Monitoring of the promutagenic DNA adduct, O⁶-methylguanine, in the exfoliated cells (e.g. oral mucosal) of tissues from individuals exposed to tobacco-specific N-nitrosamines may aid in the evaluation of tissue-specific risk of carcinogenesis. People with high levels of this adduct could be identified and the appropriate intervention taken. Current techniques for detection of O⁶-methylguanine are unsuitable for the measurement of low adduct levels in small tissue samples. This thesis describes the development of a ³²P-postlabeling method for detection of O⁶-methylguanine in microgram amounts of DNA. In the first part of the project I synthesized O⁶-methyldeoxyguanosine 3'-monophosphate (0⁶mdG3'p), needed as a chromatography marker. This was achieved using a two step approach; preparation of 0⁶-methyldeoxyguanosine (0⁶ mdG) followed by chemical phosphorylation with KH₂PO₄ in formamide. The identity of the compound was confirmed by U.V. spectroscopy and enzymatic analysis. This is the first reported synthesis of the modified nucleotide. Using the synthetic marker, high performance liquid chromatography (HPLC) procedures were then developed for isolation of 0⁶mdG3'p from digested DNA prior to postlabeling. The basic method for analysis of 0⁶-methylguanine by ³²P-postlabeling comprises five steps, a) digestion of DNA containing 0⁶-methylguanine to deoxynucleoside 3'-monophosphates using micrococcal nuclease and spleen phosphodiesterase, b) isolation of 0⁶mdG3'p from normal nucleotides using reverse-phase HPLC, c) ³²P-labeling of 0⁶mdG3'p to give 0⁶- methyldeoxyguanosine 3',5'³²P-bisphosphate (0⁶mdG3'5'p) using ³²P-ATP and polynucleotide kinase, d) 2-dimensional polyethyleneimine cellulose thin layer chromatography (PEI-TLC) to resolve 0⁶mdG3'5'p from other radioactive materials and e) autoradiography and scintillation counting to quantitate 0⁶mdG3'5'p. Several variations of the basic technique were then investigated with the goal of improving the sensitivity. One modification, encompassing a second HPLC purification of 0⁶mdG3'5'p showed the greatest sensitivity: 0.5 micromole 0⁶-methylguanine per mole normal nucleotide (0.5 µmole/mole) . Using this method, 0⁶-methylguanine was detected in the DNA of mammalian tissue-culture cells treated with an agent, N-methyl-N-nitrosourea (MNU) known through independent techniques to form this adduct. The development of ³²P-postlabeling methods for detection of other small DNA adducts is feasible using the approach described here for 0⁶- methylguanine. The performance of the ³²P-postlabeling method for 0⁶- methylguanine equals that of the best available methods when microgram quantities of DNA are assayed. This new method will complement existing techniques. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

No description available.

This study focus on synthesis of novel compounds as potential agents for the therapy of mycoses. The following four novel compounds were synthesized: 1-(4-(octylsulfanyl)-3-(trifluoromethyl)phenyl)guanidine, 1,1-dimethyl-3-(4-(octylsulfanyl)-3-(trifluoromethyl)phenyl)guanidine, 1-(4-(decylsulfanyl)-3-(trifluoromethyl)phenylguanidine, 3-(4-(decylsulfanyl)-3-(trifluoromethyl)phenyl-1,1-dimethylguanidine. All intermediary and final crystalline products formed were thoroughly purified and characterized by Thin Layer Chromatography (TLC) and Melting points. Structures were elucidated on the basis of Infrared (IR) and Nuclear Magnetic Resonance (NMR) spectroscopy. 1- (4-(octylsulfanyl)-3-(trifluoromethyl)phenyl)guanidine was evaluated for in vitro antimicrobial activity on different fungal and bacterial strains.

