STUDIES ON ORGANOTIN(IV) DERIVATIVES OF AMINO ACIDS AND DIPEPTIDES

Abstract

Oganotins have become a leading commercial organometallic first through their use in polyvinyl chloride) stabilization, and now as biocides. Today organotins are used widely as agricultural fungicides and miticides, industrial biocides and surface disinfectants, and as anthelminthics and marine antifouling agents. Although organotin compounds find many practical applications, their coordination by biological molecules is poorly understood. The enhancement of biological activity and suppression of toxicity by carrying out the complexation of biologically active compounds with metals are the major factors for the recent growing importance of organotin(IV) complexes of amino acids and peptides, as some of these have been found to show antileukemia, bactericidal and fungicidal activities. Organotin(IV) compounds, RnSnX4_n, are toxic to various organisms and are used to a significant extent as biocidal agents in agriculture and technology. Most desirable are the compounds whose biocidal properties are not only due to the organotin(IV) part of the molecule (R4Sn group), but also to the group X, because the effects are mutually combined and complemented. The anions of amino acids in place of the polar group X in organotin(IV) compounds, RnSnX4.n, also have biological importance. Particularly effective R groups in [R3SnX] are Me, Et, n-Pr, n-Bu and Ph. Remarkably, each is effective against different living species, the toxicity decreasing with increase in alkyl-chain length beyond C4. Detailed mechanisms are obscure, but [R3SnX] compounds (which inhibit mitochondrial oxidative phosphorylation) and [R2SnX2] compounds (which inhibit a-ketoacid oxidation) are known to combine with thiol and dithiol groups, respectively, in proteins and enzymes. Amino acids are the bifunctional compounds containing both an amino (i) and a carboxylic acid group. In protein molecules the amino acid residues are covalently linked through peptide bonds. Peptides are of importance in the growth of animal cells in culture, and may influence this either indirectly or by provision of amino acids. Schiff bases are the most important nitrogen donors, and are used as anticancer, antitumour, antitubercular and as analytical agents. Schiff bases in which amino groups are provided by amino acids, and their complexes with metal ions have received a considerable attention due to their possible use as potential N-pyridoxylideneamino acid systems. The pyridoxal (vitamin Bg aldehyde)amino acid Schiff bases are believed to be intermediate in biologically important amination processes. Looking into the wide applications of organotins, and biological relevance of the amino acids, peptides and Schiff bases derived from amino acids, it was thought worthwhile to synthesize and characterize new organotin(IV) complexes of these biologically important ligands, and to study their biological activities. For the sake of convenience the work embodied in the thesis is presented in the following chapters. First chapter of the thesis describes the general introduction and important applications of organotins, amino acids, peptides and Schiff bases. Available literature on organotin(IV) complexes of the amino acids, Schiff bases derived from amino acids and peptides is compiled in the form of a comprehensive review. Second chapter incorporates the details of make, purity and other specifications of materials and equipments used in the present study. The experimental details of antimicrobial, antitumour and antiinflammatory activities of the complexes have also been included. Third chapter concerns with the preparation and characterization of organotin(IV) complexes of amino acids of the general formula RnSnLm (where n = 3, R = Me, n-Bu or Ph and m = 1; n - 2, R - n-Bu or Ph and m = 2, and L = monoanion of L-histidine, DL-tryptophan, DL-methionine, L-asparagine Cm) and L-tyrosine; n - 2, R = n-Bu or Ph and m - 1, L = dianion of DL-aspartic acid and L-glutamic acid). The possible structures of the synthesized complexes have been proposed on the basis of physico-chemical studies, viz. elemental analyses, molar conductance, and electronic, infrared, far-infrared, JH NMR, 13C NMR and Sn Mdssbauer spectral studies. On the basis of spectral studies, a distorted trigonal bipyramidal