Le développement de nouvelles méthodologies de synthèse douces et soucieuses de l'environnement apparait de nos jours comme un véritable besoin. Dans ce contexte, la chimie radicalaire permet de réaliser une grande variété de réactions grâce à des initiations douces (électrochimique ou photochimique). Les indoles tétracycliques et les molécules gem-difluoroacylées étant présent dans de nombreux composé d'intérêt thérapeutique, sont des cibles pertinentes pour le développement de méthodes de synthèse radicalaire. Des indoles tétracycliques 3,4-fusionnés ont été synthétisés par Substitution Radicalaire Nucléophile Unimoléculaire (SRN1). Connue depuis les années 1960, la réaction SRN1 permet de réaliser des réactions de couplages entre un nucléophile et un accepteur d'électrons par un processus radicalaire. D'autre part, des indoles tétracycliques gem-difluoroacylés ont été synthétisés par cyclisation radicalaire tandem, initiée par catalyse électrochimique et photoredox. La catalyse photoredox, similaire à la catalyse électrochimique a connu un essor depuis sa redécouverte à la fin des années 2000. Elle est basée sur l'emploi d'un photocatalyseur qui peut être excité sous irradiation visible pour devenir oxydant ou réducteur / The development of new, soft and ecofriendly synthetic methodologies is today a real need. In this context, radical Chemistry allows to make a wide diversity of reactions thanks to soft initation steps (electrochemical or photochemical). Tetracyclic indoles and gem-difluoroacyles molecules, present in a lot of therapeutic compounds, appeared as relevant targets. 3,4-fused tetracyclic indoles, had been synthesized by Unimolecular Nucleophilic Radical Substitution (SRN1). Since the 1960s, SRN1 reaction allows coupling reactions between a nucleophilic species and a radical acceptor to be performed. On the other hand, gem-difluoroacyles tetracyclic indoles had been synthesized by tandem radical cyclisation initiated by electrochemical and photoredox catalysis. Since its rediscovery by the end of the 2000s, photoredox catalysis, similar to electrocatalysis, had seen an increasing interest. Photoredox catalysis is based on the use of a photocatalyst that become an oxidant or a reductant under visible irradiation

This dissertation describes an introduction, background and research progress in the areas of multitargeted single agents and tubulin inhibitors in cancer chemotherapy and selective Toxoplasma gondii TS inhibitors for the treatment of toxoplasmosis.<br> Tubulin inhibitors are important antitumor agents that disrupt microtubule dynamics. Thymidylate synthase (TS) inhibitors prevent cell division by interfering with de novo thymidylate synthesis. Antiangiogenic agents target tumor angiogenesis crucial for tumor growth and metastasis. Under normal circumstances, angiogenesis is typically limited to tumor cells and is mediated by receptor tyrosine kinases (RTKs). Combination chemotherapies of RTK inhibitors with cytotoxic agents that target either TS or tubulin have shown significant promise and several preclinical and clinical studies with such combinations are in progress. Multitargeted single agents with dual antiangiogenic and cytotoxic mechanisms could avoid the major limitations associated with cancer chemotherapy: multidrug resistance and dose limiting toxicities. This dissertation focuses on the design and synthesis of pyrimido[4,5-b]indoles and furo[2,3-d]pyrimidines as potential single agents with dual antiangiogenic and cytotoxic activities. These efforts led to the identification of structural features that are necessary for inhibition of RTKs and/or tubulin polymerization. Novel synthetic strategies were developed for efficient synthesis of 2,4-diamino-5-thioaryl-pyrimido[4,5-b]indoles and 4-anilino-5-methyl-furo[2,3-d]pyrimidines.