Transition metal oxides exhibit potential in various application fields due to the special d-electrons. Solid state chemistry focuses on discovering the structure-property relationships. The work in this thesis mainly discusses compounds with hexagonal or brownmillerite-type structure and their practical properties. Hexagonal YIn[subscript 1-x]Fe[subscript x]O��� (x = 0-0.3, 0.7-1.0) phases have been prepared and characterized. All phases appear to have the ferroelectric structure known for YInO���. The color of the phases changes from yellow to orange to dark red with increasing Fe content. Magnetic measurements confirm high-spin Fe����� for all phases. Similarly, solid solution YAl[subscript 1-x]Fe[subscript x]O��� (x = 0-0.4, 0.7-1.0) phases were successfully synthesized through the sol-gel method. The Al-rich compounds present paraelectric YAlO��� structure while the Fe-rich side samples exhibit YFeO��� structure. The color of the compounds appear to be yellow with small Fe content and change to brown which has higher Fe content. Brownmillerite-type oxides Ba���In[subscript 2-x]Mn[subscript x]O[subscript 5+x] (x = 0.1-0.7) have been prepared and characterized. Magnetic measurements confirm that Mn in as prepared samples is substituting as Mn������ for all values of x with observed paramagnetic spin-only moments close to values expected for two unpaired electrons. Neutron diffraction structure refinements show Mn������ occupies tetrahedral sites for orthorhombic (x = 0.1) and tetragonal (x = 0.2) phases. For Mn ��� 0.3 samples, neutron refinements show the phases are cubic with disordered cations and oxygen vacancies. The colors of the phases change from light yellow (x = 0) to intense turquoise (x =0.1), to green (x = 0.2, 0.3) or dark green (x ��� 0.4). Solid solution Ba���In[subscript 2-x]Fe[subscript x]O[subscript 5+y] (x = 0.1-1.5) also exhibit brownmillerite-type structure. The color of the compounds appear to be green with small Fe content and change to black with higher Fe content (x ��� 0.3). Magnetic measurements and M��ssbauer spectroscopy conclude the mixed valence of Fe�����/Fe������ for all the phases. Nonstoichiometry compound YCu���.���Ti���.���O[subscript 3-��] has been prepared and characterized. Structure study indicates that oxygen vacancy is favored under the synthesis condition. This change in oxygen content was further studied in the Mn-doped system. And the effect of stoichiometric difference in the Mn-doped samples was not as obvious as the initial compound. The disorder in the cation site enhanced the tolerance of the structure in the aspect of oxygen content. The hexagonal phases LnCu���.���Ti���.���O��� (Ln = Y, Tb-Lu) phases were prepared by the traditional solid state reactions. The prepared compounds were reduced at high temperature in the reduction atmosphere created by the H���/N��� gas mixture. Study on the structure and properties changes by reduction was conducted by X-ray diffraction, optical measurement, magnetic measurement and thermalgravimetric analysis. And we observed some evidence of the presence of Cu��� in the reduced phase by these characterization methods. Solid solution YMn[subscript x]Ti[subscript y]O[subscript 3-��] (y = 0.1-0.4) was successfully prepared through conventional solid state approach. All the samples showed hexagonal structure. But the structure transition from ferroelectric P6���cm to paraelectric P6���/mmc occurred when Ti amount is higher than 0.2. Based on the neutron diffraction refinement, the lattice expanded in the ab plane but contracted along the c axis direction. / Graduation date: 2013

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvii, 271 p.; also includes graphics. Includes bibliographical references (p. 245-269). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 355-382).

English abstract Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a membrane bound glycoprotein that belongs to the metallopeptidase M28 family. Two physiological substrates were found for GCPII. The first one, N-acetyl-aspartylglutamate (NAAG), serves as a neurotransmiter in the brain and GCPII hydrolyzes it to yield free glutamate in the synaptic cleft. Excess glutamate might be cytotoxic and eventually lead to excitoxic nerve cells death. Inhibition of NAAG hydrolyzing activity has been shown to be neuroprotective. Therefore, GCPII inhibition was suggested as a therapeutic target in treatment of neurological disorders where excess glutamate is involved. The second substrate, polyglutamyl folate, is a precursor of folic acid which is required for cell growth and development. GCPII cleaves off glutamate from dietary folates and thus facilitates their absorption in small intestine. Although GCPII biological relevance is known only in the brain and the small intestine, its role in the prostate is also important. GCPII has been described as a prostate cancer marker as it is expressed on the membrane of prostate cancer cells. Since GCPII is type II transmembrane protein, it is enzymatically active and undergoes internalization, it has been suggested as a promising tool for specific anticancer-drug...

