Although cis-PtCl2(NH3)2 (cisplatin) has been widely used as a chemotherapeutic agent, its use can be accompanied by toxic side effects and the development of drug resistance. Consequently, much research has been focused on the discovery of novel transition metal compounds which elicit elevated cytotoxicities coupled with reduced toxic side effects and non-cross resistance. Recently, research in this lab has focused on preparing derivatives of titanocene dichloride (TDC), a highly active chemotherapeutic agent, with pendant alkylammonium groups on one or both rings. Earlier results have demonstrated that derivatives containing either cyclic or chiral alkylammonium groups had increased cytotoxic activities. This research therefore investigated a new series of TDC complexes focusing specifically on derivatives bearing cyclic and chiral alkylammonium groups. A library of ten cyclic derivatives and six chiral derivatives were synthesized and fully characterized. These derivatives have undergone in vitro testing as anti-tumour agents using human lung, ovarian, and cervical carcinoma cell lines (A549, H209, H69, H69/CP, A2780, A2780/CP and HeLa). These standard cell lines represent solid tumour types for which new drugs are urgently needed. The potencies of all of the Ti (IV) derivatives varied greatly (range from 10.8 μM - >1000 μM), although some trends were observed. In general, the dicationic analogues exhibited greater potency than the corresponding monocationic derivatives. Additionally, the cyclic analogues bearing 1,3- and 1,4-substituted pyridines displayed potent cytotoxic activities (IC50> 20 μM). It was also found at concentrations of ~30 μM that the derivatives bearing an ephedrine derived substituent were cytotoxic. Conversely, analogues substituted with piperidinyl, morpholinyl or primary alkylammonium groups were inactive (>200 μM) against the cancer cell lines assayed. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-05-14 13:18:28.141

No description available.

Mercury-selenium (Hg-Se) interaction is perhaps the most documented bioantagonism. Since its discovery in the 1960s, extensive studies have been carried out on the wide occurrence, chemical mechanisms, and toxicological significance of this bioantagonism. However, major knowledge gaps exist in the underlying mechanism at the molecular level which is the objective of this present research. To study molecular level mechanism of this bioantagonism, four new MeHg-selenoamino acid namely, methylmercury-D,L-selenopenicillaminate, methylmercury-L-selenoglutathionate, and two methylmercury-L-selenomethioninate complexes (one via a Hg-Se bonding and the other via Hg-N bonding) were synthesized and characterized by NMR, FT-IR and mass spectrometry. Their structural and electronic properties were studied by X-ray crystallography and quantum mechanical calculations. These studies reveal that all four complexes chemically and structurally resemble their sulfur analogues. This suggests that mimicry could play a role in the MeHg-Se antagonism. Chemical coupling values from NMR suggest that MeHg+ has stronger affinity for Se than for S. It has long been proposed and analytically proven that mercury selenide, HgSe(s), is the end product of the Hg-Se bioantagonism. However, the pathway of its formation in biological systems was poorly understood. Experiments carried out in this study suggested that HgSe(s) could be formed from both inorganic Hg and MeHg in the presence of Se. In the case of MeHg, we found that its binding with selenoamino acids could result in the demethylation of MeHg and formation of HgSe nanoparticles. NMR and gas chromatography – mass spectrometry (GC-MS) studies confirmed the presence of bis(methylmercury) selenide (BMSe) and dimethylmercury as reaction intermediates based on which a demethylation pathway was proposed. Inorganic Hg interacts with selenite in presence of glutathione (GSH) and form HgSe1-xSx (0 < x < 1) nanoparticles via a black solution or precipitate. The dissolution/precipitation is reversible upon adjustment of pH. UV-visible spectra, TEM and XPS analyses revealed that the black solution is HgSe1-xSx nanoparticles with diameter < 5 nm which at high pH and upon separation becomes sparingly soluble. This study provides a new plausible explanation of tissue distribution patterns of HgSexS1-x in biological systems.

