INTERACTION OF ORGANOTIN(IV) COMPOUNDS WITH BIOLOGICALLY IMPORTANT LIGANDS

Abstract

Organotin chemistry has emerged as one of the strongest areas in the interdisciplinary organometallic field because of their diverse industrial, synthetic, catalytic and biological applications. Thelargest single industrial application of a range of di-and monoalkyltin compounds is in the stabilization of poly(vinyl) chloride (PVC). These compounds are versatile synthetic reagents and/or catalysts for either selective reactions or multistep synthesis. Further, several reports have been published during the last ten years on the organotin(IV) compounds with ligands having hetero donor atoms (O, N or S) showing antimicrobial activity against a wide spectrum of pathogenic bacteria and fungi. The most important advancement in the field of organotin(IV) chemistry in the last fifteen years is the emergence of these compounds as potential metallopharmaceuticals among the class of metal-based non-platinum chemotherapeutics. Many organotin(IV) compounds have been tested for their antitumour potential, which include organotin(IV) derivatives ofbiomolecules, such as amino acids, peptides, Schiff bases derived from amino acids, N-substituted amino acids or peptides, DNA fragments, carbohydrates and steroids etc. The chemotherapeutic significance of these compounds has been explored further by studying their interaction with some clinically recommended drugs, for example, antibiotics, antibacterial, antiinflammatory, antihypertensive and sulpha drugs. Amino acids are the basic structural units of the complex molecular structures of the proteins, which constitute a very important class of compounds found in living beings. They play an important role in the biosynthesis of proteins. Amino acids are also metabolized into various bioactive substances such as hormones, purines, pyrimidines, porphyrins, lipids, amino sugars and energy sources. Z-Ascorbic acid (vitamin C) belongs to one of the most important class of biomolecules, known as vitamins. /.-Ascorbic acid has various biochemical functions, for example, collagen synthesis, immune function, drug metabolism, folate metabolism, 00 cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Therefore, its deficiency causes a disease in humans, known as scurvy. Umbelliferone (7-hydroxycoumarin) is a major biotransformed product of coumarin. Coumarin (1, 2-benzopyrone) is a widely distributed natural product with low human toxicity and short half-life (1-1.5 h). It has been suggested that coumarin may be a pro-drug, 7-hydroxycoumarin being the active drug. The pyrimidine bases and nucleosides are nucleic acid constituents, which form basic building blocks ofDNA and RNA. In view of the wide range of applications of organotin(IV) compounds, and biological relevance of the amino acids, vitamin C, coumarins and nucleic acid bases and nucleosides, 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 in 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, amino acids, Z-ascorbic acid, coumarins, pyrimidine bases and nucleosides. A comprehensive review of the available literature on the organotin(IV) complexes of amino acids and nucleic acid constituents, and metal complexes of I-ascorbic acid and coumarins 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. multinucleai NMR and lH-l3C HMBC NMR, and 119Sn Mossbauer, ofthe synthesized organotin(IV) derivatives, the compounds have been sent to various Institutes/ Universities in India/ Abroad. The specifications of the instruments and the procedures used therein have Cii) also been included. The synthesized complexes have been sent to L. L. R. M. Medical College, Meerut (India) for their antiinflammatory, cardiovascular and antimicrobial screening, and toxicity studies. The details of the procedure used for carrying out these studies have also been included. The data obtained for the biological studies have been compiled and discussed in Chapters 3, 4, 5 and 6. The protonation and coordination equilibria were investigated by potentiometric titrations in aqueous medium (Ionic strength, / = 0.1 mol dm"3 KN03 and T = 298 ±0.1 K) using an Orion 960 plus autotitroprocessor equipped with Orion Ross flow combined glass electrode. The experimental data of the potentiometric titrations were sent to the University of Calcutta, Calcutta (India), for the calculation of stability constants using SCOGS program. Third chapter enumerates the synthesis, characterization and biological studies ofsome newtri- and diorganotin(IV) derivatives ofthe general formulae R3Sn(L) (where, R- Me, w-Bu and HL =Z-proline; R=Me, Ph and HL - /rans-hydroxy-Z-proline and Z-glutamine) and R2Sn(L)2 (where,R- w-Bu, Ph and HL - Z-proline, R=Ph, HL = /ra/w-hydroxy-Z-proline). Adetailed interpretation of the coordination modes of these amino acids towards organotin(IV) moieties is discussed on the basis ofinfrared and far-infrared, multinuclear (>H, 13C and 119Sn) NMR and II9Sn Mossbauer spectroscopic studies. Pentacoordinate trigonal-bipyramidal and hexacoordinate octahedral structures, respectively, have been proposed for the tri- and diorganotin(IV) complexes ofZ-proline and /ra«s-hydroxy-Z-proline, in which the carboxylate group acts as bidentate group. Z-Glutamine shows different coordination behaviour towards