Tiziana Fiore

Organometallic complexes with biological molecules. X: dialkyltin(IV) and trialkyltin(IV) orotates: spectroscopic and in vivo investigations

Several novel diorgano- and triorgano-tin(IV) derivatives of orotic acid, (2,6-dihydroxypyrimidine-4-carboxylic acid; H 3 or) have been synthesized. In the diorganotin(IV) derivatives, the orotic acid behaved either as a monoanionic or as a dianionic ligand, yielding R 2 Sn(H 2 or) 2 and R 2 SnHor (R = Me, Bu) species, respectively, while in the triorganotin(IV) orotates only monodeprotonation of the orotic acid occurred, giving R 3 SnH 2 or (R = Me, Bu) derivatives. Structural hypotheses are proposed and discussed for the solid state based on Mossbauer and IR spectroscopic data, and for solution on 1 H and 1 C NMR results. Finally, investigations have been carried out in vivo, showing the inhibitor properties of all of the newly synthesized derivatives towards Ciona intestinalis embryos. In particular, in order to test the cytotoxicity in vivo of Me 2 SnHor, Bu 2 SnHor, Me 3 SnH 2 or and Bu 3 SnH 2 or, exposure to these chemicals of C. intestinalis embryos at the 2-4-blastomere stage has been studied. The compound which exerts the highest cytotoxic effect is Bu 3 SnH 2 or at 10 5 M concentration because it blocks embryo development immediately. Me 3 SnH 2 or at 10 -5 M concentration inhibits cell cleavage in the embryos at the 32-blastomere stage, while Bu 2 SnHor at the same concentration gives rise to abnormal embryos. Me 2 SnHor, is less toxic than the trimethyl, dibutyl and tributyl analogues, since 40% of the total number of treated embryos resulted in normal larvae. The ligand does not affect embryonic development significantly. The results seem to indicate that the chemical species under investigation, especially Bu 3 Sn-H 2 or, interfere with polymerization of tubulin during the process of cell division in early embryo development.

Organometallic complexes with biological molecules. XI. Solid state and in vivo investigations of some diorganotin(IV)-chloramphenicol and cycloserine derivatives

Abstract Diorganotin(IV) derivatives of chloramphenicol, {=D-(-)threo-2,2-dichloro-N-[ β -hydroxy- α -(hydroxymethyl)- β -(4-nitrophenyl)ethyl]acetamide (=Hchloramph)}, and D-cycloserine, {=(R)-4-amino-3-isoxazolidone [=Hcyclos]} have been prepared. The stoichiometries of the obtained compounds were R 2 SnClantib and R 2 Snantib 2 (antib −1 =chloramph −1 , R=methyl and phenyl; antib −1 =cyclos −1 , R=methyl). The solid state configuration of the complexes was investigated by I.R. and Mossbauer spectroscopy, from which structural hypotheses were inferred. In particular, the experimental data suggested monomer structures both for R 2 Sn(IV)Clchloramph and R 2 Sn(IV)chloramph 2 , in which chloramphenicolate anion behaved as monoanionic monodentate ligand through the oxygen atom of the deprotonated secondary alcoholic group, with formation of tetrahedral R 2 SnOCl and R 2 SnO 2 environments. In R 2 Sn(IV)Clcyclos and R 2 Sn(IV)cyclos 2 derivatives, Mossbauer spectroscopy, and in particular the narrowness of the full width at half height of the resonant peaks, Γ 1 and Γ 2 , suggested the occurrence of two different absorbing tin sites with different environments around the tin(IV) atoms. According to calculations performed by applying the point charge model formalism, one site was constituted by a tin(IV) tetrahedrically coordinated by monoanionic monodentate cycloserinate groups, through the oxygen atom of the resonance stabilised hydroxamate anion, originating R 2 SnClO and R 2 SnO 2 polyhedrons both in R 2 Sn(IV)Clcyclos and R 2 Sn(IV)cyclos 2 , respectively. The second site would correspond to a tin(IV) in a polymeric octahedral configuration with Me 2 SnCl 2 ON and Me 2 SnO 2 N 2 environments, in Me 2 Sn(IV)Clcyclos and Me 2 Sn(IV)cyclos 2 derivatives, respectively, in which the second donor atoms was the amino nitrogen atom. 1 H and 13 C NMR spectra, of both chloramphenicol and its diorganotin(IV) derivatives were carried in DMSO-d 6 solution, in which R 2 Sn(IV)Clchloramph and R 2 Sn(IV)chloramph 2 underwent total, (R=Me), or partial, (R=Ph), dissociation. As far as the organotin(IV)-D-cycloserine derivatives were concerned, 1 H and 13 C NMR spectra, also carried out for the free D-cycloserine, showed that, owing to the coordinating properties of the solvent, octahedral and trigonal bipyramidal isomers were present in DMSO solution of Me 2 Sn(IV)Clcyclos and Me 2 Sn(IV)cyclos 2 . Finally, the cytotoxic activity of the free chloramphenicol, D-cycloserine and of their dimethyltin(IV) derivatives has been investigated towards Ciona intestinalis and Ascidia malaca fertilised eggs, at different developing stages.

