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Reactivity and Alkylating Potential of Some O-Heterocycles

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Reactivity and Alkylating Potential of Some O-Heterocycles Dpto. de Qu´ımica f´ısica Facultad de Ciencias Qu´ımicas PhD Thesis Chemical processes that can damage cellular DNA: Reactivity and alkylating potential of some O-heterocycles Supervisors: Author: Prf. Dr. Julio Casado Rafael Gomez´ Bombarelli Prf. Dr. Emilio Calle November 8, 2011 A Marta, Jose,´ Lali y Pepe en ningun´ orden en particular Departamento de Qu´ımica f´ısica Facultad de Ciencias Qu´ımicas The work reported here has been carried out in the Departamento de Qu´ımica f´ısica of the Universidad de Salamanca, under the advice of Prof. Dr. Julio Casado Linarejos and Prof. Dr. Emilio Calle Mart´ın. Rafael Gomez´ Bombarelli Emilio Calle Mart´ın Julio Casado Linarejos It’s been emotional. Big Chris Acknowledgements The author thanks the Spanish Ministerio de Educacion´ for a PhD fellowship (AP2006-01976) and financed research stays at the workgroups of Prof. Dr. Jose´ Rueff (Universidade Nova de Lisboa) and Prof. Dr. Franc¸ois Maurel (ITODYS, Paris-VII), who are also thanked for their hos- pitality. Financial support of the research reported in this work by the Ministerio de Ciencia e Innovacion´ (projects CTQ2010-18999, CTQ2007-63263, CTQ2004-05048), and the Junta de Castilla y Leon´ and European Regional Development Fund (project SA040A08) is also ac- knowledged. E. Bombarelli and J. Arenas are also thanked for their generous donation of CPU-time and resources. i Contents List of Figuresv List of Tables vii List of Schemes ix Abbreviations xi Preface xiii 1 Alkylating agents and the NBP Test: a review 1 1.1 Development of the method....................5 1.1.1 Early examples.......................5 1.1.2 The Epstein test.......................6 1.1.3 Biological samples......................7 1.1.4 Chromatography......................7 1.2 NBP as a DNA-model.......................8 1.2.1 Nucleophilicity of DNA....................8 1.2.2 Site selectivity....................... 10 1.2.3 To what extent is DNA modeled by NBP?............. 11 1.2.4 Strengths and weaknesses of the NBP assay............. 12 1.3 Uses............................. 13 1.3.1 Detection and quantification of alkylating agents.......... 13 1.3.2 Characterization of alkylating agents............... 15 References............................ 27 2 Reactivity and alkylating potential of diketene 35 2.1 Background.......................... 39 2.1.1 Genotoxicity of lactones.................... 39 2.1.2 Diketene......................... 41 iii CONTENTS 2.2 Materials & methods....................... 44 2.2.1 Hydrolysis of diketene.................... 44 2.2.2 Alkylating potential of diketene................. 44 2.2.3 Acidity of lactones and ketones................. 45 2.3 Results and discussion...................... 47 2.3.1 Hydrolysis of diketene.................... 47 2.3.2 Alkylating potential of diketene................. 56 2.3.3 Acidity of lactones and cycloketones............... 63 2.4 Conclusions.......................... 74 References............................ 75 3 Theoretical study of lactone hydrolysis 79 3.1 Background.......................... 83 3.1.1 Hydrolysis of esters..................... 83 3.1.2 Hydrolysis of lactones.................... 108 3.2 Materials & methods....................... 111 3.2.1 Methodology and computational details.............. 111 3.2.2 Hydrolysis of 2-5(H)-Furanone................. 112 3.3 Results and discussion...................... 113 3.3.1 Neutral hydrolysis...................... 113 3.3.2 Alkaline hydrolysis..................... 122 3.3.3 Acid hydrolysis....................... 128 3.3.4 Conclusions........................ 139 References............................ 140 4 Alkylating potential of oxetanes 145 4.1 Background.......................... 149 4.1.1 Genotoxicity of ethers.................... 149 4.1.2 Oxetanes......................... 157 4.2 Materials & methods....................... 161 4.2.1 Alkylating potential of oxetanes................. 161 4.2.2 Genotoxicity of oxetanes................... 161 4.3 Results and discussion...................... 164 4.3.1 Alkylating potential of oxetanes................. 164 4.3.2 Mutagenicity, genotoxicity and toxicity of oxetanes.......... 168 4.4 Conclusions.......................... 171 References............................ 172 iv CONTENTS 5 Reactivity and alkylating potential of hydroxyhalofuranones 177 5.1 Background.......................... 181 5.1.1 Hydroxyhalofuranones as pollutants............... 182 5.1.2 Mucohalic acids....................... 185 5.1.3 Mutagen X........................ 190 5.2 Materials & methods....................... 199 5.2.1 Reactivity of halohydroxyhalofuranones.............. 199 5.2.2 Alkylating potential of halohydroxyfuranones............ 