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The development of heterocyclic chemistry is important for various science areas and for the industry. The main task of this branch of chemistry is the search for the new, more effective synthetic methods for obtaining heterocyclic derivatives. That covers not only the formation of heterocycles, but also their functionalization, which leads to the creation of compounds having various chemical and physical properties. The accomplishments of this area are applied in biochemistry, pharmacochemistry, photophysics and other branches of science and industry. The creation of effective heterocycles synthesis methods, that may be applied for the formation of heterosystems based on pyrazolo[3,4-d]pyrimidine was the main aim in this work. During this work, three hitherto unknown peri-fused heterocyclic systems based on pyrazolo[3,4-d]pyrimidine scaffold were synthesized. The suitable conditions for the cyclization of 4-(2,2-diethoxyethyl)aminopyrimidines to 2,3-dihydroimidazo[1,2-c]pyrimidines were found. The influence of functional groups in pyrimidine moiety for the course of this reaction was investigated. It has been shown that functional groups including alkylthio, cyano, amino, formyl are tolerated in this type of reaction. The method for the replacement of ethoxy group with benzyl mercaptan in 3-ethoxy-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidines has been found.

Heterociklų chemijos vystymasis turi didelę reikšmę įvairioms mokslo sritims ir pramonės raidai. Pagrindinis šios chemijos srities uždavinys – kurti naujus heterociklinių junginių sintezės metodus, leidžiančius paprasčiau, efektyviau gauti norimos struktūros junginius. Tai apima ne tik heterociklų formavimo būdus, bet ir jų funkcionalizavimą, leidžiantį sukurti įvairiomis cheminėmis ir fizikinėmis savybėmis pasižyminčių junginių įvairovę. Šios mokslo srities pasiekimai pritaikomi biochemijoje, farmacijoje, fotofizikoje ir kitose mokslo ir pramonės šakose. Šiame darbe buvo siekiama sukurti efektyvius heterosistemų sintezės būdus, kuriuos galima pritaikyti pirazolo[3,4-d]pirimidino fragmentą turinčių heterociklų formavimui. Šio darbo metu buvo susintetintos trys iki šiol neaprašytos heterociklinės sistemos atliekant peri-kondensuotų heterosistemų sintezę iš 3-amino-4-chlor-1-metil-6-metiltio-1H-pirazolo[3,4-d]pirimidino. Surastos tinkamos sąlygos 4-(2,2-dietoksietilmino)pirimidinų ciklizacijai į 3-etoksi-2,3-dihidroimidazo[1,2-c]pirimidinus. Ištirta pirimidino žiede esančių pakaitų įtaka šiai reakcijai. Parodyta, kad ši reakcija yra suderinama su tokiomis funkcinėmis grupėmis, kaip alkiltio-, cian-, amino-, formilgrupės. Surastas metodas 3-etoksi-2,3-dihidroimidazo[1,2-c]pirazolo[4,3-e]pirimidinų etoksigrupės pakeitimui benziltiogrupe.

Advisors/Committee Members: BUTKUS, EUGENIJUS (Doctoral dissertation committee chair), BERESNEVIČIUS, ZIGMUNDAS JONAS (Doctoral dissertation committee member), DODONOVA, JELENA (Doctoral dissertation committee member), MALINAUSKAS, ALBERTAS (Doctoral dissertation committee member), MICKEVIČIUS, VYTAUTAS (Doctoral dissertation committee member), JAKUBKIENĖ, VIRGINIJA (Doctoral dissertation opponent), GETAUTIS, VYTAUTAS (Doctoral dissertation opponent), MASEVIČIUS, VIKTORAS (Doctoral dissertation supervisor).

