Pyrrolo[1,2-a]pyrazine is one of the isomers of pyrolodiazine family. Pyrrolo[1,2-a]pyrazine possesses a bicyclic heteroaromatic structure that have 10 electrons. It has various biological importances in synthetic chemistry / therefore, many different approaches to generate this skeleton have been developed so far. In this study, our prior aim was to develop a new synthetic methodology for the formation of pyrrolo[1,2-a]pyrazine moiety. In the first part of this focus, the starting compound, methyl 2-(2-methoxy-2-oxoethyl)-1-(prop-2-yn-1-yl)-1H-pyrrole-3-carboxylate was successfully synthesized, then the conversion of the ester group at the lower arm to the amine group was carried out. Heteroatom cyclization catalyzed by CuI afforded the desired substituted pyrrolo[1,2-a]pyrazine structure. In the second part, it was aimed to synthesize new compounds with unusual structures which are not described in the literature / namely, as pyrrolo[1,2-a]pyrazine N-oxide. In this direction, first pyrrole was submitted to Vilsmeier-Haack reaction to attach a formyl group at C-2. Substitution reaction then effectively gave 1-(prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde, which was a key molecule to synthesize the aldoxime. AuCl3 catalyzed cyclization of the corresponding oxime afforded pyrrolo[1,2-a]pyrazine N-oxide. In the next step, Sonogashira coupling reactions were carried out to obtain terminal alkynes (RC&equiv / CR&#039 / ) starting from 1-(prop-2-yn-1-yl)-1H-pyrrole-2-carbaldehyde. The aim of this part was to study the effect of aryl groups to the activated alkyl functional group by a metal catalyst. In this case, unexpected oxime-oxime transformation was observed, which is unprecedented in the literature

Ce travail de thèse PhD concerne l'application d'une approche intégrée pour obtenir une meilleure compréhension des mécanismes d'action de Akt et CXCR4, surexprimées dans différents cancers humains. Efforts récents dans le développement et l'évaluation biologique (activité antiproliférative) de petites entités moléculaires inhibitrices d’Akt, une sérine/thréonine protéine-kinase, ont conduit à l'identification de nouveaux inhibiteurs pyrrolo[1,2-a]quinoxaline, conçus et préparés via une stratégie multi-étapes. Certains des composés synthétisés ont montré une activité contre les lignées cellulaires leucémiques testées (Jurkat, U266, K562, U937 et HL60) supérieure à celle de composé de référence A6730. En outre, des résultats préliminaires menés sur Akt puis sur le domaine de PH isolé d’Akt, ont montré que ils peuvent être considérés comme des inhibiteurs allostériques potentiels. La seconde partie des travaux concerne la conception et la synthèse de deux nouvelles séquences peptidiques contenant quelques acides aminés "disorder promoting" et une unité CPC. Les études CD, RMN et MD ont fait ressortir leur flexibilité et ont démontré leurs capacités à assumer des ensembles de conformations stabilisées par un réseau de liaisons hydrogène. Ensuite, nous avons étudié l'effet de la chaîne alkyle reliée sur la conformation des peptides. Des études de fluorescence et DLS ont été réalisées pour évaluer les CMC et la dimension des agrégats supramoléculaires. Les tests biologiques ont souligné que ces édifices moléculaires (peptides amphiphiles nommés, PAs) montrent ainsi des activités prometteuses, voire plus que la molécule de référence (AMD3100). / This PhD thesis work has been covered in the application of an integrated approach to get a better understanding about the mechanism of action of two systems: Akt and CXCR4, proteins overexpressed in different human cancers. On the basis of previous results obtained on the antiproliferative activities of small molecule inhibitors of Akt, a serine/threonine protein kinase, a novel series of pyrrolo[1,2-a]quinoxaline derivatives have been designed and synthesized via multistep heterocyclization process. Some compounds showed promising activities against all leukemia cell lines tested (Jurkat, U266, K562, U937 and HL60), even better than the reference compound (A6730) one. In addition, docking results, conducted on the isolated PH domain, showed that these new compounds could be considered as allosteric inhibitors. The second workpackage reports on the design and the synthesis of two new peptidic sequences containing a few amino acids “disorder promoting” and a CPC unit, the CXCL12 binding motif towards CXCR4. The peptide structural preferences were analysed by CD, NMR and MD techniques that highlighted their flexibility and demonstrated the ability of these peptides to assume conformational ensembles stabilized by a network of transient and dynamic H-bonds. Afterwards we studied the alkyl chain effect on the conformation of the peptide portion. Solution fluorescence and DLS studies have been performed to evaluate CMC and the dimension of supramolecular aggregates (named peptide amphiphiles, PAs). Biological tests pointed out that these molecular buildings show promising activities, even higher than the reference molecule (AMD3100) one.