Pathological fungi carry the ability to cause serious medical problems and moreover cause various diseases. Drug therapy and new active compounds against these medical problems are still being researched. The long-term objective is to uncover the active compounds at the Faculty of Pharmacy, Charles University. In our study, we synthesized 3-(4-bromophenyl)-1,1-diethylguanidine, and 2 novel compounds: 3-(4- dodecylsulfanylphenyl)-1,1-diethylguanidine and 3-(3-bromophenyl)-1,1- diethylguanidine. We also studied the oxidation of 1-(4- tetradecylsulfanylphenyl)guanidinium nitrate, thus, making it the third novel compound 1-(4-tetradecylsulfonylphenyl)guanidinium nitrate we synthesized.

Yeung, Lai Fong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 122-124). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iii / Acknowledgement Contents --- p.iv / Abbreviations --- p.ix / List of Compounds --- p.xi / Chapter Chapter One - --- Introduction / Chapter 1.1 --- General Background of Amido Ligands --- p.1 / Chapter 1.2 --- General Background of Guanidinates --- p.2 / Chapter 1.3 --- Coordination modes of Guanidinate Ligands --- p.5 / Chapter 1.4 --- A Brief Review on the Coordination Chemistry of Guanidinate Complexes --- p.7 / Chapter 1.4.1 --- Main Group Metal Guanidinate Complexes --- p.7 / Chapter 1.4.2 --- Transition Metal Guanidinate Complexes --- p.12 / Chapter 1.4.3 --- Rare Earth Metal Guanidinate Complexes --- p.13 / Chapter 1.5 --- Preparations of Metal Guanidinate Complexes --- p.15 / Chapter 1.6 --- Applications of Guanidinate Complexes --- p.16 / Chapter 1.7 --- Objectives of This Work --- p.18 / Chapter 1.8 --- References for Chapter One --- p.19 / Chapter Chapter Two - --- Synthesis and Structural Characterization of Bis(guanidinate) Complexes / Chapter 2.1 --- Introduction to Guanidinate Complexes --- p.25 / Chapter 2.1.1 --- Guanidinate Complexes of the Alkali Metals --- p.25 / Chapter 2.1.2 --- Bis(guanidinate) Complexes of Divalent First-Row Late Transition Metals --- p.27 / Chapter 2.1.3 --- Bis(guanidinate) Complexes of Group 12 Metals --- p.28 / Chapter 2.2 --- Objectives of Our Study --- p.29 / Chapter 2.3 --- Results and Discussion --- p.30 / Chapter 2.3.1 --- Synthesis and Structures of Lithium Guanidinates --- p.30 / Chapter 2.3.1.1.1 --- Synthesis of (L1 = [(C6H3Me2-2J6)NC{N(H)Cy}NCy] (1); L2=[(C6H3Me2-2)6)NC{N(H)Pr/}NPrl (2) and L3 =[(C6H3Me2_2，6)NC{N(SiMe3)Cy}NCy] (5)) --- p.30 / Chapter 2.3.1.1.2 --- Physical Characterization of Compounds 1，2 and 5 --- p.31 / Chapter 2.3.1.1.3 --- Molecular Structures of Compounds 1，2 and 5 --- p.32 / Chapter 2.3.1.2.1 --- Synthesis of Solvated Lithium Guanidinate [Li(L1)(THF)]2(6) --- p.37 / Chapter 2.3.1.2.2 --- Physical Characterization of Compound 6 --- p.37 / Chapter 2.3.1.2.3 --- Molecular Structure of Compound 6 --- p.38 / Chapter 2.3.2 --- Synthesis and Structures of Manganese(ll) Bis(guanidinate) Complexes --- p.40 / Chapter 2.3.2.1 --- Synthesis of Manganese(ll) Bis(guanidinate) Complexes Supported by Ln (n = 1-3) --- p.40 / Chapter 2.3.2.2 --- Physical Characterization of Compounds 7-9 --- p.41 / Chapter 2.3.2.3 --- Molecular Structures of Compounds 7-9 --- p.42 / Chapter 2.3.3 --- Synthesis and Structures of Iron(ll) Bis(guanidinate) Complexes --- p.51 / Chapter 2.3.3.1 --- Synthesis of Iron(ll) Bis(guanidinate) Complexes Supported by Ln (n = 2，3) --- p.51 / Chapter 2.3.3.2 --- Physical Characterization of Compounds 10 and 11 --- p.52 / Chapter 2.3.3.3 --- Molecular Structures of Compounds 10 and 11 --- p.52 / Chapter 2.3.4 --- Synthesis and Structures of Cobalt(ll) Bis(guanidinate) Complexes --- p.57 / Chapter 2.3.4.1 --- Synthesis of Bis(guanidinate) Cobalt(ll) Complexes Supported by Ln (n = 1-3) --- p.57 / Chapter 2.3.4.2 --- Physical Characterization of Compounds 12-14 --- p.57 / Chapter 2.3.4.3 --- Molecular Structures of Compounds 12-14 --- p.58 / Chapter 2.3.5 --- Synthesis and Structures of Nickel(II) Bis(guanidinate) Complexes --- p.65 / Chapter 2.3.5.1 --- "Synthesis of Nickel(ll) Bis(guanidinate) Complexes Supported by Ln (n = 1, 2)" --- p.65 / Chapter 2.3.5.2 --- Physical Characterization of Compounds 15 and 16 --- p.66 / Chapter 2.3.5.3 --- Molecular Structures of Compounds 15 and 16 --- p.66 / Chapter 2.3.6 --- "Synthesis and Structures of Bis(guanidinate) Complexes of Group 12 Metal (M = Zn, Cd)" --- p.71 / Chapter 2.3.6.1 --- Synthesis of Zn(ll) and Cd(ll) Bis(guanidinate) Complexes Supported by Ln (n = 1-3) --- p.71 / Chapter 2.3.6.2 --- Physical Characterization of Compounds 17-20 --- p.72 / Chapter 2.3.6.3 --- Molecular Structures of Compounds 17-20 --- p.72 / Chapter 2.4 --- Summary for Chapter Two --- p.82 / Chapter 2.5 --- Experimental for Chapter Two --- p.83 / Chapter 2.6 --- References for Chapter Two --- p.92 / Chapter Chapter Three - --- "Synthesis and Structural Characterization of Mono(guanidinate) Complexes of Mn(ll), Fe(ll) and Cu(l)" / Chapter 3.1 --- Introduction --- p.95 / Chapter 3.1.1 --- Introduction of Mono(guanidinate) Complexes of the First-Row Divalent Late Transition Metals --- p.95 / Chapter 3.1.2 --- Alkyl Complexes of the Late Transition Metals --- p.99 / Chapter 3.1.3 --- Introduction of Mono(guanidinate) Complexes of Cu(l) --- p.101 / Chapter 3.2 --- Objectives of Our Study --- p.102 / Chapter 3.3 --- Results and Discussion --- p.103 / Chapter 3.3.1 --- Synthesis and Structures of Mono(guanidinate) Complexes Supported by L3 --- p.103 / Chapter 3.3.1.1 --- Synthesis of Mono(guanidinate) Metal (M = Mn 21， Fe 22) Complexes Supported by L3 --- p.103 / Chapter 3.3.1.2 --- Physical Characterization of Compounds 21 and 22 --- p.103 / Chapter 3.3.1.3 --- Molecular Structures of Compounds 21 and 22 --- p.104 / Chapter 3.3.2 --- "Synthesis and Structures of Monoalkyl Metal (M = Mn, Fe) Complexes Supported by the Guanidinate Ligand L3" --- p.110 / Chapter 3.3.2.1 --- "Synthesis of Monoalkyl Metal (M = Mn, Fe) Complexes Supported by the Guanidinate Ligand L3" --- p.110 / Chapter 3.3.2.2 --- Physical Characterization of Compound 23 --- p.111 / Chapter 3.3.2.3 --- Molecular Structure of Compound 23 --- p.111 / Chapter 3.3.3 --- Synthesis and Structure of a Copper(l) Guanidinate Complex Supported by L2 --- p.115 / Chapter 3.3.3.1 --- Synthesis of a Copper(l) Guanidinate Complex Supported by L2 --- p.115 / Chapter 3.3.3.2 --- Physical Characterization of Compound 24 --- p.115 / Chapter 3.3.3.3 --- Molecular Structure of Compound 24 --- p.116 / Chapter 3.4 --- Summary for Chapter Three --- p.119 / Chapter 3.5 --- Experimental for Chapter Three --- p.119 / Chapter 3.6 --- References for Chapter Three --- p.122 / "Appendix 1 - Physical Measurements, X-Ray Structural Analysis" --- p.125 / Appendix 2 - NMR Spectra of Compounds --- p.127 / Appendix 3 - Selected Crystallographic Data --- p.139