<br> Taxanes and vinca alkaloids are widely used tubulin inhibitors in cancer chemotherapy. However, their clinical use is compromised by two major mechanisms of drug resistance: the overexpression of Pgp and bIII-tubulin. This dissertation describes the design and synthesis of pyrimido[4,5-b]indoles as tubulin inhibitors that circumvent Pgp and bIII-tubulin mediated resistance. This work identified the structural features crucial for tubulin inhibition for the pyrimido[4,5-b]indole scaffold.<br> Infection by Toxoplasma gondii can lead to toxoplasmosis in immune compromised patients such as organ transplant, cancer and AIDS patients. Current therapy involving combination of sulfadiazine and pyrimethamine is limited by drug resistance and treatment failures. The thymidylate synthase‒dihydrofolate reductase enzyme is important for thymidylate synthesis in T. gondii, and hence can be targeted to treat T. gondii infection. TS is highly conserved across species and selectivity for tgTS over human TS is significantly more challenging. The present work provides an efficient synthesis of 2-diamino-4-oxo-5-thioaryl-pyrimido[4,5-b]indoles as selective tgTS inhibitors. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Medicinal Chemistry / PhD; / Dissertation;

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

by Poon Yam Kau. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 174-183). / Abstract --- p.1 / Chapter Chapter 1 --- General Introduction / Chapter 1.1 --- Discovery of melatonin --- p.4 / Chapter 1.2 --- Biosynthesis of melatonin --- p.4 / Chapter 1.3 --- Physiology of melatonin and other pineal indoles --- p.5 / Chapter 1.4 --- Relationship between pineal indoles and cancers --- p.6 / Chapter 1.5 --- Macrophages --- p.9 / Chapter 1.6 --- Lymphocytes --- p.11 / Chapter Chapter 2 --- Effects of different light/dark cycles on serum melatonin level in mice and effect of melatonin-feeding on serum glutamate-oxaloacetate transaminase (GOT) activity in mice / Chapter 2.1 --- Introduction --- p.14 / Chapter 2.2 --- Materials and methods --- p.15 / Chapter 2.3 --- Results --- p.22 / Chapter 2.4 --- Discussion --- p.23 / Chapter Chapter 3 --- Actions of endogenous and exogenous melatonin on murine peritoneal macrophages / Chapter 3.1 --- Introduction --- p.27 / Chapter 3.2 --- Materials and methods --- p.28 / Chapter 3.3 --- Results --- p.33 / Chapter 3.4 --- Discussion --- p.36 / Chapter Chapter 4 --- Actions of endogenous and exogenous melatonin on murine splenic lymphocytes / Chapter 4.1 --- Introduction --- p.55 / Chapter 4.2 --- Materials and methods --- p.56 / Chapter 4.3 --- Results --- p.62 / Chapter 4.4 --- Discussion --- p.69 / Chapter Chapter 5 --- In vitro effects of melatonin on murine peritoneal macrophages and splenic lymphocytes / Chapter 5.1 --- Introduction --- p.105 / Chapter 5.2 --- Materials and methods --- p.106 / Chapter 5.3 --- Results --- p.109 / Chapter 5.4 --- Discussion --- p.113 / Chapter Chapter 6 --- Effects of methoxytryptamine on murine peritoneal macrophages and splenic lymphocytes / Chapter 6.1 --- Introduction --- p.125 / Chapter 6.2 --- Materials and methods --- p.126 / Chapter 6.3 --- Results --- p.129 / Chapter 6.4 --- Discussion --- p.132 / Chapter Chapter 7 --- In vitro effects of pineal indoles on cultured tumor cell lines / Chapter 7.1 --- Introduction --- p.145 / Chapter 7.2 --- Materials and methods --- p.146 / Chapter 7.3 --- Results --- p.148 / Chapter 7.4 --- Discussion --- p.152 / Chapter Chapter 8 --- General Discussion --- p.170 / References --- p.174