The synthetic routes to three types of phosphate prodrugs of 6-hetaryl-7-deazapurine ribonucleosides based on palladium-catalyzed cross-coupling reactions have been developed. CycloSal- and phosphoramidate pronucleotides and octadecyl phosphates derived from 6- hetaryl-7-deazapurine ribonucleosides were screened for their in vitro cytostatic activity. It was shown that cytostatic activity of cycloSal phosphates was similar or slightly lower compared to the parent nucleosides. Significant drop of cytostatic activity was observed in phosphoramidate pronucleotides. Octadecyl phosphates were devoid of any cytostatic activity. 6-Hetaryl-7-deazapurine ribonucleosides with bulky groups in position 6 showed very strong and selective inhibition of adenosine kinase from Mycobacterium tuberculosis. 2'-Modified 6-hetaryl-7-deazapurine nucleosides: 2'-O-methylribonucleosides, arabinonucleosides and 2'- deoxy-2'-fluororibonucleosides, were prepared by multistep functional group transformations from a ribonucleoside. The synthesis of 2'-deoxy-2',2'-difluoro-erythro-pentofuranosyl nucleosides was based on a glycosylation of 6-chloro-7-deazapurine with a sugar synthon followed by palladium-catalyzed cross-coupling reaction and deprotection. Despite the low yields and laborious separation of the anomers,...

The aim of this thesis is the preparation and characterization of model components for organic thin-film solid-state lasers. The theses focuses on comparing different methods of determining the threshold energy, which leads to an amplified spontaneous emission of the studied derivative diketo-pyrrolo-pyrrole. The theoretical part is devoted to a summary of knowledge on the interaction of light with matter and lasers with a focus on organic solid-state lasers. The practical part is focused on preparation of model components for organic solid-state lasers, modification of apparatus for their characterization, comparison of evaluation methods for determining the threshold energy and study of the effect of different conditions of components preparation.

4-Alkyl-L-proline derivatives (APD) are specialized precursors involved in the biosynthesis of at least three groups of different natural compounds: some pyrrolo-1,4-benzodiazepines with antitumor activity, bacterial hormone hormaomycin and clinically used lincosamide antibiotic lincomycin. These compounds share a biosynthetic pathway encoded by 5 or 6 homologous genes present in the biosynthetic gene clusters of the producing organisms. Similarities in biosynthesis and differences between APD structures of these compounds could be used to prepare a hybrid producing strain of biologically more effective lincomycin derivative. Unusual amino acid 4-propyl-L-proline (PPL) is the APD precursor of lincomycin. The originally proposed scheme of the PPL pathway does not comply with our current knowledge. Therefore, it was necessary to revise this scheme according to new results. The first two steps of the PPL pathway are functionally proved. Probing the next step was the main aim of this work. The protein LmbW was overproduced and its methyltransferase activity was confirmed in vitro. LmbW is able to directly methylate intermediate of second step of the pathway while the originally scheme proposed methylation at a later stage of biosynthesis. LmbW is also able to attach a longer alkyl chain to its substrate. This...

Les pyrrolo[2,3-d]pyrimidines, également connues sous le nom de 7-déazapurines, sont une classe importante d’hétérocycliques aromatiques, de par leurs potentiels biologiques (antitumoral, antiinflammatoire, antibactérien, etc.). C’est pourquoi ce squelette a été une source d’intérêt pour les chimistes organiciens. Outre leurs atouts biologiques, ces molécules présentent également de remarquables propriétés physico-chimiques (fluorescence UV), ce qui permet de nouvelles applications en électronique. Bien que ces dernières années, un bon nombre de recherche ont été mises en oeuvre en vue de synthétiser ces molécules, il n’existe encore que peu de méthodes générales pour obtenir des pyrrolo[2,3-d]pyrimidines hautement substituées. Le but de ces travaux de thèse est de développer différentes stratégies régiosélectives et chimiosélectives de synthèse pour accéder à des pyrrolo[2,3-d]pyrimidines diversement substituées et ce, en un minimum d’étapes. Dans un premier temps, il a été synthétisé une famille de 7-méthylpyrrolo[2,3-d]pyrimidines 4,5,6 triarylées notamment via l’utilisation de deux réactions de Suzuki-Miyaura. Pour faire suite, nous avons envisagé la préparation d’une série de pyrrolopyrimidines 2,4,6-triarylées où le motif aromatique de la position 2 est introduit suivant les conditions de Liebeskind-Srogl. Enfin la préparation de pyrrolo[2,3-d]pyrimidines 4-aminées à partir d’alkynylpyrimidines a été mise au point et divers composés de cette famille ont été élaborés. / The pyrrolo [2,3-d]pyrimidines, also known as 7-deazapurines, are an important class of aromatic heterocycles by their biological potencial (antitumor, anti-inflammatory, antibacterial, etc.). Therefore, this skeleton is a source of interest for the organic chemists. A part of the biological activity, these compounds present also outstanding physicochemical properties (UV-fluorescence); enabling new applications in electronics. The last few years, a great number of researches have been put in execution with a view to synthesizing these molecules, where still few general methods exist to obtain pyrrolo [2,3-d] pyrimidines highly substituted. The aim of these works of thesis is to develop different regioselective and chemoselective synthetic strategies to accede to pyrrolo [2,3-d]pyrimidines diversely substituted and furthemore in a reduced number of steps. First has been synthesized a family of 4,5,6-triarylated-7-methylpyrrolo[2,3-d]pyrimidines including the use of two Suzuki-Miyaura's reactions. Also we contemplated the preparation of a series of 2,4,6-triarylated pyrrolopyrimidines where the aryl group at the position 2 has been introduced under Liebeskind-Srogl reaction conditions. Finally the preparation of 4-aminated pyrrolo [2,3-d] pyrimidines from alkynylpyrimidines has been fine-tuned and diverse derivative compounds have been synthesized.