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Heterociklų chemijos vystymasis turi didelę reikšmę įvairioms mokslo sritims ir pramonės raidai. Pagrindinis šios chemijos srities uždavinys – kurti naujus heterociklinių junginių sintezės metodus, leidžiančius paprasčiau, efektyviau gauti norimos struktūros junginius. Tai apima ne tik heterociklų formavimo būdus, bet ir jų funkcionalizavimą, leidžiantį sukurti įvairiomis cheminėmis ir fizikinėmis savybėmis pasižyminčių junginių įvairovę. Šios mokslo srities pasiekimai pritaikomi biochemijoje, farmacijoje, fotofizikoje ir kitose mokslo ir pramonės šakose. Šiame darbe buvo siekiama sukurti efektyvius heterosistemų sintezės būdus, kuriuos galima pritaikyti pirazolo[3,4-d]pirimidino fragmentą turinčių heterociklų formavimui. Šio darbo metu buvo susintetintos trys iki šiol neaprašytos heterociklinės sistemos atliekant peri-kondensuotų heterosistemų sintezę iš 3-amino-4-chlor-1-metil-6-metiltio-1H-pirazolo[3,4-d]pirimidino. Surastos tinkamos sąlygos 4-(2,2-dietoksietilmino)pirimidinų ciklizacijai į 3-etoksi-2,3-dihidroimidazo[1,2-c]pirimidinus. Ištirta pirimidino žiede esančių pakaitų įtaka šiai reakcijai. Parodyta, kad ši reakcija yra suderinama su tokiomis funkcinėmis grupėmis, kaip alkiltio-, cian-, amino-, formilgrupės. Surastas metodas 3-etoksi-2,3-dihidroimidazo[1,2-c]pirazolo[4,3-e]pirimidinų etoksigrupės pakeitimui benziltiogrupe.

The development of heterocyclic chemistry is important for various science areas and for the industry. The main task of this branch of chemistry is the search for the new, more effective synthetic methods for obtaining heterocyclic derivatives. That covers not only the formation of heterocycles, but also their functionalization, which leads to the creation of compounds having various chemical and physical properties. The accomplishments of this area are applied in biochemistry, pharmacochemistry, photophysics and other branches of science and industry. The creation of effective heterocycles synthesis methods, that may be applied for the formation of heterosystems based on pyrazolo[3,4-d]pyrimidine was the main aim in this work. During this work, three hitherto unknown peri-fused heterocyclic systems based on pyrazolo[3,4-d]pyrimidine scaffold were synthesized. The suitable conditions for the cyclization of 4-(2,2-diethoxyethyl)aminopyrimidines to 2,3-dihydroimidazo[1,2-c]pyrimidines were found. The influence of functional groups in pyrimidine moiety for the course of this reaction was investigated. It has been shown that functional groups including alkylthio, cyano, amino, formyl are tolerated in this type of reaction. The method for the replacement of ethoxy group with benzyl mercaptan in 3-ethoxy-2,3-dihydroimidazo[1,2-c]pyrazolo[4,3-e]pyrimidines has been found.

Advisors/Committee Members: BUTKUS, EUGENIJUS (Doctoral dissertation committee chair), BERESNEVIČIUS, ZIGMUNDAS JONAS (Doctoral dissertation committee member), DODONOVA, JELENA (Doctoral dissertation committee member), MALINAUSKAS, ALBERTAS (Doctoral dissertation committee member), MICKEVIČIUS, VYTAUTAS (Doctoral dissertation committee member), JAKUBKIENĖ, VIRGINIJA (Doctoral dissertation opponent), GETAUTIS, VYTAUTAS (Doctoral dissertation opponent), MASEVIČIUS, VIKTORAS (Doctoral dissertation supervisor).

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Les préparations de composés comportant un noyau imidazo[1,2-a]pyridinique constituent un thème de recherche important en synthèse organique, compte tenu des nombreuses activités biologiques qu’ils peuvent présenter. Dans la première partie, nous nous sommes concentrés sur le développement de nouvelles stratégies rapides et efficaces basées sur l’utilisation de cuivre et de fer pour fonctionnaliser la position 6 du cycle imidazo[1,2-a]pyridine avec diverses amines et divers thiols. Ensuite, nous avons appliqué avec succès cette procédure pour la préparation de thioéthers symétriques et dissymétriques en utilisant le 2-mercaptobenzooxasole, réactif économique qui ne présente aucun risque chimique. Dans le dernier volet de ce travail, nous nous sommes intéressés au développement de nouvelles réactions multicomposants en vue de synthétiser divers pyrrolo[3',2':4,5]imidazo[1,2-a]pyridines et 5-aminopyrido[2’,1’:2,3]imidazo[4,5-c]isoquinoléines.

The preparations of imidazo[1,2-a]pyridine is one of important research topic in organic synthesis, This entitie present some interesting biological activities. First, we devoleped a new rapid and efficient strategies to functionalize position 6 of the imidazo[1,2-a]pyridine with various amines and thiols catalysed by copper and iron. Then we applied this procedure to the preparation of symmetric and asymmetric thioethers using 2 mercaptobenzooxasole, which is an economical reagent and which presents no chemical risk. The last part of this work concerns the development of new multicomponent reactions for the synthesis of various pyrrolo[3',2':4,5]imidazo[1,2-a]pyridine and 5-amino pyrido[2’,1’:2,3] imidazo [4,5-c]isoquinoléines.