Thesis (Ph.D.)--Tufts University, 2004. / Adviser: Eliana De Bernardez Clark. Submitted to the Dept. of Chemical Engineering. Includes bibliographical references (leaves 173-181). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Charles university in Prague Faculty of Pharmacy in Hradec Králové Department of Anorganic and Organic Chemistry Candidate: Ondřej Vidrna Supervisor: PharmDr. Karel Palát, CSc Title of diploma thesis: Synthesis of substituted arylguanidines as potential drugs IX. The increasing incidence of diseases caused by fungal and mycotic pathogens, many of which acquire resistance to available antifungal substances, causes the need for a search for new molecules inhibiting their growth. The worldwide research is focused on substances derived from guanidine which were found to be potentially active against many strains of fungi and bacteria. Faculty of Pharmacy in Hradec Králové has been researching these substances for many years. The aim is to get the most active compounds from the group of substituted arylguanidines and find a structure-activity relationships effect of these substances. In this study the seven previously undescribed molecules were synthesized: 1-(4- methyl-2-octylsulfanyl)phenylguanidinium nitrate, 1-(4-methyl-2-dodecylsulfanyl) phenylguanidinium nitrate, 1-(4-methyl-2-dodecylsulfanyl)phenyl-3,3-dimethylguanidine, octyl-(4-methyl-2-nitrophenyl)sulfide, 5-methyl-2-(octylsulfanyl)aniline, dodecyl-(4-methyl-2- nitrophenyl)sulfide and 5-methyl-2-(dodecylsulfanyl)aniline. Three of them were...

Described in this thesis is the development of a key Diels-Alder reaction for use in a total synthesis of the potently immunosuppressant marine alkaloid palau'amine. This study focuses on the originally proposed structure of palau'amine. The strategy utilizes a computationally designed thiohydantoin dienophile as the 2pi component and a thermally stable 2-silyloxy-5-(silyloxymethyl)cyclopentadiene as the 4pi component in the critical Diels-Alder reaction. Essential to the design and study of these partners was the use of computational density functional theory (DFT) predictions. / Four families of dienophiles---oxazolones, dehydroalanines, hydantoins and thiohydantoins---were investigated. The hydantoins and thiohydantoins react with cyclopentadiene with up to 13:1 exo-selectivity while the dehydroalanines are modestly selective and the oxazolones are unselective. The exo-selectivity of the hydantoin and thiohydantoin dienophiles is attributed to a novel stabilizing interaction whereby the lone pair of electrons on nitrogen interacts with a developing positive charge on the diene in the transition state. In terms of reactivity, the oxazolones are the superior dienophiles. The reactivity of the thiohydantoins is greater than that of analogous hydantoins and approaches that of the oxazolones. The bolstered reactivity of the thiohydantoins is attributed to the increased donation of the nitrogen lone-pair into the thiocarbonyl bond. This phenomenon was recognized first in DFT predictions and then proven experimentally. Synthetic access to the requisite beta-(chloromethylene)thiohydantoins necessitated the development of a reaction between dilithium diamides and thiophosgene. / 2-silyloxy-5-(silyloxymethyl)cyclopentadienes were studied experimentally and computationally and found to be much more stable than conventional 5-substituted cyclopentadienes towards thermal decomposition by 1,5 hydride shift. The new dienes undergo Diels-Alder reaction with oxazolone and thiohydantoin dienophiles with exoselectivities as high as 6:1 for nonchlorinated dienophiles. Fully functionalized chlorinated exo-cycloadducts were prepared with up to 1.5:1 selectivity and subjected to oxidative ring-opening to reveal the persubstituted core of palau'amine.

No description available.