Preparou-se, neste trabalho, nove cloridratos de N,N- [(dimetilamino)metil]benzamidas-p-X-substituidas em que X = N02, Br, Cl, I, F, H, CH3, OCH3 e N(CH3)2, SÉRIE II, ainda não descritos na literatura, a partir das respectivas bases, SÉRIE I. Os compostos obtidos foram identificados por seus espectros de I.V e RMN1H, e suas purezas determinadas por análise elementar e ponto de fusão. A seguir, determinou-se os valores de vC=O (cm-l ) em HCCl3, como medida de sua polaridade tanto para os compostos da SÉRIE I como para os da SÉRIE II. A aplicação da equação de HAMMETT, simples e expandida, aos valores obtidos forneceu excelentes correlações, verificando-se que os efeitos eletrônicos que os substituintes exercem sobre o grupo carbonila são de natureza indutiva e de ressonância, não havendo predominância de um sobre o outro. Determinou-se também, por bloqueio nervoso periférico em pata de rato, o grau de atividade anestésica local de sete dos nove compostos da SÉRIE II. A aplicação da equação de HANSCH aos valores de atividade anestésica local mostrou haver correlação razoável considerando-se os efeitos eletrônicos e hidrofóbicos exercidos pelos substituintes. A análise dos coeficientes de regressão obtidos sugere haver contribuição preponderante dos efeitos eletrônicos em relação à contribuição do efeito hidrofóbico para a atividade anestésica local. / In the present work nine N,N-[(dimethyl amino)methyl]benzamides-p-X-substituededs hydrochlorides (SERIES II) were prepared from the corresponding bases, (SERIES I), where X = N02, Br, Cl, I, F, H, CH3, OCH3 and N(CH3)3. The purity of the novel compounds, SERIES II, was established by elemental analysis. The recorded infrared and 1HNMR spectra were in agreement with their structures. For both sets of compounds the carbonyl group infrared frequencies in HCCl3 were determined and used as measurement of the polarity of the group. The obtained vC=O (cm-1) values showed excellent correlations when a simple or a multiparameter HAMMETT equation was applied. This suggests that the eletronic effect of the substituents on the carbonyl stretching frequencies is of inductive and ressonanee nature, without predominances of one over the other. Were also determined by peripheryc nervous blockade on rats paw, the degree of local anesthetic activity on seven of the nine compounds of SERIES II. The application of the HANSCH equation to the local anesthetie activity values showed reasonable correlation when the eletronic and hydrophobic effects of the substituents were considered. Analysis of the obtained regression coefficents suggest that the contribution of the former effect to the local anesthetic activity predominants.