Advisors/Committee Members: Guillaumet, Gérald (thesis director), Akssira, Mohamed (thesis director), Berteina-Raboin, Sabine (thesis director), El Hakmaoui, Ahmed (thesis director).

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Les maladies tropicales négligées causées par les protozoaires kinétoplastidés du genre Leishmania et Trypanosoma représentent une menace pour près d’un demi-milliard de personnes en zone intertropicale, entrainant jusqu’à 50 000 décès par an. Parmi les molécules en développement clinique pour traiter ces pathologies, le fexinidazole est une prodrogue appartenant à la famille des 5-nitroimidazoles et qui exerce son action anti-infectieuse via une étape de bioactivation catalysée par des nitroréductases (NTR) parasitaires, enzymes dont le co-facteur est une flavine. Afin d’identifier de nouveaux nitrohétérocycles antiparasitaires substrats des NTR, une petite chimiothèque d’imidazo[1,2-a]pyridines synthétisées au laboratoire a subi un criblage in vitro ayant conduit à l’identification d’une molécule Hit, à la fois active sur Leishmania donovani et Trypanosoma brucei brucei. Ce composé a servi de point de départ à un travail de pharmacomodulation, dans un premier temps en position 8 du cycle imidazo[1,2-a]pyridine : l’introduction de groupements variés à l’aide de réactions de couplage pallado-catalysées de Suzuki-Miyaura, Sonogashira et Buchwald-Hartwig ou des réactions de SNAr, a permis de mettre en lumière plusieurs composés « tête de série » au profil biologique nettement amélioré. Dans un second temps, le travail de pharmacomodulation entrepris a été étendu aux positions 2, 3 et 6 du cycle imidazo[1,2-a]pyridine en vue de compléter les données de relations structure-activité, d’étudier en particulier l’impact du potentiel rédox et d’optimiser les paramètres physico-chimiques et pharmacocinétiques in vitro des meilleurs composés.

The kinetoplastids of the Leishmania and Trypanosoma genus are the causative agents of neglected tropical diseases that threaten nearly half a billion people in the intertropical zone, resulting in 50 000 deaths per year. Among the molecules in clinical development to treat these pathologies, fexinidazole is a prodrug belonging to the 5-nitroimidazoles family, which exerts its anti-infectious action via a bioactivation step catalyzed by parasitic nitroreductases (NTR), enzymes whose cofactor is a flavin. In order to identify novel nitroheterocycles as parasitic NTR substrates, a small chemical library of imidazo[1,2-a]pyridines synthesized by our laboratory was screened in vitro, leading to the identification of a Hit molecule active both on Leishmania donovani and Trypanosoma brucei brucei. This compound served as a starting point for a pharmacomodulation work, initially in position 8 of the imidazo[1,2-a]pyridine ring: the introduction of various chemical groups using the pallado-catalyzed coupling reactions of Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig, or SNAr reactions, highlighted several "lead" compounds with a significantly improved biological profile. In a second step, the pharmacomodulation work was extended to positions 2, 3 and 6 of the imidazo[1,2-a]pyridine ring in order to complete the structure-activity relationship data, to study in particular the impact of the…

Advisors/Committee Members: Rathelot, Pascal (thesis director), Verhaeghe, Pierre (thesis director).