organotin(IV) compounds, it acts as a monoanionic bidentate ligand coordinating through carboxylate and amino group. The triorganotin(IV) complexes of Z-glutamine have been proposed to have trigonal-bipyramidal environment around tin. The results of antiinflammatory (% inhibition) and cardiovascular activities, and toxicity (LD50 in mg/kg) of some of the synthesized derivatives have been also discussed. Civ) Fourth chapter of the thesis includes the synthesis and characterization of some new tri- and diorganotin(IV) derivatives of the general formulae R3Sn(HAsc) (where, R- Me, „-Pr, »-Bu and Ph) and R2Sn(Asc) (where, R=W-Bu and Ph), and HAsc and Asc are mono- and dianion of Z-ascorbic acid (H2Asc), respectively. The bonding and coordination behaviour in these derivatives are discussed on the basis of UV-Vis, infrared and far-infrared, multinuclear (>H and "Q magnetic resonance and "9Sn Mossbauer spectroscopic studies. These studies suggest that for R3Sn(HAsc) polymeric derivatives, the polyhedron is trigonal-bipyramidal around tin with three organic groups in the equatorial positions. In R2Sn(Asc), z-ascorbic acid acts as dianionic tetradentate ligand, and apolymeric structure with octahedral geometry around tin with trans- organic groups has been tentatively proposed. The results of antiinflammatory and cardiovascular activities ofthese compounds have been discussed. Potentiometric studies have been carried out in aqueous solution in order to understand the interaction of Me3Sn+and Me,Sn> cations with z-ascorbic acid, in solution. The interactions of these cations with H2Asc have been studied in aqueous medium so that these in vitro studies can be correlated with the observed in vivo biological activities of the organotin(IV) derivatives of Z-ascorbic acid, which have been characterized in the solid-state. It is suggested on the basis ofpotentiometric studies ofMe2Sn(IV) and Me3Sn(IV) systems with Z-ascorbic acid that under physiological conditions (pH = 7.0) Me2Sn(HAsc)(OH) (~ 60%), Me2Sn(OH)2 (~ 40%) and Me3Sn(HAsc) (~ 60%), Me3Sn(OH) (~ 40%), respectively, are existing, which may be responsible for their biological activities. Fifth chapter deals with the synthesis and characterization of some new triand diorganotin(IV) derivatives of the general formulae R3Sn(Umb) (where, R=Me, h-Bu and Ph and Umb =umbelliferone anion) and R2Sn(Umb)2 (where, R=n-Bu, n- Oct and Ph). Further, the adducts of the general formulae R3Sn(Umb).phen (where, RMe and Ph and phen - 1,10-phenanthroline) and R2Sn(Umb)2.phen (where, R=«-Bu (v) and rt-Oct) have also been synthesized. Adetailed interpretation ofthe coordination modes ofthese ligands with the organotin(IV) moiety is discussed on the basis ofUVVis, infrared, far-infrared, multinuclear ('H, 13C and 119Sn) NMR and ,19Sn Mossbauer spectroscopic studies. These investigations indicate that umbelliferone acts as a monoanioic bidentate ligand in R3Sn(Umb) coordinating through 0-7 and 0-1 in the solid-state. The polymeric R3Sn(Umb) derivatives (where R=Me and n-Bu) have been proposed to have a fra/75-trigonal-bipyramidal geometry with the three R groups in equatorial positions, while the axial positions are occupied by a phenolic oxygen and the 0-1 atom from the adjacent molecule. A pseudotetrahedral geometry has been suggested for Ph3Sn(Umb). A distorted octahedral.geometry around tin has been proposed for R2Sn(Umb)2, in which umbelliferone acts as monoanionic bidentate ligand coordinating through 0-7 and O-1.Adistorted octahedral geometry around tinhas also been proposed for R3Sn(Umb).phen as well as for R2Sn(Umb)2.phen, in which umbelliferone anion acts as a monodentate ligandcoordinating throughphenolic oxygen 0-7. The results of the antiinflammatory and cardiovascular activities, and toxicity (LD50) of the synthesized derivatives have been discussed. The results ofantimicrobial screening of a few derivatives in vitro against Staphylococcus aureus Mau [(29/58) and (78/71)], Bacillus subtilis (18/64), Escherichia coli (326/71), Escherichia coli, Candida albicans (Pn-10) and Microsporum gypseum are also included. Sixth chapter of the thesis incorporates the different synthetic strategies that have been followed in order to isolate triorganotin(IV) derivatives of uracil, 5- fluorouracil and thymidine. Though no triorganotin(IV) derivative of uracil and 5- fluorouracil could be isolated, a new triphenyltin(IV) derivative of thymidine has been successfully isolated. The newly synthesized compound has been characterized by UVVis, Infrared, far-infrared, multinuclear ('H, l3C, 119Sn) NMR and 119Sn Mossbauer spectral studies. These studies suggest that the polyhedron around tin is trigonalbipyramidal in the solid-state with three phenyl groups in the equatorial positions, (vi) while the axial positions are occupied by 0-3' and 0-2 oftwo thymidine. The results of the antiinflammatory and blood pressure lowering activities of this compound are presented. The interactions of uracil, 5-fluorouracil, thymine and thymidine with MenSn<4->+ (where,n=2or 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 coordination behaviour of these nucleic acid constituents with the organotin(IV) moieties in solution. The various species formed in aqueous solution at different pH have been explained with the help of species distribution curves.