Leung Chung Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 142-146). / Abstracts in English and Chinese. / ABSTRACT (ENGISH) --- p.iii / ABSTRACT (CHINESS) --- p.v / ACHKNOWLEDGEMENTS --- p.vii / TABLE OF CONTENTS --- p.viii / Chapter CHAPTER 1 --- Introduction and Background / Chapter 1.1 --- Introduction of Platinum Drugs --- p.1 / Chapter 1.2 --- Mechanism of Action of Cisplatin --- p.3 / Chapter 1.3 --- Structure-Activity Relationships of the Platinum Drug 、 --- p.4 / Chapter 1.4 --- QS AR Parameters --- p.9 / Chapter 1.4.1 --- Chemical Hardness: Descriptor of Chemical Reactivity --- p.9 / Chapter 1.4.2 --- Possible Reaction Pathway of Platinum Drugs --- p.12 / Chapter 1.4.2.1 --- Proposed DNA Binding Pathway of Platinum Drugs --- p.13 / Chapter 1.4.2.1.1 --- Hydrolysis Pathway --- p.13 / Chapter 1.4.2.1.2 --- DNA Binding Pathway Involving the S-containing Biomolecules (Methionine Pathways) --- p.16 / Chapter 1.4.2.1.3 --- Conclusion --- p.21 / Chapter 1.5 --- Thesis Scope --- p.22 / Chapter CHAPTER 2 --- Theory and Methodology / Chapter 2.1 --- Introduction --- p.24 / Chapter 2.2 --- Density Functional Theory (DFT) --- p.24 / Chapter 2.2.1 --- Kohn-Sham Theorem --- p.25 / Chapter 2.2.2 --- Exchange-Correlation Energy Functional --- p.27 / Chapter 2.3 --- Basis Set --- p.27 / Chapter 2.3.1 --- Relativistic Effective Core Potential --- p.27 / Chapter 2.3.2 --- Double-Zeta --- p.28 / Chapter 2.3.3 --- Polarized Basis Set --- p.29 / Chapter 2.4 --- Solvation Model --- p.30 / Chapter 2.4.1 --- Continuum Model --- p.30 / Chapter 2.4.1.1 --- Simple Solvation Model --- p.31 / Chapter 2.4.1.1.1 --- Electrostatic Component --- p.31 / Chapter 2.4.1.1.2 --- Dispersion-Repulsion Interaction --- p.33 / Chapter 2.4.1.1.3 --- Cavitatoin Energy --- p.35 / Chapter 2.4.1.2 --- Polarized Continuum Model --- p.36 / Chapter 2.5 --- Methodology --- p.39 / Chapter 2.5.1 --- Calculation of DFT Global Reactivity Index --- p.39 / Chapter 2.5.1.1 --- Calculation for the Reaction Intermediates --- p.41 / Chapter 2.5.2 --- Calculation of the Reaction Pathways --- p.42 / Chapter CHAPTER 3 --- Results and Discussion / Chapter 3.1 --- Introduction --- p.49 / Chapter 3.2 --- Optimized Structure against Experimental Geometry --- p.49 / Chapter 3.3 --- Kohn-Sham Orbitals --- p.54 / Chapter 3.3.1 --- Location of the HOMO and LUMO --- p.55 / Chapter 3.4 --- Results of the DFT Reactivity Parameter --- p.57 / Chapter 3.5 --- Chemical Structure of the Drugs in the QSAR --- p.64 / Chapter 3.6 --- QSAR Analysis --- p.67 / Chapter 3.6.1 --- The Overall QSAR Plot of the Platinum Drugs --- p.68 / Chapter 3.6.1.1 --- Empirical Applicability of the QSAR on the Platinum(IV) Drugs --- p.70 / Chapter 3.6.1.2 --- Detail QASR Study According to the Type of Platinum Drug --- p.71 / Chapter 3.6.1.2.1 --- QSAR Study of the non-“trans-DACH´ح Platinum Drugs --- p.72 / Chapter 3.6.1.2.1.1 --- "QSAR Equation of the non-""trαns-DACH"" Platinum Drugs" --- p.75 / Chapter 3.6.1.2.2 --- QSAR Analysis for the Pt-trαns-DACH Drugs --- p.77 / Chapter 3.6.1.2.2.1 --- "QSAR Study of trans-S,S-DACH Platinum Drugs" --- p.79 / Chapter 3.6.1.2.2.2 --- "QSAR Study of trans-R,R-DACH Platinum Drugs" --- p.80 / Chapter 3.6.1.3 --- Summary --- p.81 / Chapter 3.7 --- QSAR Study of the Important Intermediates Using Chemical Hardness --- p.82 / Chapter 3.7.1 --- Optimized Structure for the Intermediates --- p.84 / Chapter 3.7.2 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Parent Compounds --- p.90 / Chapter 3.7.3 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Hydrolysis Intermediates --- p.91 / Chapter 3.7.4 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Cyclic-Methionine Intermediates --- p.93 / Chapter 3.7.5 --- Conclusion --- p.95 / Chapter CHAPTER 4 --- Results and Discussion / Chapter 4.1 --- Introduction --- p.96 / Chapter 4.2 --- Study Scheme --- p.97 / Chapter 4.3 --- Optimized Structures --- p.98 / Chapter 4.4 --- Comments on the Reliability of the Calculation Model --- p.103 / Chapter 4.4.1 --- Reaction Profile in the Gas Phase --- p.104 / Chapter 4.4.2 --- Reaction Profiles Using Simple Solvation Model --- p.105 / Chapter 4.4.2.1 --- Defects of the Simple Solvation Model --- p.107 / Chapter 4.4.3 --- Reaction Profile Using PCM-UAHF Solvation Model --- p.109 / Chapter 4.4.3.1 --- Selection of the Reaction Parameters for the QSAR Study --- p.112 / Chapter 4.5 --- QSAR Study of Platinum Drugs Using the Reaction Parameters (AG and ΔG+) --- p.121 / Chapter 4.5.1 --- QSAR Analysis Using ΔG+(hydrolysis) --- p.121 / Chapter 4.5.2 --- QSAR Analysis Using ΔG(hydrolysis) --- p.123 / Chapter 4.5.3 --- QSAR Analysis Using ΔG+(guanine) --- p.125 / Chapter 4.5.4 --- QSAR Analysis Using ΔG(guanine) --- p.127 / Chapter 4.5.5 --- Further investigation of the Bidentate Pt-drugs DNA Binding --- p.129 / Chapter 4.5.5.1 --- Calculation Model --- p.129 / Chapter 4.5.5.2 --- Bidentate Pt-Drugs Reactions --- p.130 / Chapter 4.5.5.3 --- Selection of the Calculated Model for the QSAR Study --- p.133 / Chapter 4.5.5.4 --- QSAR Analysis Using ΔG+(guanine) for the Platinum Drugs with Bidentate Caboxylate Ligands --- p.136 / Chapter 4.5.5.5 --- QSAR Analysis Using ΔG(guanine) for the Platinum Drugs with Bidentate Carboxylate Ligands --- p.137 / Chapter 4.5.6 --- Conclusion --- p.138 / Chapter CHAPTER 5 --- Conclusion Remarks and Future Works / Chapter 5.1 --- Conclusion --- p.140 / Chapter 5.2 --- Future Works --- p.141 / REFERENCES --- p.142

Preparou-se, neste trabalho, nove cloridratos de N,N- [(dimetilamino)metil]benzamidas-p-X-substituidas em que X = N02, Br, Cl, I, F, H, CH3, OCH3 e N(CH3)2, SÉRIE II, ainda não descritos na literatura, a partir das respectivas bases, SÉRIE I. Os compostos obtidos foram identificados por seus espectros de I.V e RMN1H, e suas purezas determinadas por análise elementar e ponto de fusão. A seguir, determinou-se os valores de vC=O (cm-l ) em HCCl3, como medida de sua polaridade tanto para os compostos da SÉRIE I como para os da SÉRIE II. A aplicação da equação de HAMMETT, simples e expandida, aos valores obtidos forneceu excelentes correlações, verificando-se que os efeitos eletrônicos que os substituintes exercem sobre o grupo carbonila são de natureza indutiva e de ressonância, não havendo predominância de um sobre o outro. Determinou-se também, por bloqueio nervoso periférico em pata de rato, o grau de atividade anestésica local de sete dos nove compostos da SÉRIE II. A aplicação da equação de HANSCH aos valores de atividade anestésica local mostrou haver correlação razoável considerando-se os efeitos eletrônicos e hidrofóbicos exercidos pelos substituintes. A análise dos coeficientes de regressão obtidos sugere haver contribuição preponderante dos efeitos eletrônicos em relação à contribuição do efeito hidrofóbico para a atividade anestésica local. / In the present work nine N,N-[(dimethyl amino)methyl]benzamides-p-X-substituededs hydrochlorides (SERIES II) were prepared from the corresponding bases, (SERIES I), where X = N02, Br, Cl, I, F, H, CH3, OCH3 and N(CH3)3. The purity of the novel compounds, SERIES II, was established by elemental analysis. The recorded infrared and 1HNMR spectra were in agreement with their structures. For both sets of compounds the carbonyl group infrared frequencies in HCCl3 were determined and used as measurement of the polarity of the group. The obtained vC=O (cm-1) values showed excellent correlations when a simple or a multiparameter HAMMETT equation was applied. This suggests that the eletronic effect of the substituents on the carbonyl stretching frequencies is of inductive and ressonanee nature, without predominances of one over the other. Were also determined by peripheryc nervous blockade on rats paw, the degree of local anesthetic activity on seven of the nine compounds of SERIES II. The application of the HANSCH equation to the local anesthetie activity values showed reasonable correlation when the eletronic and hydrophobic effects of the substituents were considered. Analysis of the obtained regression coefficents suggest that the contribution of the former effect to the local anesthetic activity predominants.