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Les récepteurs Toll-like 7 et 8 jouent un rôle important dans l’activation de la réponse immunitaire innée et adaptative. Leur stimulation conduit à la production des cytokines pro-inflammatoires et d’interférons de type I. L’imiquimod et son dérivé le résiquimod sont les premières molécules de faible poids moléculaire décrites comme agonistes du TLR7 et TLR8. Ces deux molécules ont montré des activités anticancéreuses et adjuvantes très importantes. Récemment, les TLR 7 et 8 ont fait l’objet de plusieurs publications visant à développer de nouveaux agonistes TLR7 et/ou TLR8 dans la perspective d’être utilisés comme adjuvants vaccinaux. Malgré les rôles essentiels de TLR7 et TLR8 dans la stimulation du système immunitaire, une activation immunitaire chronique peut être responsable de plusieurs maladies infectieuses et auto-immunes. D’où l’importance de développer également des antagonistes TLR7 et/ou TLR8.Ce travail de thèse est consacré à la synthèse et le développement de nouvelles molécules hétérocycliques, analogues de l’imiquimod et de résiquimod, dans le but d’identifier de nouveaux ligands TLR7 et/ou TLR8. Des voies de synthèse innovantes, permettant une modulation chimique importante grâce à des couplages croisés pallado-catalysés, ont été mises au point et ont permis d’obtenir une cinquantaine de molécules appartenant à trois séries chimiques différentes de type imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. De nombreux essais d’alkylation ont été tentés sur ces trois séries chimiques afin d’introduire une large variété de substituants sur le cycle à cinq sommets. L’application du couplage croisé de Sonogashira nous a permis d’établir une liaison C-C et introduire diverses chaines alkyles. Ces composés ont été testés pour leur activité agoniste et antagoniste TLR7 et 8. Aucun des composés cibles n'a présenté d’activité agoniste TLR7 et TLR8, dans l'intervalle des concentrations testées. Par contre, tous les composés ont montré une activité antagoniste sélective du TLR7. Les composés les plus actifs, 5.35a et 5.35b, membres de la série pyrazolo[1,5-a]quinoxaline ont montré des IC50 de l’ordre de 10 μM. Ces résultats prometteurs nous ont permis la découverte d’une activité antagoniste TLR7 importante pour la série pyrazolo[1,5-a]quinoxaline, une série très peu développée dans la littérature. La modulation chimique des molécules actives nous permet de donner naissance à de nouveaux leaders, qui peuvent jouer un rôle important dans la thérapie de plusieurs maladies infectieuses et auto-immunes.

Toll-like receptors 7 and 8 play an important role in immune system activation. Their stimulation leads to the production of pro-inflammatory cytokines and type I interferons. Both receptors recognize viral ssRNA, as well as synthetic tricyclic imidazoquinoline derivatives such as imiquimod (TLR7 agonist) and resiquimod (TLR7/8 agonist). These two molecules showed significative anti-cancer and adjuvant activities. Many reports in the literature have been focused on the development of…

Advisors/Committee Members: Bonnet, Pierre-Antoine (thesis director), Kassab, Issam (thesis director).

▼ It was found that hypervalent iodine, such as (diacetoxyiodo)benzene and [bis(trifluoroacetoxy)iodo]benzene could mediate reaction of anilines with pyridines in mild reaction to give benzo[4,5]imidazo[1,2-a]pyridine derivatives. In this thesis, the effect of solvent and substituents group on reactivity are investigated. The optimized reaction conditions is the reaction of anilines with pyridines in the ratio of 1 to 77 without any additional solvent for 15 minutes at room temperature. The benzo[4,5]imidazo[1,2-a]pyridine was obtained in yield. It was also found that the azo compound were always obtained as the byproducts. The proposed mechanism for the reaction was presented base on all experimental evidence. It was assumed that the use of (diacetoxyiodo)benzene as the oxidant is by way of nitrenium ion as the intermediate, and the use of [bis(trifluoroacetoxy)iodo]benzene is through the cation radical intermediate. Advisors/Committee Members: Hsieh,Jen-Chieh (chair), Wu,Ming-Jung (committee member), Chu,Jean-Ho (chair).

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Les hétérocycles oxygénés, azotés et soufrés sont des motifs présents dans de nombreux produits naturels possédant des activités biologiques intéressantes. Plusieurs publications décrivant la synthèse de ces hétérocycles en particulier oxygénés et azotés reposent sur l’utilisation des métaux de transition en tant que catalyseur.Dans notre cas, nous nous sommes intéressés dans un premier temps à la synthèse cupro-catalysée des pyrano[3’,4’:4,5]imidazo[1,2-a]pyridin-1-ones selon une réaction tandem impliquant un couplage et une hétérocyclisation, à partir des dérivés de l’acide 3-iodo-, 3,6- ou (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylique et d’alcynes vrais en présence de sels de cuivre (I) dans le DMF. Les réactions développées ne nécessitent aucune utilisation de métaux de transition plus coûteux comme les complexes au palladium par exemple.

Heterocycles of oxygen, nitrogen and sulfur are patterns found in many natural products possessing interesting biological activities. Several researchers describe the synthesis of oxygen and nitrogen based heterocycles using transition metals as catalyst.In the present study, we focused initially on the copper-catalyzed synthesis of pyrano[3',4':4,5]imidazo[1,2-a]pyridin-1-ones by a tandem coupling-heterocyclisation reaction from derivatives of 3-iodo-, 3,6- or (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylic acid and terminal alkynes in the presence of copper (I) salts as catalyst in DMF. This procedure does not require the use of any expensive transition metal complexes like palladium and supplement any additives. The extension of this methodology to 2,3,5-triiodobenzoic acid allowed the regioselective synthesis of new isocoumarins substituted in positions 3, 5 and 7. Regioselective reactivity of iodine atoms in position 5 and 7 has been studied by palladium coupling reactions and nucleophilic substitution to broad its synthesis to a wide variety of new substituted isocoumarins.

