Alzheimer's disease is the most common neurodegenerative disease in the elderly. Senile plaques and nerve cells in the fiber entanglement [neurofibrillary tangle (NFT)] are the significant pathological features. Currently, clinical drugs cannot effectively treat AD and reverse its pathogenesis. Therefore, it is of great importance to research and development of new AD therapy drugs. Carbazole-based cyanine is a type of synthetic small molecule compound that shares a common base with different functional groups; for example, SLOH, SLM, and SLCOOH. They exhibited selective binding to Aβ peptides and showed strong inhibition of Aβ peptide aggregation. It was found that one of the cyanines, SLOH, could significantly improve the cognitive ability of 3× Tg-AD mice treated for 40 days from the age of 4 months. In vivo, SLOH reduced Aβ levels and decreased hyperphosphorylation of tau both in the hippocampus and cortex by downregulating the activity of Akt/GSK3β and protein phosphatase 2A, SLOH can also activate the calcium pathway through activating CAMKII and cAMP-response element-binding (CREB). SLM significantly improved cognitive deficits in AD mice both in AD mice aged 4 months and 8 months. Both oligomeric Aβ and phosphorylated tau were decreased, and this was due to the activation of autophagic flux. The other cyanine compound SLCOOH also exhibited significant improvement in the cognitive ability of 4-month 3× Tg-AD mice after two months of treatment. There was significantly reduced Aβ deposition, decreased total tau, and reduced tau hyperphosphorylation by inhibiting the activities of glycogen synthase kinase-3β in 4-month 3× Tg-AD mice. SLCOOH treatment cleared Aβ and tau by upregulating the autophagy pathway, which inhibited the activity of mTOR/p70S6K. Moreover, SLCOOH structurally restored synapses and spines and regulated the Ca2+/CaMKII/CREB signaling pathway, leading to enhanced synaptic plasticity and cognitive ability in AD mice. Furthermore, we found SLCOOH ameliorated synaptic deficits by downregulating N-methyl-D-aspartate receptors (NMDAR), thereby modulating intercellular calcium ion (Ca2+) loading and upregulating neuronal calcium dependent signaling. Thus, our results demonstrated that these three carbazole-based cyanines mitigated cognitive decline by targeting Aβ and tau pathology in 3× Tg-AD mice. Those data strongly support that these three carbazole-based cyanines as a potent therapy for AD.

Alzheimer's disease is the most common neurodegenerative disease in the elderly. Senile plaques and nerve cells in the fiber entanglement [neurofibrillary tangle (NFT)] are the significant pathological features. Currently, clinical drugs cannot effectively treat AD and reverse its pathogenesis. Therefore, it is of great importance to research and development of new AD therapy drugs. Carbazole-based cyanine is a type of synthetic small molecule compound that shares a common base with different functional groups; for example, SLOH, SLM, and SLCOOH. They exhibited selective binding to Aβ peptides and showed strong inhibition of Aβ peptide aggregation. It was found that one of the cyanines, SLOH, could significantly improve the cognitive ability of 3× Tg-AD mice treated for 40 days from the age of 4 months. In vivo, SLOH reduced Aβ levels and decreased hyperphosphorylation of tau both in the hippocampus and cortex by downregulating the activity of Akt/GSK3β and protein phosphatase 2A, SLOH can also activate the calcium pathway through activating CAMKII and cAMP-response element-binding (CREB). SLM significantly improved cognitive deficits in AD mice both in AD mice aged 4 months and 8 months. Both oligomeric Aβ and phosphorylated tau were decreased, and this was due to the activation of autophagic flux. The other cyanine compound SLCOOH also exhibited significant improvement in the cognitive ability of 4-month 3× Tg-AD mice after two months of treatment. There was significantly reduced Aβ deposition, decreased total tau, and reduced tau hyperphosphorylation by inhibiting the activities of glycogen synthase kinase-3β in 4-month 3× Tg-AD mice. SLCOOH treatment cleared Aβ and tau by upregulating the autophagy pathway, which inhibited the activity of mTOR/p70S6K. Moreover, SLCOOH structurally restored synapses and spines and regulated the Ca2+/CaMKII/CREB signaling pathway, leading to enhanced synaptic plasticity and cognitive ability in AD mice. Furthermore, we found SLCOOH ameliorated synaptic deficits by downregulating N-methyl-D-aspartate receptors (NMDAR), thereby modulating intercellular calcium ion (Ca2+) loading and upregulating neuronal calcium dependent signaling. Thus, our results demonstrated that these three carbazole-based cyanines mitigated cognitive decline by targeting Aβ and tau pathology in 3× Tg-AD mice. Those data strongly support that these three carbazole-based cyanines as a potent therapy for AD.

