Modelado, diseño racional y desarrollo de compuestos de interés tecnológico y farmacológico

Thesis

Authorship

Lanza Castronuovo, Priscila Ailin

Date

25/03/2019

Summary Information provided by the agent in SIGEVA

Molecular Modelling methodologies are used in order to select, in some cases, and design, in others, molecules with potential applications previously targeted. In the first part, taking advantage of the unusual properties of Tröger base derivatives, its potential will be explored as different molecular devices, among them its potential application as antenna molecules for solar cells sensitized by organic dyes (organic DSSCs). These peculiarities arise from their molecular form, they being... Molecular Modelling methodologies are used in order to select, in some cases, and design, in others, molecules with potential applications previously targeted. In the first part, taking advantage of the unusual properties of Tröger base derivatives, its potential will be explored as different molecular devices, among them its potential application as antenna molecules for solar cells sensitized by organic dyes (organic DSSCs). These peculiarities arise from their molecular form, they being chiral even without asymmetric carbons, their "V"-shaped geometry, their considerable rigidity and, mainly, their unusual properties of selective charge transport. In particular, this last feature allows us to expect an unusual photochemistry, as it will be seen in Chapter 3. To this end, a set of possible donor / acceptor systems is proposed, bridged by Tröger bases and those that are most promising and more synthetically accessible will be chosen for an interdisciplinary study in collaboration with a group specialized in synthesis and the group headed by the Co-director, who will perform the photophysical and photochemical tests. Ultimately, a "proof of principles" system of the Donor-bridge Tröger-Acceptor system is sought with a paradigm different from the one used so far in organic DSSCs, that is to say the scheme Donor-conjugate bridge ? - Acceptor. In this design, the bridge not only electronically communicates the redox centers but could also exert control over the initial charge separation, its recombination, its photophysics and even participate as a photo / electroactive nucleus. Preliminary studies in the research group, allowed to demonstrate that, sometimes, this aliphatic bridge can act as an efficient connector or "cable" between the redox centers (surprisingly as a conjugated ? system would do) and in others as an insulator, that is to say as a bridge with a weak coupling, typical of aliphatic bridges. The modeling can predict or estimate at a deep level of detail these properties in a great variety of donor-bridge-acceptor dyads, but its synthesis is difficult, involving a mechanism with a many steps, starting from substituted anilines. This mechanism was not described to the present in a detailed way, step by step, beyond incomplete and even contradictory proposals. Therefore, it will also be studied using quantum chemistry DFT methods. It was uncovered in detail the reaction mechanism leading to the synthesis of symmetric and asymmetric dyads (Chapter 4). This description tries to facilitate the design of the best conditions and strategies of synthesis on rational bases, that is to say knowing each elementary stage of all the reasonable possible pathways to its formation. In the second part, modeling methods will be applied to understand the mechanism of inhibition of the human P-gp protein, a transmembrane efflux pump of the ABC type, which promotes the resistance to multiple drugs (MDR), a fundamental obstacle that dilutes the effectiveness of anti-tumor treatments, since it is expressed in most types of cancer at some stage. There are available potent but highly toxic inhibitors that rise enough side effects for not having allowed for its clinical use. As a convenient alternative to them, compounds isolated from native and naturalized plants from the central region of Argentina will be demonstrated to be a promising starting point. The description of the mechanism of inhibition at the molecular level will allow proposing various derivatizations in order to increase the potency of a product obtained from Melia azedarach and the search for compounds by chemical similarity for their in sílico study. These studies were carried out in an interdisciplinary collaboration with the group of Prof. María Cecilia Carpinella at the Universidad Católica de Córdoba (UCC). The most promising compounds were acquired or synthesized and new leaders were obtained, more effective than the starting product studied.