Xu, Xiao-ping. / "March 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 152-166). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

A reemergência de algumas bactérias Gram-positivas, em particular, do gênero Staphylococcus, como principal foco causador de infecções hospitalares, tem se intensificado nas últimas décadas, e, apesar da existência de potentes fármacos voltados para o tratamento de infecções causadas por este gênero de bactéria, as taxas de morbidade e mortalidade prevalecem com perfil crescente. Além disso, um grande problema associado a cepas de MRSA (Methicillin-Resistant Staphylococcus aureus) é o fenótipo de multi-resistência, característica que confere a este microrganismo resistência não apenas à meticilina como também a uma série de outros fármacos, exceto frente à vancomicina e à teicoplanina. Muito tem se feito, mas ainda são poucos os resultados efetivamente aplicáveis no tratamento de infecções com caráter de multi-resistência, justificando, desta forma, a necessidade de desenvolvimento de sucedâneos que sejam consideravelmente mais efetivos para a solução deste problema. Baseado nestes fatos, a proposta deste estudo envolveu o planejamento, síntese, identificação e estudos de QSAR (Quantitative Structure-Activity Relationships) em duas e três dimensões de derivados 5-nitro-2-tiofilidênicos com atividade antimicrobiana frente a cepas padrão e multi-resistente de Staphylococcus aureus. A escolha dos grupos substituintes foi realizada em duas etapas. Na primeira delas seguiu-se metodologia de substituição em anéis aromáticos proposta por Topliss para a otimização da bioatividade de compostos. Em uma segunda etapa, predominantemente quantitativa, foram selecionados mais alguns derivados baseando-se em faixa de hidrofobicidade ótima pré-determinada experimentalmente e na variação de efeito estérico dos grupos substituintes. Quatorze derivados 5-nitro-2-tiofilidênicos foram sintetizados, estruturalmente identificados e avaliados quanto à atividade antimicrobiana frente às cepas padrão (ATCC 25923) e multi-resistente (3SP/R33) de Staphylococcus aureus por determinação da concentração inibitória mínima empregando-se método de macrodiluição sucessiva em tubos. Salienta-se que a cepa 3SP/R33 se mostra resistente a dezenove antibióticos empregados na prática médica e apresenta suscetibilidade apenas à vancomicina. As concentrações inibitória e bactericida mínimas apresentadas pelos compostos sintetizados mostraram sofrer influência significativa da hidrofobicidade sobre as referidas atividades de acordo com os estudos de QSAR-2D e QSAR-3D, sendo os resultados obtidos para a cepa multi-resistente absolutamente compatíveis com os anteriormente determinados para a cepa padrão. Os estudos de QSAR-2D indicaram que a atividade antimicrobiana das 5nitro-2-tiofilideno benzidrazidas substituídas sofre influência significativa de duas propriedades físico-químicas que são a hidrofobicidade e a distribuição eletrônica. A relevância dos descritores estruturais σ e efe na determinação da atividade antimicrobiana, sinalizam que a distribuição eletrônica influencia fortemente o aumento da potência antimicrobiana dos compostos em estudo tanto pela influência dos efeitos indutivo e de ressonância na estrutura química do ligante, como também pelos campos moleculares gerados ao redor de grupos substituintes, sugerindo uma possível interação dos mesmos com uma área específica do sítio receptor. Nos estudos de QSAR-3D, foi evidenciado, em concordância com o estudo clássico anteriormente realizado, que a hidrofobicidade prevalece como propriedade de fundamental importância no estabelecimento da atividade antimicrobiana. Foi observada a importância da presença de regiões hidrofílicas pontuais nos compostos de forma a propiciar processos de solvatação e dessolvatação que são críticos na difusão através de membranas biológicas. Pode-se afirmar que a análise de QSAR, considerando os aspectos tridimensionais ligantes, ressaltou