Advisors/Committee Members: Abarbri, Mohamed (thesis director).

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Depuis plus d’un siècle, la chimie hétérocyclique représente l’un des plus vastes domaines de recherche en chimie organique. En particulier, les hétérocycles bicycliques fusionnés à 5 chaînons, contenant à la fois des atomes de soufre et d’azote, présentent, de par leur rareté et leur potentiel biologique, un champ d’intérêt croissant pour les équipes de recherche et développement académiques ou des entreprises pharmaceutiques. Parmi les nombreux composés bicycliques [5-5], notre étude s’est focalisée sur le noyau imidazo[2,1-b][1,3,4]thiadiazole décrit sporadiquement dans la littérature et pour lequel les voies d’accès actuelles ne se limitent qu’à une seule méthode faisant intervenir une étape de cyclisation et des conditions drastiques. Ce verrou entraine inéluctablement une faible diversité fonctionnelle autour de cet hétérocycle, restreignant ainsi les domaines d’applications notamment biologiques. Afin de pallier à cette problématique, nous avons initié une étude de la réactivité de chacune des trois positions fonctionnalisables du bicycle imidazo[2,1-b][1,3,4]thiadiazole, développant ainsi diverses réactions pallado-catalysées (Suzuki-Miyaura, CH-arylation, Buchwald-Hartwig), de substitution nucléophile aromatique et de Pictet-Spengler. L’étude des propriétés biologiques des différents composés synthétisés et hautement valorisables durant ces travaux a abouti à la découverte de deux séries de molécules inhibant sélectivement les kinases DYRK-1A et CLK-1, deux protéines d’intérêt dans le traitement des affections du système nerveux central (neuropathies, Alzheimer…).

For more than a century, heterocyclic chemistry is one of the largest area in organic chemistry research. In particular, because of their rarity and their biological potential, [5-5] fused ring heterocycles containing both sulfur and nitrogen atoms are a large area of interest for both academic and industrial research and development teams. Among these numerous [5-5] bicycles, our study is focused on imidazo[2,1-b][1,3,4]thiadiazole scaffold, which is quite few described in the literature and whose pathways are limited to almost one method involving a cyclisation step and drastic conditions. This lock leads inevitably to low functional diversity around this heterocycle, thus restricting its applications, including biological. In order to overcome this problematic, we then initiated the reactivity study of each three positions of the bicycle imidazo[2,1-b][1,3,4]thiadiazole, developing thereby several palladium couplings (Suzuki-Miyaura, direct arylation, Buchwald-Hartwig), as well as aromatic nucleophilic substitution and Pictet-Spengler reaction. The study of the biological properties of the different compounds synthesized in this work and highly valuable led to the discovery of two series of molecules, inhibiting selectively DYRK-1A and CLK-1, two kinases of interest in the treatment of dysfunction of central nervous system (neuropathies, Alzheimer…).

Advisors/Committee Members: Routier, Sylvain (thesis director), Buron, Frédéric (thesis director).