本論文報導了幾個系列的新型鋅酞菁配合物以及氟硼二吡咯染料的合成與表徵。 這些精心設計的化合物可作為高效的和選擇性的光敏劑應用於靶向性光動力療法和細菌的光動力失活。 / 第一章概述了光動力療法，包括歷史發展、光物理和生物機制及其臨床應用現狀。 重點介紹了用於靶向性光動力療法的第三代光敏劑，其中包括基於靶向性配體、納米載體的光敏劑以及可激活的光敏劑。 另外，本章還簡單介紹了用於抗菌光動力療法的光敏劑。 / 第二章報導了一種新型的由細胞核定位的短肽共軛修飾的鋅酞菁配合物的合成與表徵。 此短肽分子的氨基酸序列為：Gly-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val。 我們研究了該化合物的光物理性質、聚集行為以及離體光動力活性，同時與其非肽共軛修飾的化合物進行了詳細的比較。 利用HT29人結腸腺癌細胞，研究發現此多肽共軛修飾的酞菁展示了較高的細胞吸收、更高的細胞內活性氧的產生效率和光毒性。 同時活體實驗證明此化合物增加了酞菁在裸鼠腫瘤的停留時間。 這些結果在本章中均進行了詳細的報導。 / 第三章敘述了另一種多肽共軛修飾的鋅酞菁化合物的製備和光物理性質。 這個多肽包含了一個環狀的氨基酸序列，即 Arg-Gly-Asp-D-Phe-Lys，此多肽被認為能以腫瘤相關的血管新生時的高表達的跨膜受體（如 α[subscript v]β₃ 整合素）為靶向。 利用 α[subscript v]β₃ 整合素高表達的 U87-MG 人惡性膠質瘤細胞，我們研究了這個化合物的細胞吸收、細胞內活性氧的產生、離體光動力活性以及亞細胞定位。 同時，用 α[subscript v]β₃ 整合素低表達的 MCF-7 人乳腺癌細胞作為對照。 / 通常，腫瘤細胞外的pH值比正常細胞組織的低，因此，我們合成一個由酸敏感的縮醛鍵連接的酞菁二聚體。 此二聚體會發生自身淬滅且對pH有響應。 通過電子吸收和熒光光譜， 我們詳細地研究了這個化合物在不同酸性條件下的光物理性質和斷開動力學。 由於酞菁環具有強的二聚化趨勢，這個二聚體能自身淬滅，因而呈現“失活狀態。 通過降低檸檬酸緩衝液的pH值，這個化合物的乙縮醛鍵能優先斷開，並且斷開的速率隨pH值的降低而增加。 兩個酞菁環的分開增強了熒光強度和單態氧的產生。 這個二聚光敏劑還能在 HT29 細胞內被激活，從而產生較強的細胞內熒光。 相比之下，由乙二醇鏈連接的類似物基本上沒有熒光發射。 同時，這個可斷開的二聚物對HT29細胞光毒性也比不可斷開的類似物高（半致死量：IC₅₀ = 0.35 vs. 0.59 μM）。 第四章對這些結果進行了詳細的報導。 / 在第五章中，我們報導了兩種以腫瘤靶向配體葉酸共軛修飾的二（苯乙烯基）－氟硼二吡咯衍生物的合成、光譜表徵以及光物理性質。 在這兩個化合物中，葉酸和二（苯乙烯基）－氟硼二吡咯是通過不同長度的乙二醇鏈連接的。 我們研究了這兩個化合物的鏈長對KB人鼻咽癌細胞和MCF-7細胞的吸收和離體光動力活性的影響。 前者能高表達葉酸受體，而後者作為低葉酸受體表達的一個對照。 與MCF-7細胞相比，兩個化合物都展示了對KB細胞較高的吸收和光毒性（半致死量：IC₅₀ = 0.062 vs. 2.56 μM 和0.177 vs. 0.995 μM）。 此外，具有較長鏈的化合物優先定位在溶酶體中，而較短鏈的那個化合物則較多停留在細胞的內質網。 / 第六章重點開發了一系列多胺以及不同長度的聚賴氨酸（包括2、4、8個賴氨酸）共軛修飾的鋅酞菁配合物，并用於抗菌光動力療法。 我們報導了它們的合成、光物理性質以及對甲氧西林青霉素敏感的格蘭陽性金黄色釀膿葡萄球菌和格蘭陰性綠膿桿菌的光動力抗菌活性。 其中，三-N-甲基化的酞菁顯示了特別高的效果，在濃度為16 nM時，能降低大於5 log10 的金黄色釀膿葡萄球菌。 / 第七章闡述了前面幾章的實驗部份。 論文的最後附上所有新化合物的核磁共振氫譜和碳譜。 / This thesis describes the synthesis and characterization of several series of novel zinc(II) phthalocyanines and boron dipyrromethenes (BODIPYs), which are carefully designed as efficient and selective photosensitizers for targeted photodynamic therapy (PDT) and photodynamic inactivation of bacteria. / Chapter 1 presents an overview of PDT, including its historical development, photophysial and biological mechanisms, and current research directions. Emphasis is placed on the third-generation photosensitizers for targeted PDT, including targeting ligand-based photosensitizers, nanoparticle-based photosensitizers, and activatable photosensitizers. A brief review of photosensitizers that can be used for antimicrobial PDT is also given. / Chapter 2 reports the synthesis and characterization of a novel zinc(II) phthalocyanine conjugated with a short peptide with a nuclear localization sequence, namely Gly-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val. The photophysical properties, aggregation behavior, and in vitro photodynamic activity of this compound have been investigated and compared with its non-peptide-conjugated analogue. It has been found that the peptide-conjugated phthalocyanine shows an enhanced cellular uptake, higher efficiency in generating intracellular reactive oxygen species (ROS), higher photocytotoxicity against HT29 human colorectal adenocarcinoma cells, and enhanced tumor-retention property in tumor-bearing nude mice. The results are reported in detail in this chapter. / Chapter 3 describes the preparation and photophysical properties of another analogue conjugated with a peptide containing the cyclic Arg-Gly-Asp-D-Phe-Lys sequence, which is known to target the upregulated transmembrane protein receptors such as α[subscript v]β₃ integrin during angiogenesis. The cellular uptake, intracellular ROS generation, in vitro photodynamic activity, and subcellular localization of this conjugate have been investigated against U87-MG human glioblastoma cells, which have a high expression of α[subscript v]β₃ integrin. MCF-7 human breast adenocarcinoma cells, which have a low expression of α[subscript v]β₃ integrin, have been used as a negative control. / On the base that the extracellular pH in