Supramolecular Assemblies Based on Complexes of Nonionic Amphiphilic Cyclodextrins and a meso-Tetra(4-sulfonatophenyl)porphine Tributyltin(IV) Derivative: Potential Nanotherapeutics against Melanoma

Amphiphilic cyclodextrin (ACyD) provides water-soluble and adaptable nanovectors by modulating the balance between the hydrophobic and hydrophilic chains at both CyD sides. This work aimed to design nanoassemblies based on nonionic and hydrophilic ACyD (SC6OH) for the delivery of a poor-water-soluble organotin(IV)-porphyrin derivative [(Bu3Sn)4TPPS] to melanoma cancer cells. To characterize the porphyrin derivatives under simulated physiological conditions, a speciation was performed using complementary techniques. In aqueous solution (≤ 20 μM), (Bu3Sn)4TPPS primarily exists as a monomer (2 in Figure 1), as suggested by the low static anisotropy (ρ ≈ 0.02) with a negligible formation of porphyrin supramolecular aggregates. MALDI-TOF spectra indicate the presence of moieties (i.e., [(Bu3Sn)3TPPS](-)) that are derivatives of the monomeric species. Spectrofluorimetry coupled with potentiometric measurements primarily assesses the presence of the hydrolytic [(Bu3Sn)4TPPS (OH)4](4-) species under physiological conditions. Nanoassemblies of (Bu3Sn)4TPPS/SC6OH were prepared by dispersion of organic films in PBS at pH 7.4 and were investigated using a combination of spectroscopic and morphological techniques. The UV-vis and emission fluorescence spectra of the (Bu3Sn)4TPPS/SC6OH reveal shifts in the peculiar bands of the organotin(IV)-porphyrin derivative due to its interaction with the ACyD supramolecular assemblies in aqueous solution. The mean size was within the range of 100-120 nm. The ξ-potential was negative (-16 mV) for the (Bu3Sn)4TPPS/SC6OH nanoassemblies, with an entrapment efficiency of approximately 67%. The intracellular delivery, cytotoxicity, nuclear morphology and cell growth kinetics were evaluated via fluorescence microscopy on A375 human melanoma cells. The delivery of (Bu3Sn)4TPPS by ACyD with respect to free (Bu3Sn)4TPPS increases the internalization efficiency and cytotoxicity to induce apoptotic cell death and, at lower concentrations, changes the cellular morphology and prevents cell proliferation.

Organometallic complexes with biological molecules : IX. Diorgano- and triorgano-tin(IV)[meso-tetra(4-sulfonatophenyl)porphinate] derivatives : Solid-state and solution-phase structural aspects and in vivo effects

Diorgano- and triorgano-tin(IV) derivatives of meso-tetra(4-sulfonatophenyl)porphine (H4TPPS) with general formula (R2Sn)2TPPS and (R3Sn)4TPPS (TPPS4−=[meso-tetra(4-sulfonatophenyl)porphinate]4−, R=Me, Bu, Ph) have been obtained and their solid-state configuration inferred on the basis of IR and Mossbauer spectroscopy, while solution-phase studies have been carried out by 1H and 13C NMR in DMSO-d6, together with determination of the in vivo cytotoxicity of the new derivatives towards embryonic development of Ciona intestinalis. In particular, octahedral and trigonal-bipyramidal eq-R3Sn polymeric configurations are proposed, in the solid state, respectively for (R2Sn)2TPPS and (R3Sn)4TPPS complexes, with the arylsulfonate groups behaving as monoanionic bidentate bridging ligands. The 1H and 13C NMR data lead to the conclusion that the metal-to-ligand ratio (2:1 or 4:1), binding site (the sulfonato-group oxygens), and the coordination polyhedron around the metal (trans-octahedral or trigonal-bipyramidal) found in the solid state are preserved in solution.

