesses three stereogenic centers, 11 carbon atoms, and 38 atoms in total, were considered. Conformational searches, by empirical force-field molecular dynamics, pointed out the existence of 8-13 relevant conformers per stereoisomer. Thermochemical calculations at the ab initio level in the harmonic approximation of the vibrational modes, allowed the evaluation, at 298.15 K, of the standard Gibbs free energy of the conformers. The (13)C NMR chemical shift of a given carbon atom in each stereoisomer was considered as the average chemical shift value of the same atom in the different conformers. The averages were obtained by the Boltzmann distribution, using the relative standard free energies as weighting factors. Computed parameters related to linear correlation plots of experimental (13)C chemical shifts versus the corresponding computed average data allowed us to distinguish among the four stereoisomers.

The antitumor activity of di-n-butyltin(IV) glycylglycinate, and the correlation with the structure of dialkyltin(IV) glycylglycinates in solution

The in vivo activity of Bu2nSnGlyGly, Na(Cl2GaGlyGly), and ClGaGlyGly (GlyGly2- = glycylglycinate) has been investigated in connection with a number of tumors. Positive results have been obtained only for the Bu2nSnIV complex in the case of leukemia P-388. In order to try to interpret the pharmacological data on a molecular basis, the nature of the species present in solutions of AlK2Sn GlyGly complexes, as well as the reactivity of aqueous Me2SnGlyGly, have been studied. The presence of chelated species (I), Figure 1, in organic solvents, and the equilibrium (I) in equilibrium (II), Figure 1, in water and mixed water-organic solvent systems, have been inferred from conductance measurements, as well as from studies by Mössbauer (in frozen solution), 1H, 13C, and 119Sn NMR, and ir spectroscopy. Moreover, solvated (II) would release AlK2SnIV moieties, as evidenced by the slow formation of (Me2SnO)n from aqueous Me2Sn GlyGly. The involvement of (I) and (II) in the transportation of these drugs across cell membranes is discussed.

Spectroscopic study of the interaction of NiII-5-triethyl ammonium methyl salicylidene ortho-phenylendiiminate with native DNA

The interaction of native calf thymus DNA with the cationic Ni(II) complex of 5-triethyl ammonium methyl salicylidene ortho-phenylendiimine (NiL(2+)), in 1mM Tris-HCl aqueous solutions at neutral pH, has been monitored as a function of the metal complex-DNA molar ratio by UV absorption spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy. The dramatic modification of the DNA CD spectrum, the appearance of a broad induced CD band in the range 350-400nm, the strong increase of the DNA melting temperature (T(m)) and the fluorescence quenching of ethidium bromide-DNA solutions, in the presence of increasing amounts of the NiL(2+) metal complex, support the existence of a tight intercalative interaction of NiL(2+) with DNA, analogous to that recently reported for both ZnL(2+) and CuL(2+). The intrinsic binding constant (K(b)) and the interaction stoichiometry (s), determined by UV spectrophotometric titration, are equal to 4.3x10(6)M(-1) and 1.0 base pair per metal complex, respectively. Interestingly, the value of K(b) is slightly higher and 10 times higher than that relative to the CuL(2+)-DNA and the ZnL(2+)-DNA systems, respectively. Speculations can be performed to rationalize the observed trend, on the basis of the electronic and geometrical structures of the three complexes of the same ligand. Analogously to what previously observed for CuL(2+), the shape of the CD of the NiL(2+)-DNA system at NiL(2+)-DNA molar ratios higher than 0.5 is indicative of the formation of supramolecular aggregates in solutions, as a possible consequence of the electrostatic interaction between the cationic complex and the negatively charged phosphate groups of DNA.

The interaction of native DNA with dimethyltin(IV) species.