tumors is generally lower than that in normal tissues, we have developed a pH-responsive self-quenched phthalocyanine dimer connected with an acid-sensitive ketal linker. The basic photophysical properties of this compound and its cleavage kinetics upon exposure to different acidic conditions have been extensively studied by electronic absorption and fluorescence spectroscopy. Owing to the strong dimerization tendency of the phthalocyanine ring, this dimer is self-quenched and in the "OFF" state. By lowering the pH (< 6.5) in citrate buffer solutions, the linker is preferentially cleaved, and the rate of cleavage increases as the pH decreases. The separation of the phthalocyanine moieties leads to enhancement in fluorescence intensity and singlet oxygen production. This dimeric photosensitizer can also be activated inside HT29 cells causing strong intracellular fluorescence. By contrast, the fluorescence is hardly observed for the non-cleavable ethylene glycol-linked analogue. The photocytotoxicity of the cleavable dimer is also higher than that of the non-cleavable counterpart (IC₅₀ = 0.35 vs. 0.59 μM). The results are reported in detail in Chapter 4. / In Chapter 5, we describe the synthesis, characterization, and photophysical properties of two distyryl BODIPY derivatives conjugated with a folic acid as a tumor-targeting ligand via an ethylene glycol spacer with different chain length. The effects of the chain length on the cellular uptake and in vitro photodynamic activities of these compounds have been examined against KB human nasopharyngeal epidermal carcinoma cells and MCF-7 cells. The former are known to have a high expression of folate receptors, while the latter have been used as a negative control. Both compounds show enhanced cellular uptake and higher photocytotoxicity toward KB cells when compared with MCF-7 cells (IC₅₀ = 0.062 vs. 2.56 μM and 0.177 vs. 0.995 μM). The conjugate with a longer spacer shows preferential localization in the lysosomes, while the analogue with a shorter linker accumulates in the endoplasmic reticulum of the cells. / Chapter 6 focuses on the development of a series of zinc(II) phthalocyanines substituted with a polyamine moiety or a polylysine chain containing 2, 4, or 8 lysine units for antimicrobial PDT. Their synthesis, photophysical properties, and photodynamic antimicrobial activities against Gram (+) methicillin-sensitive Staphylococcus aureus and Gram (-) Pseudomonas aeruginosa are reported. The tri-N-methylated phthalocyanine is particularly potent showing a more than 5 log₁₀ reduction of the Staphylococcus aureus at 16 nM. / Chapter 7 gives the experimental details for the work described in the preceding chapters. ¹H and ¹³C{¹H} NMR of all the new compounds are given in the Appendix. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Ke, Meirong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 159-176). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / Abstract (in Chinese) --- p.v / Acknowledgment --- p.viii / Table of Contents --- p.xi / List of Figures --- p.xvi / List of Schemes --- p.xxiv / List of Tables --- p.xxv / Abbreviations --- p.xxvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Introduction of Photodynamic Therapy --- p.1 / Chapter 1.2 --- Mechanisms of Photodynamic Therapy --- p.2 / Chapter 1.2.1 --- Photophysical Mechanisms --- p.2 / Chapter 1.2.2 --- Biological Mechanisms --- p.4 / Chapter 1.3 --- Clinical Status of Photodynamic Therapy --- p.5 / Chapter 1.4 --- Overview of Photosensitizers --- p.7 / Chapter 1.5 --- Targeted Photodynamic Therapy --- p.13 / Chapter 1.5.1 --- Targeting Ligand-Based Photosensitizers --- p.13 / Chapter 1.5.1.1 --- Synthetic Peptides --- p.13 / Chapter 1.5.1.2 --- Proteins --- p.16 / Chapter 