Organometallic complexes with biological molecules: VII. Dialkyl- and trialkyl-tin (IV)[meso-tetra(4-carboxyphenyl)porphinate] derivatives : Solid-state, solution-phase structural aspects and in vivo effects

The synthesis, the structural features and the in vivo biological activity of diorganotin(IV) and triorganotin(IV) derivatives of [meso-tetra(4-carboxyphenyl)porphine] (H 4 TPPC) are reported. Derivatives with general formula (R 2 Sn) 2 TPPC and (R 3 Sn) 4 TPPC (R=Me, Bu, and Ph) were obtained, and the main information extracted from the infrared and Mossbauer spectral data, in the solid state, was in favor of the occurrence of five-coordinated tin(IV) atoms, in a polymeric trigonal-bipyramidal configuration, attained through two differently coordinated, estertype and chelating respectively, carboxylate anions in [R 2 Sn] 2 TPPC, while in [Alk 3 Sn] 4 TPPC five-coordination of the tin(IV) atom is reached through bridging carboxylate groups. 1 H and 13 C NMR spectra, in DMSO-d 6 or CDCl 3 suggested that the soluble derivatives, at room temperature or at 342K, were present in solution as simple monomers. The interactions of (trimethyltin) 4 [meso-tetra(4-carboxyphenyl)porphinate] (TMTPPC) and (tributyltin)4[mesa-tetra(4-carboxyphenyl)porphinate] (TBTPPC) with Bluescript KS(+) plasmid and cultured 3T3 fibroblasts were studied. Both compounds have a clear inhibitory effect on the growth of cultured mouse embryonal fibroblasts (NIH-3T3), TBTPPC being much more active. No evidence was found, however, for DNA cleavage by the compounds at molar ratios as high as 1:10 (TMTPPC, TBTPPC/DNA base pairs). According toour observations, the cytotoxicity of TBTPPC and TMTPPC does not seem to be besed on direct interation with DNA

Organometallic complexes with biological molecules, VI. Diorganotin(IV) and triorganotin(IV) ampicillin and methicillin derivatives : Spectroscopic investigations in the solid state

Derivatives of D(-)-α-aminobenzylpenicillin (ampicillin) and of 2,6-dimethoxyphenylpenicillin (methicillin) with diorgano- and triorgano-tin(IV) moieties have been synthesized. The stoichiometries of the compounds obtained were of the type R 2 SnCIL.H 2 O, R 3 SnCILNa.H 2 O [L=ampicillin or methicillin monoanion; R=Me, Bu, Ph] and R 2 Snampic 2 . 2H 2 O (ampic=ampicillin; R=Me, Bu, Ph). For R 2 SnCIL.H 2 O and R 3 SnCILNa.-H 2 O, infrared (IR) data suggest five-coordination around the tin(IV) atom; in R 2 Snampic 2 .2H 2 O six-coordination is most likely to occur. Thermogravimetric (TG) analysis excludes any involvement in the coordination of tin(IV) by water molecules, in any of the compounds. Trigonal bipyramidal configurations in the solid state are proposed for both R 2 SnCIL.H 2 O and R 3 SnCILNa.H 2 O (L=ampicillin or methicillin) on the basis of the above-mentioned IR and Mossbauer data. As far as R 2 Snampic 2 .2H 2 O compounds are concerned, the coordination geometry at tin could be, as previously reported for analogous R 2 Snamox 2 .2H 2 O derivatives, skew-trapezoidal bipyramidal, the monoanionic bidentate chelating ampicillin residue being in the trapezoidal plane and having bent axial organic groups. Electronegativity equalization procedures have been applied to idealized trigonal bipyramidal structures for R 2 SnCIL.H 2 O and R 3 SnCILNa.H 2 O (L=ampicillin or methicillin) and to octahedral trans-R 2 for R 2 Snampic 2 .2H 2 O, to estimate the partial atomic charges on the tin atoms, Q Sn , which have been correlated with the isomer shift (6) Mossbauer parameter

Organometallic Complexes with Biological Molecules. XIV. Biological Activity of Dialkyl and Trialkyltin(IV) (Meso-tetra(4-carboxy- phenyl)porphinate) Derivatives

Molecules. XIV. Biological Activity of Dialkyl and Trialkyltin(IV) [Meso-tetra(4-carboxyphenyl)porphinate] Derivatives C. Mansueto, E. Puccia, F. Maggio, R. Di Stefano, T. Fiore, C. Pellerito, F. Triolo and L. Pellerito* Dipartimento di Biologia Animale, Universita di Palermo, Via Archirafi 18, 90123 Palermo, Italy Dipartimento di Chimica Inorganica, Universita di Palermo, Viale delle Scienze, Parco d’Orleans, 90128 Palermo, Italy

Diorganotin(IV) N-acetyl-L-cysteinate complexes: Synthesis, solid state, solution phase, DFT and biological investigations

Diorganotin(IV) complexes of N-acetyl-L-cysteine (H(2)NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. FTIR results suggested that in R(2)Sn(IV)NAC (R = Me, Bu, Ph) complexes NAC(2-) behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through ester-type carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From (119)Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R(2)Sn(IV) trigonal bipyramidal configuration. In DMSO-d(6) solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu(2)SnCl(2) and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu(2)SnCl(2), suggesting that the binding with NAC(2-) modulates the marked cytotoxic activity exerted by Bu(2)SnCl(2). Therefore, these novel butyl derivatives could represent a new class of anticancer drugs.

