A. Pellerito

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 : 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: 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.