a necessidade de um balanço lipofílico-hidrofílico para um bom desempenho das 5-nitro-2-tiofilideno benzidrazidas ρ-substituídas como agentes antimicrobianos. A partir dos resultados obtidos evidenciou-se, neste estudo, o forte potencial de derivados 5-nitro-2-tiofilidênicos como possível alternativa para o desenvolvimento racional, em nível molecular, de fármacos voltados para o tratamento de infecções causadas por cepas multi-resistentes de Staphylococcus aureus. / In the last decade, there has been a reemergence of Gram-positive bacteria, in particular Staphylococcus, which isconsidered one of the. most causing of nosocomial infections. Although potent antistaphylococcal drugs are available, this infection continues presenting increasing morbidity and mortality rates. Besides, a serious problem associated with MRSA (Methicillin-Resistant Staphylococcus aureus) is the phenotype of multidrug resistance, which is, resistance not only to methicillin but also to many other drugs, except to vancomycin and teicoplanin. Many efforts have been made in a tentative to reduce this problem, nevertheless there is only a few number of alternatives to combat Staphylococcus aureus multidrug-resistant strains, justifying the necessity of development of more effective compounds to the treatment of these infections. Based in these facts, the purpose of this study was the design, synthesis, structural identification and 2D-QSAR and 3D-QSAR (Quantitative Structure-Activity Relationships) studies of 5-nitro-2-thiophylidene derivatives with antimicrobial activity against multidrug-resistant strains of Staphylococcus aureus. The choice of substituent groups was made in two stages. The first stage comprises on application of Topliss operational scheme for aromatic substitution. In a second quantitative stage, more derivatives were selected according by hydrophobicity range previously determined. Other standard considered at the selection of substituent groups was the variation of steric effect. Fourteen 5-nitro-2-thiophylidene derivatives were synthesized, structural identified and tested against standard (A TCC 25923) and multidrug-resistant (3SP/R33) strains of Staphylococcus aureus. The Minimal Inhibitory Concentration, MIC, was determined using the serial dilution tests in two sequential stages. The 3SP/R33 strain is resistant to nineteen antimicrobial agents in use, except to vancomycin. The minimal inhibitory and bactericidal concentrations of synthesized compounds showed, according by 2D-QSAR and 3D-QSAR studies, a significant influence of hydrophobic properties on antimicrobial activity determination and the results obtained for multidrug-resistant strain were consistent with those determined for A TCC 25923 strain. 2D-QSAR studies showed that antimicrobial activity are mainly influenced by two physico-chemical properties: hydrophobicity and electronic distribution. The relevance of σ e ephe parameters on antimicrobial activity determination, denotes the contribution of inductive and resonance effects for the polar performed by the substituent groups, probably suggesting an interaction between them and specific receptor site. 3D-QSAR studies showed that hydrophobicity is a essential property to antimicrobial activity determination, sustained the same conclusions previously obtained by Hansch Analysis. It was observed a great concern of small hydrophilic regions distributed on derivatives in order to promote solvation and desolvation process, that have critical importance on diffusion process through the biological membranes. QSAR studies considering three-dimensional properties of ligands indicated the necessity of accurate hydrophilic-hydrophobic balance on nitrothiophene derivatives for their good performance as antimicrobial agents. The results obtained in this preliminary study have shown the potential of synthesized compounds as alternatives to the treatment of infections caused by multidrug-resistant strains of Staphylococcus aureus.