The reaction of aqueous native DNA (calf thymus) with the solvated organotin(IV) species [(CH3)2SnCl2(C2H5OH)n], as well as with [(CH3)2Sn(OH)(H2O)n]+ and (CH3)2Sn(OH)2 (i.e., the hydrolysis products of aqueous (CH3)2SnCl2 at pH approximately 5 and pH approximately 7.4 respectively), was investigated by 119Sn Mössbauer spectroscopy. The addition of [(CH3)2SnCl2(C2H5OH)n] to DNA yielded a solid product, possibly (CH3)2Sn(DNA phosphodiester)2, where the environment of the tin atom is trans-octahedral with linear CSnC skeleton, and the equatorial atoms may consist of oxygen or nitrogen from water as well as from the nucleic acid constituents. No interaction with DNA apparently takes place due to hydrolyzed dimethyltin(IV) species, which occur in aqueous phases at approximate physiological pH values. The reaction pathway is then assumed to require weakly solvated, easily dissociable species such as [(CH3)2SnCl2(C2H5OH)n], which would imply in vivo reactivity of cellular DNA with organotins from hydrophobic sites.

Intercalation of daunomycin into stacked DNA base pairs. DFT study of an anticancer drug.

Abstract We have computationally studied the intercalation of the antitumor drug daunomycin into six stacks of Watson-Crick DNA base pairs i.e., AT-AT, AT-TA, GC-AT, CG-TA, GC-GC, GC-CG) using density functional theory (DFT). The proton affinity of the DNA intercalater daunomycin in water was computed to be 159.2 kcal/mol at BP86/TZ2P, which is in line with the experimental observation that daunomycin is protonated under physiological conditions. The intercalation interaction of protonated daunomycin with two stacked DNA base pairs was studied through a hybrid approach in which intercalation is treated at LDA/TZP while the molecular structure of daunomycin and hydrogen-bonded Watson-Crick pairs is computed at BP86/TZ2P We find that the affinity of the drug for the six considered base pair dimers decreases in the order AT-AT > AT-TA > GC-AT > GC-TA > GC-CG > GC-GC, in excellent agreement with experimental data on the thermodynamics of the interaction between daunomycin and synthetic polynucleotides in aqueous solution. Our analyses show that the overall stability of the intercalation complexes comes mainly from π-π stacking but an important contribution to the computed and experimentally observed sequence specificity comes from hydrogen bonding between daunomycin and hetero atoms in the minor groove of AT base pairs.

Mono-organotin(IV) and tin(IV) derivatives of 2-mercaptopyridine and 2-mercaptopyrimidine: X-ray structures of methyl-tris(2-pyridinethiolato)tin(IV) and phenyl-tris(2-pyridinethiolato)tin(IV)·1.5CHCl3

Mono-organotin(IV) and tin(IV) derivatives of 2-mercaptopyridine (HSPy) and 2-mercaptopyrimidine (HSPym), RSnL 3 (R=Me, n-Bu, Ph; L=SPy, SPym; R=Bz=benzyl, o-CIBz, oClC 6 H 4 , p-ClC 6 H 4 , o-tolyl, p-tolyl; L=SPy), RSnCIL 2 (R=Me, n-Bu, Ph; L=SPy, SPym), RSnCI 2 L (R=Me, n-Bu; L=SPy, SPym) and SnCI 4-n L n (L=SPy, SPym; n=2,4) were obtained from RSnCI 3 or SnCI 4 and NaL or by neutralization (R=Ph,p-tolyl; L=SPy, SPym). RSnCIL 2 and RSnCI 2 L were better prepared by comproportionation of RSnCI 3 and RSnL 3 . MeSn(Spy) 3 and PhSn(SPy) 3 .1.5CHCI 3 crystals, as determined by single-crystal X-ray diffraction, are monoclinic. In the discrete monomeric RSn(SPy) 3 units, three bidentate SPy ligands together with R form a distorted pentagonal bipyramid around tin. One S and the C(R) atom are in the axial positions. Two S atoms and three N atoms form the pentagonal plane. From 119 Sn Mossbauer and IR data, analogous structures are inferred for the other solid RSnL 3 compounds, except for R=Bz, o-CIBz, o-CIC 6 H 4 and o-tolyl, in which tin would be hexacoordinated. In the compounds RSnCIL 2 and RSnCI 2 L, tin is at the center of an octahedron or a trigonal bipyramid, respectively. For Sn(SPym) 4 and SnCI 2 (SPym) 2 , the same type of octahedral structure as was previously found for Sn(Spy) 4 .HSPy and SnCI 2 (Spy) 2 is proposed. According to IR and 1 H, 13 C and 119 Sn NMR data, the solid-state molecular structures are retained in chloroform and dimethyl sulfoxide solution.

