ORGANOTIN(IV) DERIVATIVES OF DIPEPTIDES AND NUCLEOTIDES

Abstract

The chemistry of organotin(IV) compounds has emerged as one of the strongest areas in the interdisciplinary organometallic field owing to their wide spectrum of industrial, synthetic and biological applications. Triorganotin(IV) compounds have been found useful as industrial biocides in material protection as an antifouling agent, as surface disinfectants and as agricultural biocides. On the other hand, dialkyltin(IV) compounds have been used as stabilizers for poly(vinyl)chloride and as curing agents for the room temperature "vulcanization" of silicones. Organotin(IV) compounds have also been used as versatile synthetic reagents for various organic transformations and as catalyst for the production of polyurethanes. However, their chemistry has experienced a quantum growth because of their place among potential biologically active metallopharmaceuticals exhibiting antitumour, antimicrobial, anti-inflammatory, antiviral and antituberculosis activities. Their significance from chemotherapeutic point of view has been enhanced further, because of their interactions with some clinically recommended drugs. Furthermore, the speciation of organotin(IV) compounds in biological systems has revealed that their biological activity may be due to the presence of easily hydrolysable groups yielding intermediates such as RnSn(4"n)+ (n = 2 or 3) moieties, which may bind with DNA or proteins. Moreover, they have also been proposed as models for the interaction with the high-affinity site of ATPase and low affinity site of ATPase and haemoglobins. In this wide context, several studies have addressed the interaction of organotin(IV) moieties with biomolecules. However, in order to obtain a better insight into the coordination behaviour of organotin(IV) moieties inside the biological medium, it is necessary to study their interactions with smaller biomolecules, for example, peptides and nucleic acid constituents viz. nucleobase, nucleosides and nucleotides, and hence to formulate the structure-activity correlations to devise new derivatives with potential biological activity. Peptides are the basic building blocks of proteins, characterized by peptide bonding (-C(O)-NH-), and play an important role in their biosynthesis. Several peptide, viz. insulin, secretin, calcitonin, adrenocorticotrophin, prolactin, vasopressin, oxytocin, and glucagon exhibit wide range of physiological functions in the body. Other peptides, (ii) such as penicillin, tyrocidine, actinomycin and cyclosporin, are used as antihypertensive, antibacterial, antitumour, and antiviral agents. Purines and pyrimidines, the nitrogenous bases, along with cyclic, five membered pentose sugar (ribose in RNA and deoxyribose in DNA) and phosphate group combined to form DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). The structure and properties of these biomolecules, serves not only as building blocks of nucleic acid but also play vital role in several biochemical processes such as enzyme synthesis and intermediary metabolism. Organotin(IV) compounds, though having many practical applications, still present considerable scope for the study of their interaction behavior with biomolecules. Peptides and nucleic acid constituents such as nucleobases, nucleosides and nucleotides can bind with metal ions efficiently because of their unique structural feature, therefore, model studies using low molecular weight peptides, e.g. oligopeptides and nucleotide constituents may provide further insight into the metal-protein interactions. In view of the wide range of applications of organotin(IV) compounds, and biological relevance of the peptides and nucleic acid constituents, it was considered significant to synthesize, characterize and study the biological activity of new organotin(IV) complexes of these biologically important ligands. In order to maintain the clarity of the presentation, the work embodied in the thesis is systematically divided into the following chapters. First chapter of the thesis presents the general introduction and an overview of some important applications of organotin(IV) compounds and molecules of biological relevance viz. peptides and nucleotides. A critical and comprehensive review of the available literature on the organotin(IV) complexes of peptides and nucleotides with special reference to their synthetic procedures, structural characterization and biological significance has also been presented. Second chapter incorporates the details of make, purity and other specifications of the materials used in the present study. For the spectroscopic studies viz. multinuclear (iii) magnetic resonance and ll9Sn Mossbauer, of the synthesized organotin(IV) derivatives, the compounds have been sent to various Institutes/Universities in India/abroad. The specifications of the instruments and the details of the procedures used therein have been included. For the anti-inflammatory, cardiovascular activities and toxicity studies of the synthesized complexes, the samples have been sent to LLRM, Medical College, Meerut, India. The detailed methodology used for these studies has also been included. The data obtained for the biological studies have been compiled and discussed in