1.5.1.3 --- Aptamers --- p.18 / Chapter 1.5.1.4 --- Folic acid --- p.19 / Chapter 1.5.1.5 --- Other Biological Ligands --- p.20 / Chapter 1.5.2 --- Nanoparticle-Based Photosensitizers --- p.20 / Chapter 1.5.2.1 --- Biodegradable Nanoparticle-Based Photosensitizers --- p.21 / Chapter 1.5.2.2 --- Non-Biodegradable Nanoparticle-Based Photosensitizers --- p.23 / Chapter 1.5.3 --- Activatable Photosensitizers --- p.25 / Chapter 1.5.3.1 --- Environment-Activated Photosensitizers --- p.26 / Chapter 1.5.3.2 --- Enzyme-Activated Photosensitizers --- p.27 / Chapter 1.5.3.3 --- Nucleic Acid-Activated Photosensitizers --- p.29 / Chapter 1.6 --- Antimicrobial Photodynamic Therapy --- p.32 / Chapter 1.6.1 --- General Introduction --- p.32 / Chapter 1.6.2 --- Photosensitizers for Antimicrobial Photodynamic Therapy --- p.34 / Chapter Chapter 2 --- A Phthalocyanine-Peptide Conjugate with High in vitro Photodynamic Activity and Enhanced in vivo Tumor-Retention Property --- p.36 / Chapter 2.1 --- Introduction --- p.36 / Chapter 2.2 --- Results and Discussion --- p.37 / Chapter 2.2.1 --- Molecular Design and Synthesis --- p.37 / Chapter 2.2.2 --- Electronic Absorption and Photophysical Properties --- p.42 / Chapter 2.2.3 --- In Vitro Photodynamic Activities --- p.44 / Chapter 2.2.4 --- In Vivo Studies --- p.50 / Chapter 2.3 --- Conclusion --- p.52 / Chapter Chapter 3 --- Synthesis, Characterization, and Photodynamic Activity of a cylic RGD-Conjugated Phthalocyanine --- p.53 / Chapter 3.1 --- Introduction --- p.53 / Chapter 3.2 --- Results and Discussion --- p.54 / Chapter 3.2.1 --- Molecular Design and Synthesis --- p.54 / Chapter 3.2.2 --- Electronic Absorption and Photophysical Properties --- p.57 / Chapter 3.2.3 --- In Vitro Photodynamic Activities --- p.59 / Chapter 3.3 --- Conclusion --- p.67 / Chapter Chapter 4 --- A pH-Responsive Fluorescent Probe and Photosensitizer Based on the Dimerization Property of Phthalocyanines --- p.69 / Chapter 4.1 --- Introduction --- p.69 / Chapter 4.2 --- Results and Discussion --- p.70 / Chapter 4.2.1 --- Synthesis and Characterization --- p.70 / Chapter 4.2.2 --- Electronic Absorption and Photophysical Properties --- p.74 / Chapter 4.2.3 --- In Vitro Studies --- p.80 / Chapter 4.3 --- Conclusion --- p.84 / Chapter Chapter 5 --- Synthesis, Characterization, and Photodynamic Activities of BODIPY-Folate Conjugates --- p.86 / Chapter 5.1 --- Introduction --- p.86 / Chapter 5.2 --- Results and Discussion --- p.87 / Chapter 5.2.1 --- Synthesis and Characterization --- p.87 / Chapter 5.2.2 --- Electronic Absorption and Photophysical Properties --- p.92 / Chapter 5.2.3 --- In Vitro Studies --- p.94 / Chapter 5.3 --- Conclusion --- p.100 / Chapter Chapter 6 --- Synthesis, Characterization, and Antimicrobial Photodynamic Activities of Cationic Phthalocyanines --- p.102 / Chapter 6.1 --- Introduction --- p.102 / Chapter 6.2 --- Results and Discussion --- p.103 / Chapter 6.2.1 --- Synthesis and Characterization --- p.103 / Chapter 6.2.2 --- Electronic Absorption and Photophysical Properties --- p.108 / Chapter 6.2.3 --- In Vitro Photodynamic Antimicrobial Activities --- p.112 / Chapter 6.3 --- Conclusion --- p.114 / Chapter Chapter 7 --- Experimental Section --- p.115 / Chapter 7.1 --- General --- p.115 / Chapter 7.2 --- Synthesis --- p.119 / Chapter 7.2.1 --- Synthesis for Chapter 2 --- p.119 / Chapter 7.2.2 --- Synthesis for Chapter 3 --- p.125 / Chapter 7.2.3 --- Synthesis for Chapter 4 --- p.128 / Chapter 7.2.4 --- Synthesis for Chapter 5 --- p.132 / Chapter 7.2.5 --- Synthesis for Chapter 6 --- p.138 / Chapter 7.3 --- pH-Response Properties of 4.6 and 4.7 in Citrate Buffer Solutions --- p.143 / Chapter 7.4 --- In Vitro Studies --- p.144 / Chapter 7.4.1 --- Cell Lines and Culture Conditions --- p.144 / Chapter 7.4.2 --- Photocytotoxicity Assay --- p.145 / Chapter 7.4.3 --- Photodynamic Antimicrobial Inactivatoin Studies --- p.147 / Chapter 7.4.4 --- Intracellular ROS Measurements --- p.148 / Chapter 7.4.5 --- Cellular Uptake (Determined by Extraction Method) --- p.149 / Chapter 7.4.6 --- Cellular Uptake (Determined by Confocal Microscopy) --- p.150 / Chapter 7.4.7 --- Cellular Uptake (Determined by Flow Cytometry) --- p.152 / Chapter 7.4.8 --- Fluorescence Microscopic Studies --- p.153 / Chapter 7.4.9 --- Subcellular Localization Studies --- p.153 / Chapter 7.4.10 --- pH-Dependent Intracellular Fluorescence Studies --- p.155 / Chapter 7.5 --- In Vivo Imaging and Ex Vivo Organ Biodistribution --- p.156 / Chapter Chapter 8 --- Conclusion and Outlook --- p.157 / References --- p.159 / Chapter Appendix --- NMR Spectra of New Compounds --- p.177

Leung, Ching Hei. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 101-110). / Abstracts in English and Chinese. / Acknowledgements --- p.i / 摘要（Abstract in Chinese) --- p.iii / Abstract --- p.v / List of Abbreviations --- p.vii / List of Figures and Tables --- p.ix / Table of Content --- p.xi / Chapter CHAPTER 1 --- Introduction / Chapter 1.1 --- History and development of photodynamic therapy --- p.1 / Chapter 1.2 --- Basic principle of photodynamic therapy: the beauty of the treatment --- p.3 / Chapter 1.3 --- "Photosensitizers: From discovery, synthesis to modifications" --- p.6 / Chapter 1.4 --- Enhancement of selective retention of PS in cancerous tissue --- p.10 / Chapter 1.5 --- Development of silicon (IV) phthalocyanine derivatives --- p.14 / Chapter 1.6 --- Death mechanisms in photodynamic therapy --- p.17 / Chapter 1.7 --- Objectives of the present study --- p.18 / Chapter CHAPTER 2 --- Materials and Methods / Chapter 2.1 --- Synthesis of BAM-SiPc --- p.20 / Chapter 2.2 --- Preparation of BAM-SiPc solution for photodynamic treatment --- p.20 / Chapter 2.3 --- Cell line and culture conditions --- p.21 / Chapter 2.4 --- Animal tumor model --- p.23 / Chapter 2.5 --- PDT laser source --- p.23 / Chapter 2.6 --- In vitro photodynamic activity assay --- p.23 / Chapter 2.6.1 --- Preparation of cells for photodynamic treatment / Chapter 2.6.2 --- In vitro photodynamic treatment / Chapter 2.6.3 --- Cell viability assay / Chapter 2.7 --- "Determination of reactive oxygen species production by 2',7'- dichlorofluorescein diacetate (DCFDA) assay" --- p.28 / Chapter 2.8 --- Analysis of cell cycle arrest --- p.28 / Chapter 2.9 --- Biodistribution of BAM-SiPc --- p.29 / Chapter 2.10 --- In vivo photodynamic treatment --- p.30 / Chapter 2.11 --- Assay for plasma enzyme activities --- p.30 / Chapter 2.12 --- Determination of cellular uptake of BAM-SiPc --- p.31 / Chapter 2.13 --- Metabolism of BAM-SiPc --- p.31 / Chapter 2.14 --- Histochemical staining --- p.32 / Chapter 2.14.1 --- Preparation of paraffin-embedded tissue section / Chapter 2.14.2 --- Haematoxylin and Eosin (H & E) staining / Chapter 2.14.3 --- Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay / Chapter 2.15 --- Conjugation of BAM-SiPc with LDL --- p.34 / Chapter 2.15.1 --- Analysis of the phototoxicity and cellular uptake of BAM- SiPc in the presence of LDL / Chapter 2.15.2 --- Gel filtration analysis of the mixture of LDL and BAM- SiPc / Chapter 2.16 --- Statistical analysis --- p.35 / Chapter CHAPTER 3 --- Results / Chapter 3.1 --- In vitro photodynamic activity assays --- p.36 / Chapter 3.2 --- Tissue distribution of BAM-SiPc in HepG2- bearing nude mice --- p.39 / Chapter 3.3 --- Anti-tumor activities of in vivo PDT with BAM-SiPc --- p.42 / Chapter 3.3.1 --- In vivo effect of PDT treatment with BAM-SiPc on HepG2 and HT29 tumor growth / Chapter 3.3.2 --- Dosage effect on anti-tumor activities