205 5.3 Results and discussion...................... 207 5.3.1 Reactivity of halohydroxyhalofuranones.............. 207 5.3.2 Alkylating potential of halohydroxyfuranones............ 234 5.4 Conclusions.......................... 252 References............................ 253 A Appendix A1 A.1 DNA-Intercalating photochromic spiropyran.............. A5 A.1.1 Methodology and computational details.............. A5 A.1.2 Results and discussion.................... A6 A.1.3 Conclusions........................ A16 References............................ A17 B Resumen en espanol˜ C1 Publication list C3 v List of Figures 1.1 Mutagenicity - NBP assay correlation............................... 16 2.1 Typical kinetic run for the neutral hydrolyis of DIK....................... 48 2.2 Variation in kDIK with pH.................................... 49 1 H2O 2.3 ∆‡H /∆‡S relationship for kDIK in the different w/d media................. 51 H2O 2.4 Typical kinetic run of alkaline hydrolysis of DIK........................ 52 2.5 Reaction order for the alkaline hydrolysis of DIK........................ 53 DIK – 2.6 Variation in kOH with [OH ] and w/d ratio............................ 54 ∆‡ ∆‡ DIK 2.7 H / S relationship for kOH in the different w/d media................. 56 2.8 Variation in the UV-Vis spectra of the NBP-DIK alkylation mixture and typical kinetic profile 57 2.9 Formation and decomposition of the NBP-DIK adduct in excess DIK............. 58 2.10 Acyl and alkyl BPL-NBP and DIK-NBP transition states.................... 61 2.11 HOMO of the isoDIK molecule.................................. 67 3.1 Hydrolysis rate of some acetates in concentrated sulfuric acid................. 87 3.2 Kinetic order in water for the acid hydrolysis of some acetates................. 95 3.3 Dependence of hydrolysis rate constant on pH for several esters............... 103 3.4 Hydrolysis rates of some β-lactones as a function of medium acidity.............. 109 3.5 Structure of the addition transition state of BIVL in the BAL1 mechanism.......... 115 3.6 BAC2 minima and transition states for DIK........................... 118 3.7 Structure of the addition and cleavage transition states of GBL in the alkaline BAC2 mech- anism................................................. 122 3.8 Transition state for the unimolecular ring-opening reaction of dissociated DIK....... 126 3.9 Equilibrium geometry for the AAL1 transition state for BIVL................. 132 3.10 Structure of the AAC1 cleavage transition state, and its acyl cation product......... 133 3.11 Structure of the intermediate and the transition states in the AAC2 mechanism for GBL.. 134 4.1 a) UV-Vis spectrum of NBP-TMO mixtures b) Typical kinetic run of alkylation by oxetanes 164 TMO -4 4.2 a) Variation in k with [NBP]. [TMO] = 5.0 10 M. b) Variation in A with [TMO]o, obs × 1 [NBP] = 0.040 M. pH = 3.80, T = 37.5 ℃, 7:3 w/d......................... 166 4.3 Revertants per plate in the Salmonella and BTC E. coli tests.................. 169 4.4 Results of the Comet assay..................................... 170 vii LIST OF FIGURES 4.5 Relative proliferation as measured in the MTT Assay...................... 171 5.1 Carbonyl compounds studied................................... 208 5.2 Calculated absolute KHyd ...................................... 209 5.3 Calculated absolute KHem ..................................... 212 5.4 Variation in the UV-Vis spectra of MXA with pH........................ 215 app 5.5 Spectrophotometric determination of the pKa of MXA.................... 216 1 app 5.6 H NMR determination of the pKa of MXA.......................... 217 5.7 Calculated equilibrium geometries for mucohalic acids..................... 218 – 5.8 Energy of MXAop as a function of the C=C–C–O dihedral angle............... 219 5.9 Variation with time in the UV-Vis spectra of MXA in the reaction with OH– ......... 222 5.10 Kinetic profiles of the reaction of MXA with OH– ........................ 223 5.11 Reaction order of MXA hydrolysis with respect to hydroxide................. 224 MXA – 5.12 Variation in kOH exp with OH ................................... 224 5.13 Spectrograms showing the formation of the AN-MXA adducts................ 234 5.14 Typical kinetic profile of the alkylation reaction of AN by MXA................ 235 5.15 Spectrograms showing the formation of the NBP-MXA adducts................ 238 5.16 Typical kinetic profile of the alkylation reaction of NBP by MXA............... 239 A.1 Calculated geometries for the photochrome........................... A8 A.2 a) Reported UV-Vis spectra of the open and closed forms of SP, in the absence and pres- ence of DNA. Reproduced from. 4 b) Calculated UV-Vis spectra of TTC; isolated TTC in its intercalation geometry; TTC bound to [tri(dA-dT)]2; CL.................... A12 A.3 SP TTC-[tri(dA-dT)]2 intercalation complex..........................
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