Organometallic Complexes with Biological Molecules: VIII. Synthesis, Solid State and in vivo Investigation of Triorganotin(IV) Derivatives of l-Homocysteic Acid

Several new triorganotin(IV) derivatives of L-homocysteic acid (L-HCAH) with formula R3Sn(L-HCA) (R=Me, nBu, Ph) have been synthesized. Their solid-state configurations were determined by IR and Mossbauer spectroscopy. The tin(IV) atom is five-coordinated in all the complexes, with the L-homocysteic acid behaving as a monoanionic bidentate ligand coordinating the tin(IV) atom through a chelating or bridging carboxylate group. The sulfonate (SO3−) and NH3+ groups of L-homocysteic acid maintain their free acid configuration and hence do not participate to the coordination of the tin(IV) atom. Coordination hypotheses have been checked through the correlation between the Mossbauer parameter isomer shift, δ, and partial atomic charge on the tin atoms, QSn, performed, for all the new organotin(IV) compounds, on the basis of an equalization procedure applied to idealized trigonal-bipyramidal structures for R3Sn(L-HCA). 1H and 13C NMR spectra of the complexes show that pentacoordination of the tin atom, with R groups in the equatorial plane of a trigonal bipyramid, is retained in DMSO solution. The NMR data confirm also that the uncoordinated NH3+ group of the ligand is still present in solution. Results gathered after exposure of two- to four-cell embryos of the sea urchin Paracentrotus lividus (Echinodermata) to the triorganotin(IV) L-homocysteate derivatives as well as to the parent triorganotin(IV) chlorides document cytotoxicity of the complexes, while free L-homocysteic acid exerts no significant toxic activity. The trimethyltin(IV) L-homocysteate derivative seems to exert a lower cytotoxicity than the tributyl- and triphenyl-tin(IV) ones. Different structural lesions have been identified by comparative analysis of mitotic chromosomes from untreated embryos (negative controls) and embryos treated with triorganotin(IV) L-homocysteate derivatives, such as (1) suppression of the stretch among sister chromatids at the beginning of anaphase stage; (2) deeply stained zones mainly located at the telomeric regions of chromosomes; (3) arm breakages; and (4) chromosome bridges among daughter chromosomes at anaphase stage. A colchicine-like effect of triorganotin(IV) L-homocysteate derivatives was observed.

Organometallic complexes with biological molecules: XII. Solid‐state and solution studies on dialkyltin(IV)– and trialkyltin(IV)–thiaminepyrophosphate derivatives

Dialkyltin(IV) and trialkyltin(IV) derivatives of the coenzyme thiaminepyrophosphate (H2TPP) have been synthesized with general formula R2Sn(HTPP)2·nH2O (Alk = Me, n = 2; Alk = Bu, n = 4) and R3SnHTPP·nH2O (R=Me, n = 2; R = Bu, n = 1), respectively. The solid-state structure of the complexes has been investigated through infrared and Mossbauer spectroscopy. The infrared data suggest the involvement of only phosphate oxygen atoms in the coordination of both dialkyl- and trialkyl-tin(IV) moieties, with phosphate anions behaving as monoanionic bidentate bridging or chelating groups, with the tin(IV) involved in six- and five-fold coordination geometries, respectively, in R2Sn(HTPP)2·nH2O (R = Me, n = 2; R = Bu, n = 4) and R3SnHTPP·nH2O (R = Me, n = 2; R = Bu, n = 1). The 119Sn Mossbauer data, and in particular rationalization of the experimental nuclear quadrupole splittings, Δ, through the point-charge model formalism, suggests the occurrence of an octahedral trans-R2 structure in R2Sn(HTPP)2·nH2O (R = Me, n = 2; R = Bu, n = 4) and a trigonal-bipyramidal structure in R3SnHTPP·nH2O (R = Me, n = 2; R = Bu, n = 1). 1H and 13C NMR spectra, in D2O, suggested that the soluble derivatives, at room temperature, in solution, maintained the solid-state structure. The interactions of dibutyltin(IV)–thiaminepyrophosphate (DBTPP) and tributyltin(IV)–thiaminepyrophosphate (TBTPP) complexes with Bluescript KS(+) plasmid and immortalized 3T3 fibroblasts were studied. Both compounds have a clear inhibitory effect on the growth of immortalized mouse embryonal fibroblasts (NIH-3T3), TBTPP being the much more active. No evidence was found, however, for DNA cleavage by the compounds at molar ratios as high as 1:10 (DBTPP, TBTPP/DNA base pairs). According to our observations, the cytotoxicity of TBTPP does not seem to be based on direct interaction with DNA, but in the presence of TBTPP (1:10, TBTPP/DNA bp), plasmid DNA seems to be more susceptible to cleavage by UV. Copyright