STUDIES ON NOVEL ORGANOTIN(IV) DERIVATIVES OF PEPTIDES

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. Organotin(IV) compounds, particularly dialkyltin(IV) compounds, have been used as stabilizers for poly(vinyl)chloride and as curing agents for the room temperature"vulcanization" of silicones. Triorganotin(IV) compounds have been found useful as industrial biocidcs in material protection as an antifouling agent, as surface disinfectants and as agricultural biocides. Organotin(IV) compounds have also been used as versatile synthetic reagents for various organic transformations and as catalysts for the production of polyurethanes. However, their chemistry has experienced a quantum growth because of their place among potential biologically active metal^pharma ceuticals exhibiting antitumour, antimicrobial, antiinflammatory, antiviral and anti tuberculosis activities. Their significance from chemotherapeutic point of view has been enhanced further, because oftheir interactions with some clinically recommended drugs, viz. antibiotics, antibacterial, antiinflammatory, antihypertensive and sulpha 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 (histidine only) and low affinity site of ATPase and haemoglobins (histidine and cysteine). In this wide context, several studies have addressed the interaction of organotin(IV) moieties with biomolecules, viz. amino acids and their derivatives, peptides, DNA and nucleic acid residues, carbohydrates, coenzymes, vitamins, porphyrins and steroids. 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 amino acids and peptides, and hence to formulate the structure- (ii) activity correlations to devise new derivatives with potential biological activity. Peptides are the basic building blocks of proteins (characterized by the peptide bond) and play an important role in their biosynthesis. Many peptides, viz. insulin, vasopressin, oxytocin and glucagon exhibit wide range ofbiological and physi ological functions in the body. Several peptides such as bradykinin, penicillin and actinomycin are potentially useful as antihypertensive, antibacterial, antitumour, and antiviral agents. Knowledge of specific or selective bonding of metal and organometal species to donor sites in biological structures and also in simple biologically relevant oligofunctional molecules is still far from completeness. Although organotin(IV) compounds find many practical applications, the study of their coordination behaviour with biological molecules still presents considerable scope for efforts to be directed in this field. As peptides and proteins are well known and efficient biological metal ion binders because of their unique structural features, therefore, model studies using oligopeptides as low molecular weight protein mimics may furnish vital insight into the metal ion-protein interactions. In view ofthe wide range ofapplications of organotin(IV) compounds, and biological relevance of the amino acids and peptides 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- oforganotin(IV) compounds and peptides. Acritical and comprehensive review of the available literature on the organotin(IV) complexes of penicillamine and peptides with special reference to their synthetic methods, structural characterization and biological significance has also been presented. Second chapter incorporates the details ofmake, purity and other specifications of the materials used in the present study. For the spectroscopic studies,

viz. multinuclear and multidimensional NMR and ll9Sn M6ssbauer, of the synthesized organotin(IV) derivatives, the compounds have been sent to various Institutes/ Universities in India/Abroad. The specifications of the instrumentsand the procedures used therein have 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. A few complexes have been sent to Pharmachemie BV, Medical Department, NL-2003 RN Haarlem (The Netherlands) for antitumour activity. 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 and 5. Third chapter concentrates on the synthesis, characterization and structureactivity relationship of some new di- and triorganotin(IV) derivatives of the general formulae R2Sn(L/HL') and Ph3Sn(HL/H2L'), where R is w-Bu and Ph, and L/HL is dianion/monoanion of D-penicillamine (H2L-1) and Z.