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New organotin compounds containing alkoxy- functionalities have been prepared. The methods of preparation of the tetraorganotin species have involved three routes. Hydrostannation reactions using triphenyltin hydride have resulted in the synthesis of triphenyltin derivatives of a series of alkoxy- substituted allyl ethers. The addition of tin IV chloride, diphenyltin dichloride and phenyltin trichloride to alkoxy- substituted aryl- and benzyl- Grignard reagents have also been successful. Alkoxy- substituted benzyltin compounds have been prepared by following an alternative preparation of benzylmagnesium halides from that commonly used to prepare Grignard reagents. Nucleophilic substitution of (iodomethyl)triphenyltin by a novel ligand has been effective. The structures of the products have been investigated by ¹H, ¹³C and ¹¹⁹Sn nmr. Single crystal X-ray diffraction studies have led to the determination of the crystal structures of tetra-2-anisyltin, tetrakis-(2-methoxybenzyl)tin and <I>N,N</I>'-bis(5-triphenylstannoxymethyl-2-phenyl-1,3-dioxan-5-yl)ethanediamide. Selective tin-carbon bond cleavage has been effected by the use of iodine and bromine to give rise to mono- and dihalo- organotin compounds and the crystal structures of tri-2-anisyltin iodide and di-2-anisyltin dibromide have been elucidated by X-ray crystallography. Chloro(3-ethoxypropyl)diphenyltin has been synthesised directly from diphenyltin dichloride and has been found to contain a penta-co-ordinate tin centre with a four membered chelate ring as a result of intramolecular tin-oxygen co-ordination. Other tin-carbon bond cleavage reactions by halogens have been studied by ¹H and ¹¹⁹Sn nmr and GLC and the results discussed.

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The aza crown, sym-1,2-benzo-aza-17-crown-5, was synthesized from 6-aza-3,9-dioxa-1,11-undecanediol, and , -dibromo-o-xylene in the presence of potassium tert-butoxide. This new crown ether was reacted with 4-bromobenzyl bromide and chloroacetyl chloride to form the N-substituted 4-bromobenzyl and chloroacetyl derivatives, respectively. The aza crown and its derivatives were identified with spectroscopic data. The bidentate phosphine amine, Ph2P(CH2)3NH2, was prepared via reduction of 3-(diphenylphosphino)propionitrile by lithium tetrahydroaluminate. Schiff-base reactions between the amine group in Ph2P(CH2)3NH2 and the aldehyde group in benzaldehyde and 4-formyl-benzo-15-crown-5 provided the respective phosphine derivatives. These products were identified with spectroscopic and analytical data. Finally, palladium derivatives of these phosphine-Shiff base ligands (Ph2P(CH2)3NCHR; R = Ph, benzo-15-crown-5) were synthesized from the reactions between (Ph2CN)2PdCl2 and the ligands.

Mercury-selenium (Hg-Se) interaction is perhaps the most documented bioantagonism. Since its discovery in the 1960s, extensive studies have been carried out on the wide occurrence, chemical mechanisms, and toxicological significance of this bioantagonism. However, major knowledge gaps exist in the underlying mechanism at the molecular level which is the objective of this present research. To study molecular level mechanism of this bioantagonism, four new MeHg-selenoamino acid namely, methylmercury-D,L-selenopenicillaminate, methylmercury-L-selenoglutathionate, and two methylmercury-L-selenomethioninate complexes (one via a Hg-Se bonding and the other via Hg-N bonding) were synthesized and characterized by NMR, FT-IR and mass spectrometry. Their structural and electronic properties were studied by X-ray crystallography and quantum mechanical calculations. These studies reveal that all four complexes chemically and structurally resemble their sulfur analogues. This suggests that mimicry could play a role in the MeHg-Se antagonism. Chemical coupling values from NMR suggest that MeHg+ has stronger affinity for Se than for S. It has long been proposed and analytically proven that mercury selenide, HgSe(s), is the end product of the Hg-Se bioantagonism. However, the pathway of its formation in biological systems was poorly understood. Experiments carried out in this study suggested that HgSe(s) could be formed from both inorganic Hg and MeHg in the presence of Se. In the case of MeHg, we found that its binding with selenoamino acids could result in the demethylation of MeHg and formation of HgSe nanoparticles. NMR and gas chromatography – mass spectrometry (GC-MS) studies confirmed the presence of bis(methylmercury) selenide (BMSe) and dimethylmercury as reaction intermediates based on which a demethylation pathway was proposed. Inorganic Hg interacts with selenite in presence of glutathione (GSH) and form HgSe1-xSx (0 < x < 1) nanoparticles via a black solution or precipitate. The dissolution/precipitation is reversible upon adjustment of pH. UV-visible spectra, TEM and XPS analyses revealed that the black solution is HgSe1-xSx nanoparticles with diameter < 5 nm which at high pH and upon separation becomes sparingly soluble. This study provides a new plausible explanation of tissue distribution patterns of HgSexS1-x in biological systems.