Lorenzo Pellerito

An in vitro comparative assessment with a series of new triphenyltin(IV) 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with anticancer activities: Structural modifications, analysis of efficacy and cytotoxicity involving human tumor cell lines

Four new triphenyltin(IV) complexes of composition Ph(3)SnLH (where LH=2-/4-[(E)-2-(aryl)-1-diazenyl]benzoate) (1-4) were synthesized and characterized by spectroscopic (((1))H, ((13))C and ((119))Sn NMR, IR, ((119))Sn Mössbauer) techniques in combination with elemental analysis. The ((119))Sn NMR spectroscopic data indicate a tetrahedral coordination geometry in non-coordinating solvents. The crystal structures of three complexes, Ph(3)SnL((1))H (1), Ph(3)SnL((3))H (3), Ph(3)SnL((4))H (4), were determined. All display an essentially tetrahedral geometry with angles ranging from 93.50(8) to 124.5(2)°; ((119))Sn Mössbauer spectral data support this assignment. The cytotoxicity studies were performed with complexes 1-4, along with a previously reported complex (5) in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with the results from other related triphenyltin(IV) complexes (6-7) and tributyltin(IV) complexes (8-11) having 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates framework. In general, the complexes exhibit stronger cytotoxic activity. The results obtained for 1-3 are also comparable to those of its o-analogs i.e. 4-7, except 5, but the advantage is the former set of complexes demonstrated two folds more cytotoxic activity for the cell line MCF-7 with ID(50) values in the range 41-53 ng/ml. Undoubtedly, the cytotoxic results of complexes 1-3 are far superior to CDDP, 5-FU and ETO, and related tributyltin(IV) complexes 8-11. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of triphenyltin(IV) complexes 1-7 and tributyltin(IV) complexes 8-11 is also discussed against a panel of human tumor cell lines.

Dibutyltin(IV) complexes containing arylazobenzoate ligands: chemistry, in vitro cytotoxic effects on human tumor cell lines and mode of interaction with some enzymes

SummaryDibutyltin(IV) complexes of composition Bu2Sn(LH)2, where LH is a carboxylate residue derived from 2-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L1H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L2H) (2) and 4-[(E)-(4-hydroxy-5-methylphenyl)diazenyl]benzoate (L3H) (3), were synthesized and characterized by spectroscopic (1H, 13C and 119Sn NMR, IR, 119Sn Mössbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer.

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.

Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: A novel and potential approach to cancer therapy

Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta-coordination, as a consequence of a long range O···Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate.

Solution structure of R2Sn(IV)-β-N-acetyl-neuraminate (R = Me, Bu) complexes in D2O and DMSO-d6: Experimental NMR and DFT computational study

Two diorganotin(IV)–NANA complexes (NANA (1) = β-N-acetyl-Neuraminic Acid = 5-amino-3,5-dideoxy-D-glycero-β-D-galactononulosic acid) with formula Me2Sn(IV)NANA (2) and Bu2Sn(IV)NANA (3) were synthesized and characterized by 1H, 13C and 119Sn NMR spectroscopy, both in D2O and DMSO-d6 solutions. The experimental data in DMSO suggested the monosaccharide bidentate chelation via O1 carboxylate and vicinal O2 alkoxide atoms, which, in D2O, can be dynamically extended to a third binding site (O8 atom) of the pendant chain. Coordination at the tin atom is discussed on the basis of experimental NMR data and DFT calculation.

Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine] manganese(III)chloride

In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu2Sn)2TPPS and (Bu3Sn)4TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [meso-Tetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me2Sn)2MnTPPS, (Bu2Sn)2MnTPPS, (Me3Sn)4MnTPPS and (Bu3Sn)4MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu2Sn)2MnTPPS and (Bu3Sn)4MnTPPS were highly cytotoxic by inducing apoptosis in melanoma cells, as shown by DNA fragmentation analysis and by apoptotic nuclei fluorescence, and when used at lower concentrations, they affected only cellular proliferation. An arrest of cell proliferation was also observed with (Me3Sn)4MnTPPS, but at the highest concentrations used. Moreover, the lower concentration of (Bu3Sn)4MnTPPS induced a change in cell morphology, from a polygonal to an elongated and spindle-shaped phenotype, likewise to its cognate (Bu3Sn)4TPPS, previously tested. Western blotting analysis showed indeed that both tributyltin compounds, i.e. (Bu3Sn)4MnTPPS and (Bu3Sn)4TPPS, lowered levels of the major proteins involved in tumorigenesis: ß-catenin, c-myc and snail. We also demonstrated that all compounds entered the cells and localized in the nuclei. In conclusion, our results show that, in spite of the Mn(III) metal introduction, the butyl derivatives always have a higher efficacy than methyl derivatives, and the tributyltin compounds in particular have an interesting effect in vitro on A375 cell proliferation.