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Organic π-conjugated molecules and materials with large real parts and small imaginary parts of the third-order polarizability are of great interest for all-optical switching applications. In this dissertation, we use quantum-chemical and molecular-dynamics approaches to investigate the structure-property relationships that influence the nonlinear optical properties of π-conjugated molecules and materials. We begin with an overview of nonlinear optics, focusing in particular on the electronic properties of linear π-conjugated systems and some of the important problems that have limited device applications of these molecules to date. This is followed by a brief review of the computational methods employed in these studies. We then turn to the main results of the dissertation. Chapter 3 describes the structural dependence of the transition dipole moment between the first two polymethine excited states. Chapter 4 discusses the relationship between BLA, which depends on the geometric structure, and BOA, which probes electronic structure. Chapter 5 describes the benchmarking of computational methods to describe the symmetry-breaking of long polymethines and preliminary evidence regarding the role of vibrational modes in symmetry-breaking. Chapter 6 explains the negative third-order polarizability of tetraphenylphosphate and analogous systems. Chapter 7 focuses on molecular-dynamics studies of polymethine aggregation, particularly the relationships between chemical structure and the geometric and electronic structures of aggregates. Finally, Chapter 8 provides a synopsis of the work and discussion of further directions.

L’objectif de cette thèse consistait à développer des colorants de la famille des polyméthines absorbant dans le proche infrarouge et présentant des propriétés d’optique non-linéaire (ONL) prononcées. De nouveaux chromophores ont été préparés et leurs propriétés spectroscopiques ont été systématiquement étudiées afin d’établir des relations structures-propriétés. Cette stratégie a permis l’identification des facteurs permettant d’exalter la réponse ONL des polyméthines et de prédire leur comportement face à de subtiles modifications structurales. Trois familles de colorants ont été préparées : des monométhines aza-dipyrrométhènes de bore, des heptaméthines symétriques ainsi que des heptaméthines dissymétriques.Dans un premier temps, des aza-bodipys possédant des groupements donneurs périphériques sont synthétisés. Une étude spectroscopique approfondie permet d’identifier les structures présentant une absorption à deux photons importante en vue d’applications en limitation optique aux longueurs d’onde des télécommunications (1500 nm). Le chapitre suivant a pour but de rationaliser les équilibres de la limite cyanine. L’étude de la substitution centrale de nombreux dérivés heptaméthines a permis de moduler leurs propriétés optiques sur une large gamme spectrale et de mettre en évidence une nouvelle structure électronique limite de type bis-dipôle. Parmi cette famille de colorants, des dérivés keto-heptaméthines ont été utilisées en imagerie biologique (cellules et cerveau) par microscopie non-linéaire. Enfin, l’élaboration de structures heptaméthines dissymétriques originales est détaillée dans le dernier chapitre. Ces chromophores ont révélé des propriétés ONL du second ordre idéales pour des applications en modulation électro-optique. / The aim of this thesis consisted in developing dyes from the polymethine family absorbing in the near-infrared (NIR) region and featuring pronounced nonlinear optical (NLO) properties. Several new chromophores have been prepared and their spectroscopic properties have been systematically investigated in order to establish structure-properties relationships. This strategy has permitted the identification of the factors that enhance the NLO response of polymethines and allowed the prediction of their optical behaviour depending on subtle structural modifications. Three families of dyes have been prepared and investigated: boron aza-dipyrro-monomethines (aza-bodipys), symmetrical heptamethines and unsymmetrical heptamethines.In a first time, aza-bodipys possessing electro-donating peripherical substituants has been synthesized. A detailed spectroscopic study allow the identification of structures that present a high two-photon absorption (TPA), towards optical limiting applications at telecommunication wavelengths (1500 nm). The next chapter rationalizes the equilibrium surrounding the cyanine limit. The study of the central substitution of several heptamethines derivatives permitted the fine tuning of their optical properties upon a large spectral region and evidenced a new bis-dipolar electronic structure. Within this dye family, keto heptamethine derivatives has been tested in bio-imaging experiments (living cells and brain) using non-linear microscopy. Finally, the elaboration of original unsymmetrical heptamethines is detailed in the last chapter. These chromophores revealed ideal second order NLO properties for applications in electro-optic modulation.

De nouvelles sondes oligonucléotidiques fluorescentes spécifiques des structures d'acides nucléiques en double brin ont été obtenues. Ces oligonucléotides formant des triples hélices, sont liés par leurs extrémités 5'-ou/et 3' à une série de marqueurs fluorescents de la famille des cyanines monométhines possédant des propriétés intercalantes, par des bras polyméthylène de longueur variable. Dans tous les cas, l'hybridation des sondes avec les cibles en double brin s'accompagne d'une forte augmentation de l'intensité du signal fluorescent émis qui dépend de la structure de la cyanine et des paramètres de sa liaison aux oligonucléotides (longueur du bras de liaison et sa position de fixation sur les oligonucléotides et sur les marqueurs). En présence d'une cible simple brin, les modifications du signal ne sont pas significatives. La présence du marqueur stabilise les triples hélices. Les sondes comportant le thiazole orange, attaché par le noyau benzothiazole via un bras de liaison à huit méthylènes, présente le meilleur compromis en termes de stabilisation, d'intensité de fluorescence et d'augmentation d'intensité de fluorescence lors de l'hybridation.<br />Dans le but d'obtenir de nouvelles sondes utilisables en milieu cellulaire et in vivo, de nouveaux marqueurs fluorescents de type squaraine ont été synthétisés et couplés pour la première fois, à notre connaissance, à des oligonucléotides. Les conjugués correspondant émettent un signal fluorescent détectable au-delà de 650 nm et possèdent des rendements quantiques de fluorescence élevés. La photostabilité des marqueurs et des conjugués, en milieu acide faible et à 37 °C a été fortement augmentée après incorporation d'atomes de fluor sur le squaraine.