Our research aim was to design, synthesize, and study the competitive enzyme inhibition kinetics of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives as potential non-²-lactam ²-lactamase inhibitors. All compounds (1-13) passed the Lipinski’s rule of 5 test and were docked into the active site of TEM-1 ²-lactamase. PBD derivatives 1-7 were synthesized in high yields and tested for their potency against TEM-1 and P99 ²-lactamases. Kinetic data showed that compounds 1, 4, 5, and 7 possessed inhibitory activity against TEM-1 ranging from 4-34 %. Docking results revealed significant interactive spanning of the active site of TEM-1 by PBDs. The limited inhibitory activity of the compounds, 1-7 could be attributed to the lack of solubility and bulky nature of the molecules, thus limiting the optimal ligand-enzyme interactions. 1,2,4- Oxadiazolinones (8-13) were further synthesized to reduce the steric hindrance of the PBD scaffolds while promoting the electrophilicity of the potentially active lactam and also evaluated for potency.

Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) derivatives possess cancerostatic and anti-infective properties thus making them candidates of possible antibacterial agents. ²-lactam antibiotics are vital weapons for the treatment of bacterial infections, but their existence and effectiveness has been faced with resistance from ²-lactamases. Therefore, the need for new effective antimicrobial drugs is very crucial. In this work, we synthesized in high yields, PBD analogs 1−3, 5 and 7−9 in three to four synthetic steps from commercially available L-proline and isatoic anhydride. MTT Assay was employed to test the in vitro cytotoxicity of PBD analogs 1, 2, 5 and 7 on cancer cell lines including MCF-7, SKBR-3, SKMEL-2, CaCo 2 and Mia Paca. These compounds decreased the cell viability of MCF-7 by roughly 20% however, 1 and 5 had no effect on the SKMEL-2 cell lines. The inhibitory efficacy of these PBDs were also tested against TEM-1 and P99 Serine class A and C ²-lactamases.

Lors de son développement, une tumeur ne peut survivre sans passer par une étape invasive afin de subvenir à ses besoins en nutriment et en oxygène. Cette étape, appelé angiogenèse tumorale, conduit à la formation de vaisseaux sanguins dits « tumoraux », différents des vaisseaux sanguins normaux. Afin de stopper la croissance de la tumeur, il est possible de détruire les vaisseaux sanguins tumoraux formés pendant l’angiogenèse tumorale grâce à des molécules antivasculaires. Ces molécules vont désorganiser la structure du vaisseau et diminuer le flux sanguin au sein de la tumeur pour mener à la nécrose de cette dernière. Parmi ces molécules antivasculaires, la prodrogue phosphate de la combrétastatine A-4 naturelle (CA-4) est le composé actuellement le plus efficace en développement clinique de phase III contre le cancer de la thyroïde. L’objectif de ce travail de thèse a été d’étudier des nouveaux analogues contraints d’aroylindoles et des dérivés de chromène. La série préparée comportera donc la partie triméthoxyphénylique commune à la plupart de ces dérivés, en particulier aux 3-aroylindoles, à savoir des pyrrolo [3,4-a] carbazolediones, et le motif privilégié 2,2-diméthylchromène. Nous avons enfin réalisé l’étude systématique des activités biologiques des molécules synthétisées en déterminant leur cytotoxicité sur mélanome B16, leur aptitude à inhiber la polymérisation de la tubuline et à modifier la morphologie de cellules EA hy926. / Pas de résumé en anglais

This diploma thesis is focused on the properties characterization of new organic materials with respect to their potential application in organic electro-optic devices. The theoretical part contains a themed literature search on application of organic materials for organic electronics and photonics. The basic principles of these devices are described. The practical part includes the preparation of thin films for organic photovoltaics of two types: based on low molecular weight organic compounds (diketo-pyrrolo-pyrroles derivates) and based on polymer (mixture of copolymer of poly(phenylenevinylene) and molecular senzitizer – derivate of fullerene). The first part of experiment is focused on characterization of optical and electrical properties of selected diketo-pyrrolo-pyrroles derivates and the second part is study the influence of annealing to polymer layer.