Chapters 3, 4, 5 and 6. Third chapter includes the synthesis, characterization and structure-activity relationship of some new diorganotin(IV) derivatives of the general formulae R2Sn(L), where R is Me, «-Bu, «-Oct and Ph, and L is dianion of histidinylalanine (H2His-Ala), histidinylleucine (H2His-Leu), tryptophanylglycine (H2Trp-Gly) and tyrosinylphenylalanine (H2Tyr-Phe). The probable structures of the synthesized derivatives have been discussed on the basis of elemental analysis, infrared, multinuclear NMR and 119Sn Mossbauer spectroscopic studies including 2D heteronuclear multiple bond correlation (HMBC) NMR studies. On the basis of spectral studies, a distorted trigonal-bipyramidal structure for the diorganotin(IV) derivatives, in which ligands are dianion tridentate coordinating through Namino, C(0)0^carboXyi and Npeptide, has been proposed. Single crystal X-ray structures of «-Bu2Sn(Trp-Gly) and Me2Sn(Tyr-Phe).MeOH are also discussed which further confirms the proposed distorted trigonal-bipyramidal configuration with the organic groups of the organotin(IV) moiety and peptide nitrogen are lying in equatorial position, and the amino nitrogen and carboxylic oxygen atoms are axially placed. Molecular packing of «-Bu2Sn(Trp-Gly) and Me2Sn(Tyr-Phe).MeOH shows some intermolecular hydrogen bonding interactions. The data obtained for the in vivo anti-inflammatory activity (% inhibition), toxicity (LD50 in mg/kg) and cardiovascular activity of the synthesized derivatives have been compiled and discussed in order to formulate the structure-activity correlation. Fourth chapter of the thesis deals with the synthesis and the results of spectroscopic investigations of some new triorganotin(IV) derivatives of dipeptides with (iv) general formula R3Sn(HL), where R is Me, rc-Bu, and Ph, and L is monoanion of histidinylalanine (H2His-Ala), histidinylleucine (H2His-Leu), tryptophanylglycine (H2Trp-Gly) and tyrosinylphenylalanine (H2Tyr-Phe). The bonding and coordination behaviour in these derivatives are discussed on the basis of various physico-chemical studies as mentioned in the third chapter (excluding 2D NMR). These investigations suggest that, a distorted trigonal-bipyramidal structure, in which ligands acts as monoanion bidentate coordinating through Namjno and C(0)0_carboxyi group, has been proposed for all the triorganotin(IV) derivatives. The inter-/intramolecular hydrogen bonding may be responsible for the associated structure and for the low solubility of the derivatives in common organic solvents. The data obtained for the anti-inflammatory and cardiovascular activities, and toxicity of the synthesized triorganotin(IV) derivatives are also discussed. Fifth chapter enumerates the synthesis and characterization of three diorganotin(IV) derivatives of guanine with general formula R2Sn(Gu)2, where R is Me, >7-Bu, and Ph, and Gu is monoanion of guanine. The bonding and coordination behaviour in the synthesized derivatives have been discussed on the basis of elemental analysis, infrared, 'H NMR and 119Sn Mossbauer spectroscopic studies. On the basis of various physico-chemical studies, a distorted trigonal-bipyramidal environment around tin has been observed in which the organic groups and one guanine molecule coordinating through nitrogen (N-9), lie in the equatorial plane whereas one of the axial position is occupied by another guanine coordinating through nitrogen (N-9) and a weak bonding through oxygen of C(6)=0 of the adjacent molecule leads to the axially bridged polymeric structure in the solid state. The results obtained for the anti-inflammatory and cardiovascular activities of all the synthesized diorganotin(IV) derivatives are also discussed. Sixth chapter of the thesis incorporates the synthetic strategies of some new diand triorganotin(IV) derivatives of guanosine (H2GuO) and disodium guanosine 5'- monophosphate Na2(5'-GMP). The characterization of these newly synthesized compounds have been carried out by infrared, far-infrared, multinuclear ( H, C and (v) Sn) NMR and Sn Mossbauer spectral studies. The characterization results indicate that guanosine molecule act as monodentate ligand which interact with the organotin moiety through 0-2' of the hydroxyl group of ribofuranose residue along with the involvement of water molecule. On the other hand, (5'-GMP)2" acts as bidentate ligand and shows its coordination with the organotin(IV) moiety through oxygen of the phosphate group. The structure of these derivatives is polymeric in nature which is responsible for their low solubility in common organic solvents. Also, the involvement of water molecule interaction through hydrogen bonding is evident. The results obtained for the anti-inflammatory, cardiovascular activities and toxicity of the synthesized di- and triorganotin(IV) derivatives are discussed. The interaction of guanosine 5'- monophosphate with MenSn(4n)+ (where n = 2 or 3) cation in aqueous solution at 25 °C and ionic strength of 0.1 mol dm"3 of KN03, have been studied potentiometrically in order to understand the interaction of these nucleic acid constituents with the organotin(IV) moieties, in solution. The various species formed in aqueous solution at different pH have been described with the help of species distribution curves.