by BAM-SiPc mediated PDT / Chapter 3.4 --- Analysis of intrinsic toxicity induced by BAM-SiPc mediated PDT --- p.48 / Chapter 3.4.1 --- H & E staining of liver sections of nude mice after in vivo PDT / Chapter 3.4.2 --- Plasma enzyme activity assays of PDT treated mice / Chapter 3.5 --- BAM-SiPc metabolism in in vitro culture cells and liver homogenate --- p.53 / Chapter 3.5.1 --- Cellular uptake of BAM-SiPc / Chapter 3.5.2 --- BAM-SiPc metabolism in cultured normal liver cells and cancer cells / Chapter 3.5.3 --- BAM-SiPc metabolism by mice liver homogenate / Chapter 3.6 --- Death mechanism induced by BAM-SiPc mediated PDT --- p.62 / Chapter 3.6.1 --- Events related to cell death induced by in vitro BAM-SiPc mediated PDT / Chapter 3.6.2 --- Death mechanism exerted by in vivo BAM-SiPc mediated PDT / Chapter 3.7 --- Effect on phototoxicity of BAM-SiPc in the presence of LDL --- p.70 / Chapter 3.7.1 --- Effect on phototoxicity of BAM-SiPc after mixing BAM- SiPc with LDL / Chapter 3.7.2 --- Gel filtration for analysis of the LDL-BAM-SiPc mixture / Chapter CHAPTER 4 --- Discussion / Chapter 4.1 --- Anti-cancer effect of BAM-SiPc on different cancer cell lines --- p.76 / Chapter 4.2 --- Tissue distribution of BAM-SiPc in HepG2 bearing nude mice --- p.77 / Chapter 4.3 --- In vivo effect of BAM-SiPc mediated PDT on HepG2 and HT29 tumor growth --- p.80 / Chapter 4.4 --- Analysis of the safety of using BAM-SiPc as a potential agent in PDT --- p.83 / Chapter 4.5 --- Metabolism of BAM-SiPc --- p.84 / Chapter 4.6 --- Mechanism of the apoptosis triggered by BAM-SiPc mediated PDT --- p.88 / Chapter 4.7 --- Death mechanism induced by in vivo PDT with BAM-SiPc --- p.93 / Chapter 4.8 --- Phototoxicity of BAM-SiPc in the presence of LDL --- p.94 / Chapter CHAPTER 5 --- Conclusion and Future perspective / Chapter 5.1 --- Conclusion --- p.97 / Chapter 5.2 --- Future perspective --- p.98 / References

For the purpose of incorporating indoles into organometallic complexes for catalysis, as well as in the generation of new heterocyclic systems, various reactions have been carried out at C2, C6 and C7 of the indole system. In order to achieve this, 3-substituted 4,6-dimethoxyindoles and 6-hydroxy- 4-methoxyindoles were necessary as starting materials. Consequently, a lithium-bromide-templated one-pot procedure for the synthesis of some 3-substituted 4,6-dimethoxyindoles and a selective demethylation procedure for 3-substituted 6-hydroxy-4-methoxyindoles were developed. Various kinds of novel methylene-bridged bi-, tri-, and tetradentate pyridyl-indole ligands were synthesised via Vilsmeier-Haack, Friedel-Crafts or electrophilic addition reactions on the indole heterocycle. However, their metal complexing properties were generally weak and variable. Nevertheless, some of the tridentate pyridylindole ligands showed strong anion binding to halides, whereas a remarkable ligand transformation occurred with a bidentate 2-pyridylindole ligand and zinc(II), giving a substituted indolo[2,3-c]pyrrolo-[3,2,1-ij]quinoline system. Two new types of tetradentate Schiff base ligands were prepared from 2-formyl-indoles and 7-formyl-6-hydroxyindoles, and diamines. These preformed ligands were reacted with first- and second-row transition metals to give neutral metal complexes. Novel heterocyclic systems such as 4H-pyrrolo[3,2,1-ij]quinolines, 3H-pyrrolo-[1,2-a]indoles, and 1H-furo[2,3-g]indoles were synthesised from 2-formyl-, 7-formyl-, and 6-hydroxyindoles, utilising mainly intra-molecular Wittig reactions, Claisen-Schmidt condensations or acid- and base-catalysed cyclisations. A common feature of the prepared 4H-pyrrolo[3,2,1-ij]quinolines and 3H-pyrrolo-[1,2-a]indoles was their intense fluorescent character, which was examined as well.