geometry has been proposed for five-coordinated R3SnL (where L = monoanion of amino acids) and R2SnL (where L = dianion of amino acids) complexes. Whereas, a distorted octahedral geometry with cisorganic groups has been proposed for the six-coordinated R2SnL2 type of complexes. Thermal studies of a few complexes have been carried out in the temperature range 25-1000° C using TG, DTG and DTA techniques. The wei ght loss consideration at main decompositon stages indicates the conversion of the complex to SnO or Sn02. The order of decomposition and other kinetic parameters of triphenyltin histidinate have also been evaluated. In vitro antimicrobial activities of some complexes have been determined against pathogenic bacteria [Streptococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus Penicillin resistance (2500 units)] and fungi (Candida albicans, Cryptococcus neoformans, Sporotrichum schenckii, Trichophyton mentagrophtyes and Aspergillus fumigatus). The tested compounds show good activity in comparison to the parent compounds. Some complexes, which show excellent antifungal activity, have also been screened in vivo against multi-infection fungal (C. albicansvaginal and systemic, C. neo/ormcms-lungs and T. mentagrophytes-skin infection) model in mice. The cytotoxicity of a few compounds has been screened in vitro against seven human tumour cell lines, viz. MCF-7, EVSAT, WiDr, 1GROV, M19 MEL, A498 and H226. The activities found experimentally w^re better than those obtained for cisplatin and carboplatin. (iv) Fourth chapter describes the synthesis and the results of spectroscopic investigations of organotin(IV) complexes of Schiff bases of the general formulae, n-Bu2Sn(ONO) and PhnSnL (where ONO = dianion of tridentate Schiff bases derived from the condensation of 2-hydroxy-l-naphthaldehyde or acetyl acetone with glycine, L-0-alanine, DL-valine, DL-4-aminobutyric acid, lmethionine, L-leucine and phenylglycine; n = 2, L = dianion of tridentate Schiff bases derived from 2-hydroxy-l-naphthaldehyde; n = 3, L = monoanion of Schiff bases derived from benzaldehyde and amino acids, viz. glycine, dla- alanine, DL-valine, 2- aminobutyric acid, L-methionine, D-phenylalanine and L-leucine). A distorted trigonal bipyramidal structure has been proposed for all the five-coordinated organotin(IV) complexes of Schiff bases on the basis of physico-chemical and spectral studies as mentioned in third chapter, including 117Sn NMR spectra of some complexes. SnO or Sn02 has been obtained as an end product in the thermal decomposition of some complexes as revealed by the per cent weight loss and powder X-ray determination of the residue. Mathematical analysis of TGA data of a few n-Bu2Sn(ONO) complexes involving the Coats-Redfern equation, Horowitz-Metzger equation and Fuoss method shows that the first order kinetics is followed. Kinetic parameters, such as the energy and entropy of activation and pre-exponential factor, are also calculated. The synthesized complexes have been tested against pathogenic bacteria and fungi, and a few selected complexes have also been screened against seven human tumour cell lines as mentioned in third chapter. The activities found experimentally were much better than those of the standards. Fifth chapter of the thesis deals with the synthesis and structural features of diorganotin(IV) complexes of the general formula R2SnL (where R = n- Bu or Ph and L = dianion of dipeptides, viz. alanylphenylalanine, phenylalanylleucine, phenylalanylphenylalanine, glycylleucine and glycylisoleucine). A distorted trigonal bipyramidal structure with cis-organic groups has been (v) proposed for all the five-coordinated diorganotin(IV) complexes of dipeptides on the basis of physico-chemical and spectral studies as used in third chapter. The complexes have been tested in vitro against bacteria (Escherichia coli, Rhizobium meliloti, Pseudomonas putida and Aeromonas formicans) and fungi (Asper gillus niger, Penicillium chrysogenum, Aureobasidium pullulans and Verticillium dahliae). The cytotoxicity of a few complexes have been screened against seven human tumour cell lines as used in third chapter. The complexes have shown considerable activity. The LD50 values of some complexes (>500 mgAg) have also been determined in the albino rats. The complexes have also shown remarkable antiinflammatory activity.