Dynamics of tin nuclei in alkyltin(IV)–deoxyribonucleic acid condensates by variable-temperature tin-119 Mössbauer spectroscopy

The dynamics of tin nuclei in the condensates SnR2(DNA monomer)2 and SnR3(DNA monomer)(R = Me or Et), freeze-dried, has been investigated by variable-temperature 119Sn Mossbauer spectroscopy. Linear functions In (At/A77.3)(T), In farel,abs(T) and 〈x2〉(T)(At= total area under the resonant peaks, fa the relative and the absolute estimates of Lamb-Mossbauer factors, and 〈x2〈 the mean-square displacements of the Mossbauer nucleus extracted from farel and faabs respectively) have been found at T 77.3 K, which indicate harmonic motions and the lack of phase transitions. The latter is also suggested by the temperature-invariant hyperfine parameters, isomer shift, nuclear quadrupole splitting (ΔE) and peak widths. From the slopes of the functions In At(T) and In farel(T), the dynamics of tin in alkyltin(IV)–DNA condensates is found to be analogous to that in organotin(IV) salts and complexes, on the assumption of effective vibrating masses, corresponding to molecular groups. The coincidence between farel,abs, as well as the related 〈x2〉, data, indicates that the negative charge on the DNA backbone phosphodiester groups is fully neutralized by alkyltin(IV) cations in SnR2(DNA monomer)2(R = Me or Et) as well as in SnEt3(DNA monomer), while only partially in SnMe3(DNA monomer) and in SnMe2(DNA monomer)2 obtained by standard procedures for DNA condensation. From the magnitude of the functions, as well as of the Debye temperatures, on fingerprint criteria, SnIVR2 moieties are assumed to bridge phosphodiester groups in toroidal condensates through interstrand bonding, while SnIVR3 would be appended to the double helix. Motions would involve SnR2(mononucleotide)2 and SnR3(mononucleotide) units as the effective vibrating masses. Two tin co-ordination sites occur for SnIVR2 moieties at the DNA surface, both trans-octahedral, and a single trigonal-bipyramidal site for SnIVR3, the organometal moieties being co-ordinated by phosphodiester and water oxygen atoms, according to ΔE rationalization by point-charge model structure simulations, as well as to Mossbauer–Zeeman spectra of the SnIVEt2– and SnIVEt3–DNA condensates.

The hydrolysis of Me2SnIV and Me3SnIV moieties monitored through 119Sn Mössbauer spectroscopy

Abstract The 119 Sn Mossbauer parameters δ, isomer shift, and Δ E , nuclear quadrupole splitting, have been determined in frozen aqueous solutions of Me 2 Sn IV and Me 3 Sn IV moieties at varying pH. The resulting functions n versus pH (where n is the average number of protons released per mole of the organotin aquocation) agree satisfactorily with functions from potentiometry. The structures of the aquocations, as well as of the hydroxides, and of the mono-hydroxo complex [Me 2 Sn(OH)(OH 2 ) n ] + , are correlated to the Δ E exp data by point-charge model calculations.

Synthesis and structural studies by infrared and Mössbauer spectroscopy of adducts of tin(IV) and organotin(IV) derivatives with 2,2′-azopyridine

Abstract A number of complexes have been prepared by the reaction between 2,2′-azopyridine(AZP) and tin(IV) halides and organotin(IV) halides, and characterized by elemental analysis and infrared and variable temperature 119Sn Mossbauer spectroscopies. All of the new compounds have 1:1 stoichiometry, with the AZP ligand occupying two coordination sites by bonding through one of the ring and one of the azo group nitrogen atoms, to give rise to distorted octahedral structures. In the diorganotin complexes the two organic groups occupy trans positions. The infrared and Mossbauer spectroscopic data suggest that these compounds are monomeric in the solid state.