Dick de Vos

Synthesis, characterization and in vitro antitumor activity of di- and triorganotin derivatives of polyoxa- and biologically relevant carboxylic acids.

An overview of the development of anti-tumor organotin derivatives, sometimes as active in vitro as doxorubicin, is presented and discussed. Solubility in water is an important issue, dominating the in vivo testing of compounds with promising in vitro properties. Several water-soluble organotin compounds gave the best in vitro activities. Novel, useful organotin anti-tumor compounds should be designed toward improved water solubility.

Synthesis, characterization and in vitro antitumour activity of triphenyl- and tri-n-butyltin benzoates, phenylacetates and cinnamates

Spectroscopic, structural and antitumour properties of triphenyltin and tri-n-butyltin benzoates, phenylacetates and cinnamates are compared with those of their corresponding pentafluorophenyl analogues.

The Development of Novel Organotin Anti-Tumor Drugs: Structure and Activity

An overview of the development of anti-tumor organotin derivatives in selected classes of compounds is presented and discussed. High to very high in vitro activity has been found, sometimes equaling that of doxorubicin. Solubility in water is an important issue, dominating the in vivo testing of compounds with promising in vitro properties. The cytotoxicity of the compounds was increased by the presence of a bulky group, an active substituent or one or more polar substituents. Polar substituents may also improve the water solubility. Although organotin derivatives constitute a separate class of compounds, the comparison with cisplatin is inevitable. Among the observed toxicities, neurotoxicity, known from platinum cytostatics, and gastrointestinal toxicity, typical for many oncology drugs, have been detected. Further research to develop novel, useful organotin anti-tumor compounds should be carried out.

Dibutyltin perfluoroalkanecarboxylates: synthesis, NMR characterization and in vitro antitumour activity

Three dibutyltin perfluoroalkanecarboxylates have been synthesized, characterized by H-1-, C-13-, F-19- and Sn-117-NMR, Mossbauer, IR and mass spectroscopy. The structure of tetra-n-butylbis(trifluoroacetato)distannoxane has been elucidated by X-ray crystallography. The in vitro antitumour activity of the three compounds against seven human tumour cell lines was found to be as high as or even higher than that for reference compounds used clinically

Synthesis and characterization of triphenyl- and tri-n-butyltin pentafluorobenzoates, -phenylacetates and -cinnamates. X-ray structure determination of tri-n-butyltin pentafluorocinnamate

A crystal structure analysis of F5C6CH  CHCOOSnBu3 shows that the compound is polymeric because of the presence of bidentate carboxylate ligands bridging two tin atoms in trans-R3SnO2 arrangement. This results in a five-coordinated trigonal-bipyramidal geometry around the tin atom with two apical oxygen atoms and three equatorial butyl groups. Mossbauer and CP-MAS 117Sn NMR data for triphenyl- and tri-n-butyltin pentafluorobenzoates, -phenylacetates and cinnamates, taking the X-ray structure of F5C6CHCHCOOSnBu3 as a reference, converge to similar polymeric five-coordinated structures in the solid state. In contrast, 13C and 119Sn NMR data in chloroform solution unambiguously indicate tetrahedral four-coordination at tin for all compounds. Failing aromatic 13C chemical shift increments and complex nJ(13C19F) multiplet patterns necessitated recording of 2D 19F13C HMQC spectra in order to fully characterize the new compounds in solution.

In vitro effect of organotin-substituted steroids in human tumor cell lines

Abstract Four steroidal organotin compounds have been prepared and compared in vitro with a parent steroid and two model compounds in a series of human tumor cell lines. The organotin steroids (compounds 1 and 2) showed promising in vitro activity. Another compound with important characteristics in terms of bond angles and stereochemistry (compound 3) was a highly effective antitumor agent. This compound may serve as a model for further investigation on the structure-activity relationship in antitumor organotin compounds.

DI-n-BUTYL-, TRI-n-BUTYL- AND TRIPHENYLTIN STEROIDCARBOXYLATES: SYNTHESIS, NMR CHARACTERIZATION AND IN VITRO ANTITUMOUR ACTIVITY

1 Vrije Universiteit Brüssel, Pleinlaan 2, B-1050 Brussels, Belgium a Department of General and Organic Chemistry, Faculty of Applied Sciences b High Resolution NMR Centre 2 Universite Libre de Bruxelles a Service de Resonance Magnetique, CPI-232, Boulevard du Triomphe, B-1050 Brussels, Belgium b Chimie Organique Physique, Faculte des Sciences, Avenue F. D. Roosevelt, 50, B-1050 Brussels, Belgium 3 Laboratory for Tumor Biology and Pharmacology, Academic Hospital Rotterdam, P. O. Box 2040, NL-3000 CA Rotterdam, the Netherlands 4 Medical Department, Pharmachemie Β. V., Haarlem, the Netherlands 5 Laboratoire de Chimie de la Matiere Condensee, URA CNRS 1466, Tour 54, 5e etage, Universite Pierre et Marie Curie, 4 Place Jussieu, F-75252 Paris Cedex 05 France

Characterisation and in vitro cytotoxicity of triorganophosphinegold(i) 2-mercaptobenzoate complexes.

The preparation and full NMR (1H, 13C and 31P) characterisation of three [R3PAu(2mba)] complexes, Where R = Et, Ph and Cy, and 2mba is the anion derived from 2-mercaptobenzoic acid is reported. An interesting solvent dependence in the 1H spectra is rationalised in terms of competing intra- and inter-molecular hydrogen bonding. An X-ray analysis of the [Ph3 PAu(2mba)] species reveals a linear P—Au—S arrangement and association in the lattice via the familar carboxylic acid dimer motif. The in Vitro cytotoxicity against seven human tumout lines is also described. The complexes display moderate to very high activity. Particularly noteworthy is their greater activity against the H226 cell line (non-small cell lung cancer) compared with that displayed by a range of cytotoxic drugs.

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.

Molecular basis of the interaction of novel tributyltin(IV) 2/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with an improved cytotoxic profile: Synthesis, structure, biological efficacy and QSAR studies

A series of tributyltin(IV) complexes based on 2/4-[(E)-2-(aryl)-1-diazenyl]benzoate ligands was synthesized, wherein the position of the carboxylate and aryl substituents (methyl, tert-butyl and hydroxyl) varies. The complexes, Bu(3)SnL(1-4)H (1-4), have been structurally characterized by elemental analysis and IR, NMR ((1)H, (13)C, and (119)Sn) and (119)Sn Mössbauer spectroscopy. All have a tetrahedral geometry in solution and a trigonal bipyramidal geometry in the solid-state, except for Bu(3)SnL(4)H (4) that was ascertained to have tetrahedral coordination by X-ray crystallography. Cytotoxicity studies were carried out on human tumor cell lines A498 (renal cancer), EVSA-T (mammary cancer), H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19 MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon cancer). Compared to cisplatin, test compounds 1-4 had remarkably good activity, despite the presence of substantial steric bulk due to Sn-Bu ligands. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of organotin(IV) benzoates, along with some reference drug molecules, is also discussed against a panel of human tumor cell lines. Molecular structures of the tributyltin(IV) complexes (1-4) were fully optimized using the PM6 semi-empirical method and docking studies performed with key enzymes associated with the propagation of cancer, namely ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II. The theoretical results are discussed in relation to the mechanistic role of the cytotoxic active test compounds (1-4).