-carnosine (H2L-2), and IILV H2L' is dianion/monoanion of triglycine (H3L-3). The probable structures of the synthesized derivatives have been discussed on the basis ofelemental analysis, infrared, far-infrared, multinuclear ("H, l3C and ,l9/1,7Sn) NMR and mSn Mossbauer spectroscopic studies. On the basis ofspectral studies, a distorted trigonal bipyramidal structure, in which ligands are tridentate coordinating through Namjno, C(0)Ocarboxyi and S,hioi/NpeP,ide, has been proposed for all the diorganotin(IV) derivatives. Whereas a linear polymeric structure with a distorted trigonal bipyramidal environment around tin has been tentatively proposed for Ph3Sn(IV) derivatives in which the ligands may act as bidentate coordinating through Naminoand C(0)0carb0Xvi. 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 in vivo antiinflammatory activity (% inhibition), toxicity (LD50 in mg/kg) and cardio vascular 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 (iv) spectroscopic investigations ofsome new diorganotin(IV) derivatives ofdipeptides with general formula R2Sn(L), where R = n-Bu and Ph, L is the dianion of glycyltryptophane (H2L-1), valylvaline (H2L-2) and alanylvaline (H2L-3); R=n-Bu, Lis the dianion of glycyltyrosine (H2L-4), leucyltyrosine (H2L-6) and leucylleucine (H2L-7); and R=Ph, Lis the dianion of glycylphenylalanine (H2L-5) and leucylalanine (H2L-8). The bonding and coordination behaviour in these derivatives are discussed in the light of various physico-chemical studies as mentioned in the third chapter, including 2-D heteronuclear multiple quantum coherence (HMQC) and heteronuclear multiple bond correlation (HMBC) NMR studies of some complexes. The ''"Sn Mossbauer studies, together with the NMR data, indicate that, for these 1:1 monomeric derivatives, the polyhedron around tin in R2Sn(L) is atrigonal bipyramid with the organic groups and Npepllde in the equatorial positions, while the axial positions are occupied by acarboxylic oxygen and the amino nitrogen atom. The data obtained for the antiinflammatory and cardiovascular activities, and toxicity of all the synthesized diorganotin(IV) derivatives are discussed. Further, the results for the in vitro antitumour activity of the di-w-butyltin(IV) derivatives of dipeptides, against a panel of seven cancer cell lines of human origin, viz. WiDr (a colon cancer), H226 (a non-small cell lung cancer), EVSA-T (a mammary cancer), MCF-7 (a mammary cancer), M19 (a melanoma), IGROV (an ovarian cancer) and MEL A498 (a renal cancer) are also compiled. The ID50(ng/mL) are compared and discussed with those ofsome clinically used reference compounds, viz. m-platin, doxorubicine, etoposide, 5-fluorouracil, methotrexate and taxol. Fifth chapter enumerates the synthesis and characterization of some new triorganotin(IV) derivatives of dipeptides with general formula R3Sn(HL), where RMe and/or w-Bu and/or Ph, HL is the monoanion of glycyltryptophane (H2L-1), valylvaline (ILL-2), alanylvaline (H2L-3), glycyltyrosine (H2L-4), glycylglycine (H2L- 5), leucyltyrosine (H2L-6), leucylleucine (H2L-7), leucylalanine (H2L-8), glycylleucine (H2L-9), glycylisoleucine (H2L-10) and glycylvaline (H2L-11). The bonding and co ordination behaviour in the synthesized derivatives are discussed in the light ofvarious (v) physico-chemical studies as mentioned in the third chapter, including the low temperature and 2-D NMR studies of some complexes. These investigations suggest that, in the solid state, all the ligands in R3Sn(HL) act as monoanionic bidentate coordinating through the 0-C=0 and NH2 groups. The l,9Sn Mossbauer studies, indicate that, for these polymeric derivatives, the polyhedron aroundtin in R3Sn(HL) is a trigonal bipyramid withthe three organic groups in the equatorial positions, while the axial positions are occupied by a carboxylic oxygen and the aminonitrogen atom from the adjacent molecule. The results obtained for the antiinflammatory and cardio vascular activities, and toxicity of all the synthesized triorganotin(IV) derivatives of dipeptidesare discussed. Further, data for the invitro antimicrobial activity(minimum inhibitory concentration in ug/mL) of the synthesized triorganotin(IV) derivatives of dipeptides, against gram-positive bacteria: Staphylococcus aureus Mau (29/58) and (78/71) and Bacillus subtilis (18/64); gram-negative bacteria: Escherichia coli (326/ 71) and Escherichia coli; yeast: Candida albiacans (Pn-10); mould: Microsporum gypseum; and on the autotrophic form of unicellular flagellate Euglena gracillis on growth (toxicity, ED50 in 10"3 mol/uL) and on the plastid system (bleaching activityinduction of chloroplast free mutants), have also been compiled and discussed. The results obtained for the in vitro antitumour activity of Ph3Sn(IV) derivative of H2L-9, screened against a panel of seven cancer cell lines of human origin, as mentioned in the fourth chapter, have also been discussed .