▼ Human are constantly exposed to potentially toxic chemicals from the environment, diet, and therapeutic interventions. However, the gut harbors a diverse community of microorganisms, which may alter the exposure and toxicity of these chemicals. Heterocyclic amines (HCAs) are mutagens presented in meat cooked at high temperature, and they are strongly associated with the increased risk of colorectal cancer. Bacterial transformation of HCAs may alter their structures and thus their toxicity, but little is known regarding the influence of gut microbiota on the risk associated with these chemicals due to the existing knowledge gap regarding the microbiota-chemical interactions. The work described in this thesis concerns the chemical and biochemical mechanisms of commensal gut bacterial transformation of HCAs and their liver metabolites, as well as toxicological and physiological relevance of the microbial transformations. The knowledge obtained provides mechanistic insights on how gut microbiota alter chemical toxicity and supports gut microbiota as a factor in the risk assessment of toxic chemicals. Chapter 1 introduces the background information concerning the microbial metabolism of glycerol in the human gut and its relevance to HCA transformation. In addition, an overview of the potential targets of gut bacteria-derived acrolein is given. In Chapter 2, we aimed to address the generality of bacterial conjugation of HCAs with acrolein. MeIQx is an imidazoquinoxaline mutagen ten times more mutagenic than PhIP toward bacterial DNA in vitro assays. E. hallii, Lactobacillus reuteri, and Lactobacillus rossiae were found to convert MeIQx to a new microbial metabolite characterized on the basis of HRMS and NMR as 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido-[2′,1′:2,3]imidazo[4,5-f]quinoxaline (MeIQx-M1). Acrolein derived from the decomposition of 3-HPA, which is a product of glycerol reduction mediated by GDH activity, was identified as the active compound responsible for the formation of MeIQx-M1. MeIQx-M1 appears to have slightly reduced cytotoxic potency toward human colon epithelial cells, and diminished mutagenic potential toward bacteria after metabolic activation. In Chapter 3, the physiological and toxicological relevance of the microbial transformation of MeIQx to MeIQx-M1 was characterized. To address whether the microbial transformation influences the intestinal transport of MeIQx, the intestinal uptake of MeIQx and its metabolite MeIQx-M1 was quantified with ex vivo rat intestinal segments, however, only negligible amounts of both MeIQx and MeIQx-M1 were transported. In addition, neither MeIQx nor MeIQx-M1 were cytotoxic towards liver HepaRG cells at dietary levels or higher concentrations. Physiologically based pharmacokinetic modeling suggests that increased microbial transformation of MeIQx can reduce plasma levels of MeIQx, potentially contributing to reduced systemic exposure of MeIQx in human. In Chapter 4, the impact of commensal gut microbes on the transformation of HCA liver metabolites,… Advisors/Committee Members: Sturla, Shana J., id_orcid0000-0001-6808-5950, Lacroix, Christophe, id_orcid0000-0003-4360-2020, Steinberg, Pablo, Schwab, Clarissa.

▼ Human cytomegalovirus (HCMV) is an opportunistic virus which causes serious pathologies in immunocompromised populations. Although several drugs have been approved for the treatment of HCMV-related diseases, various limitations of these compounds make the development of new and improved drugs very desirable. The benzimidazole riboside 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) was found to be a potent and selective inhibitor of HCMV in vitro, but was degraded too quickly in vivo to be of interest as a clinical candidate. Several different strategies were used to design analogs of TCRB which would resist the glycosidic bond cleavage observed for TCRB, including the synthesis of C-nucleosides, and N-nucleosides with alternative heterocycles. A series of acyclic imidazo[1,2-a]pyridine nucleoside analogs was synthesized using the 2,6-dichloroimidazo[1,2-a]pyridine and 2,6,7-trichloroimidazo[1,2-a]pyridine heterocycles and various acyclic side-chains. Although structurally similar to other cyclic and acyclic nucleoside analogs which exhibit good antiviral activity, these analogs demonstrated very little antiviral activity. The C-nucleosides 2,5,6-trichloro-3-(beta-D-ribofuranosyl)pyrazolo[1,5- a]pyridine and 2,5,6-trichloro-3-(alpha-D-erythrofuranosyl)pyrazolo[1,5- a]pyridine are also desirable synthetic targets which would be hydrolytically stable. Many different routes to the common synthetic intermediate for this compound, 2,5,6-trichloropyrazolo[1,5-a]pyridine, were attempted. Despite a variety of synthetic approaches directed toward the synthesis of this common intermediate, none were found to be suitable for the synthesis of the desired nucleosides. Nucleosides incorporating 2,5,6-trichloroindole could also be far more stable than their TCRB congeners, because the 3-position of indole cannot be easily protonated. One indole analog of TCRB, 2,5,6-trichloro-3-formyl-l-(beta- D-ribofuranosyl)indole (FTCRI), demonstrated very potent and selective antiviral activity. A series of further modifications was pursued in an attempt to further increase the antiviral potency or decrease the cytotoxicity. Compounds modified at the indole 2-position were generally less active and more cytotoxic. Modifications made at the 3-position of the heterocycle had a wide variety of effects, depending on the nature of the changes made. Changes in the sugar moiety also produced a wide variety of biological effects, but some were distinctly more active and less toxic. 2, 5,6-Trichloro-3-formyl-1-(5-O-acetyl-beta- D-ribofuranosyl)indole and 2,5,6-trichloro-3-acetyl-1-(2-deoxy-beta- D-ribofuranosyl)indole were especially selective, with the former being much more potent than FTCRI, the latter being much less cytotoxic. Advisors/Committee Members: Townsend, Leroy B. (advisor), Drach, John C. (advisor).