Le chondrosarcome (CHS), cancer du cartilage est une tumeur chimio- et radiorésistance dont le seul traitement efficace reste la chirurgie. Une prodrogue vectorisée et activable en hypoxie, ICF05016, est actuellement développée par l’UMR 1240, et évaluée en préclinique comme potentielle alternative théra-peutique pour ce cancer. La structure de cette molécule regroupe i) une moutarde cytotoxique, ii) un vecteur ammonium quaternaire chargé positivement possédant un tropisme pour l’aggrécane, protéoglycane majoritaire de la matrice extracellulaire tumorale, iii) une gâchette de type 2-nitroimidazole permettant une activation sélective en situation d’hypoxie, une des caractéristiques principales du CHS.Ces travaux de thèse ont consisté à pharmaco-moduler cette prodrogue bispécifique ICF05016 en modifiant la position du vecteur ainsi que la nature de l’agent cytotoxique. Ainsi sept prodrogues vectorisées ont été synthétisées présentant une chaine vectrice N,N,N-triméthylpropylaminium soit en C-4, soit en N-1 du cycle imidazole. Leur activation par réduction chimique, mimant l’hypoxie, ainsi que leur affinité pour l’aggrécane ont été confirmées in tubo par des analyses de RMN 31P et de SPR, toutefois elles se sont avérées non sélectives en termes de cytotoxicité (CI50 comprises entre 15 et 1 µM, et ce, quelles que soient les conditions d’oxygénation) et faiblement sensibles à une bio-réduction enzymatique. La fonctionnalisation par un vecteur ammonium quaternaire de la gâchette 2-nitroimidazole annihile donc l’activation en hypoxie des prodrogues.Cette stratégie a ensuite été étendue au cancer de la prostate en remplaçant le vecteur ammonium quaternaire par un ligand de type urée affin pour l’antigène membranaire spécifique de la prostate (PSMA). La première molécule synthétisée, qui possède un espaceur triazole, a démontré une affinité pour le récepteur PSMA, par une étude de compétition avec un radioligand, ainsi qu’une activation in tubo par bioréduction enzymatique. Toutefois aucune cytotoxicité n’a été constatée sur les lignées LNCaP-Luc et PC3-Luc. Une seconde molécule combinant un espaceur triazole avec une séquence peptidique identifiée pour la molécule PSMA-617, actuellement en cours d’essai clinique, est actuellement développée mais sa synthèse doit être optimisée, notamment au niveau de l’étape de cycloaddition 1,3-dipolaire. / Chondrosarcoma (CHS), the malignant tumor of the cartilage, is a chemo- and radio-resistant cancer. Surgical resection is still considered the mainstay of treatment of this pathology. A dual targeted hypoxia-activated prodrug, ICF05016 was developed by the UMR 1240 and evaluated in preclinical studies as a potential therapeutic alternative for CHS. The latter is a nitroheteroaryl-based compound designed as follows: a phosphorodiamidic mustard functionalized with a quaternary ammonium (QA) used as targeting function, and a 2-nitroimidazole group to trigger fragmentation and then release the bis-alkylating mustard anion by bioreduction under hypoxic conditions, chemical hallmark of CHS.This project deals with the pharmacomodulation of ICF05016, more specifically by modification of the position of the targeting moiety as well as the nature of the cytotoxic agent. Seven QA-targeted prodrugs have been synthesized with N,N,N-trimethylpropylaminium tethered to the imidazole either in the C-4, or the N-1 position. These prodrugs were cleaved in vitro under chemical reductive conditions, which mimic in vivo hypoxia conditions. In addition, the binding of these derivatives to aggrecan was highlighted by surface plasmon resonance. In vitro assays on human CHS cells (H-EMC-SS) demonstrated quite equivalent cytotoxicities, whatever the oxygen conditions used and their evaluation as substrate of an oxygen-insensitive nitroreductase revealed the almost total lack of activation. A QA targeting moiety grafted on the trigger seems to alter hypoxia activation.New prodrugs with prostate specific membrane antigen (PSMA)-targeting ligand were synthesized to extend this HAP strategy to prostate cancer. The first tested compound, having a triazole spacer, presented selective affinity for PSMA in an in vitro binding experiment as well as activation under enzymatic reduction. However, no cytotoxicity was observed on LNCaP-Luc and PC3-Luc cells. The synthesis of a prodrug combining the spacer of PSMA-617, currently in clinical trial, and a propyltriazole moiety, was initiated but the 1,3-dipolar cycloaddition still need to be optimized.