L'azaelliptitoxine, molécule antitumorale, a été élaborée par modélisation moléculaire à partir des structures de l'ellipticine et de l'étoposide. La présence de deux motifs 2 et 3-indolylméthanamines dans le squelette de ses dérivés 11-aminés, aussi biologiquement actifs, nous a conduit à développer deux stratégies de synthèse stéréosélectives de ces composés, basées sur la méthodologie d'addition nucléophile de l'indole sur les nitrones alpha-chirales développée au laboratoire. La première stratégie a nécessité la préparation énantiosélective d'un nouveau sérinal précurseur de la nitrone considérée, dont le motif bêta-aminoalcool est protégé sous la forme d'une oxazolidinone. L'addition nucléophile de l'indole en milieu acide sur cette nitrone a permis l'obtention de deux hydroxylamines diastéréoisomères, conduisant à la formation stéréosélective de quatre dérivés 11-aminés de l'azaelliptitoxine avec de bons rendements. Une seconde stratégie a été imaginée, mettant en jeu une addition nucléophile d'un 2-lithioindole sur deux dérivés électrophiles de type N-Boc-oxazolidine ou nitrone, dérivés de la L-sérine. Les travaux réalisés ont permis d'accéder à certains de ces intermédiaires clé. Cette étude nous a permis de mettre en évidence des conditions de pivaloylation chimiosélective du noyau indolique vs. une fonction amine secondaire. Les études résultant de la déprotection de ce noyau indolique ont montré une déprotection chimiosélective de ce même noyau vis-à-vis d'une amine primaire préalablement N-pivaloylée, mais aussi une déprotection chimiosélective des amines secondaires préalablement N-pivaloylée vis-à-vis des amines pimaires.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

The complementary value of vibrational spectroscopy and mass spectrometry in obtaining structural information on a range of tricyclic indoles with various ring patterns has been investigated, focusing particularly on whether these heterocycles with a functional group containing oxygen in the third ring should be described as ketoindoles or hydroxindolenines. Parallels between certain fragmentations of ionised indoles and electrophilic substitution in solution have been identified. A mechanistically interesting and analytically useful interesting dimerisation, leading to the formation of [2M-H]+ ions, has been discovered in the positive ion electrospray mass spectra of 3-alkylindoles. This dimerisation, which occurs in the nebuliser of the instrument, offers a potential new route to bisindoles under milder conditions than those employed in classical solution chemistry. Facile formation of C=N bonds by condensation of C=O and H2N has been shown to provide a means of preparing protonated imines and protonated quinoxalines from mixtures of the requisite (di)carbonyl compounds and (di)amines, thus further illustrating how organic synthesis is possible in the droplets in the nebuliser of the instrument. Possible metal catalysed coupling reaction routes to bisindoles have been explored. Acyl transfer reactions from nitrogen to carbon have been investigated in 1-acyl-2-methylindoles and orthogonally protected sulphonamides. These processes have been shown to be intermolecular and intramolecular, respectively. The latter rearrangement, which may be prevented when necessary by choosing the nitrophenylsulphonamide protecting group, offers a route to acyl, carboalkoxy and carboaryloxy aromatic compounds, some of which are difficult to prepare.