De nos jours, une des stratégies majeures dans la modulation de la pharmacocinétique des composés bioactifs est leur vectorisation et l’obtention de formes prodrogues. Ce travail est centré sur la vectorisation d’antitumoraux phosphorés à l’aide de peptides favorisant le passage membranaire. Nous avons alors réalisé la conjugaison d’aminoalkyl-bisphosphonates avec des séquences peptidiques afin de modifier leur temps de rétention dans l’organisme et d’augmenter leur internalisation cellulaire. Différents espaceurs possédant un motif carbonylé insaturé ont été évalués dans le couplage par la réaction d’addition aza- et thiaMichael afin d’aboutir à l’obtention d’un conjugué peptide-alendronate. Une approche prodrogue a également été réalisée avec la synthèse de dérivés de type bisphosphinates et l’obtention d’un analogue de l’alendronate. / Nowadays, one of the main strategies for pharmacokinetic modifications of bioactive compounds is their vectorization and the synthesis of prodrug derivatives. This work is focused on the vectorization of phosphorus antitumor agents with cell-penetrating peptides. We have then conjugated aminoalkyl-bisphosphonates with peptidic sequence to modify their retention time and increase their cellular internalization. Several linkers bearing an insaturated carbonyl moiety have been evaluated in conjugation by aza- and thia-Michael addition reaction to obtain a conjugated peptide-alendronate compounds. A prodrug approach has been conducted with the synthesis of bisphosphinate derivatives and an analog of alendronate has been obtained.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-04T13:24:36Z No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T15:55:49Z (GMT) No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Made available in DSpace on 2016-01-25T15:55:49Z (GMT). No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) Previous issue date: 2015-03-31 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Carboidratos têm sido utilizados como organocatalisadores em síntese orgânica devido a sua quiralidade intrínseca. Neste trabalho foi sintetizado um novo organocatalisador aproveitando a estrutura da D-galactose como indutor de quiralidade. A síntese ocorreu em cinco etapas, a saber: proteção seletiva das hidroxilas das posições 1, 2, 3 e 4, seguida pela iodação da posição 6, substituição nucleofílica pelo grupo azido, redução à amina e por fim uma reação com anidrido ftálico. O rendimento global foi de 60 %. O organocatalisador foi testado na reação de adição de Michael entre o dibenzilideno acetona e a azalactona derivada da alanina. 20 mol% do catalisador conduziu ao produto com 57 % de rendimento e com total controle da régio- e diasteroseletividade. No escopo, vários produtos com funcionalização no esqueleto de dbas foram preparados e devidamente caracterizados pelas técnicas convencionais de análise. A determinação da estereoquímica relativa foi realizada através do uso de HPLC com fase estacionária quiral e foi atribuída como 1,2-anti após a comparação do tempo de retenção com um padrão já descrito na literatura. De maneira geral, é reportada, pela primeira vez, uma metodologia mais geral para a dessimetrização diasterosseletiva entre dbas e azalactonas catalisadas por ácido de Brønsted. / Carbohydrates have been used as organocatalysts in organic synthesis due to its inherent chirality. In this work, D-galactose was choose as a chiral pool in the catalyst design and it was prepared in five steps: selective ketalyzation of hydroxyl groups, following by an iodination and nucleophilic substitution in the presence of azide. To complete, reduction of the azide to amine and a coupling reaction with phthalic anhydride leading to the catalyst. Overall yield was 60 % for five steps. Then, the catalyst was adopted in the Michael addition reaction between dibenzylidene acetone and azalactone derivative of alanine. The product was obtained in 57% yield and with fully control of both regio- and diastereoselectivity. Next, various funcionalizated dbas were evaluated under the optimized reaction condition and the corresponding final products were fully characterized through conventional elemental analysis. The relative stereochemistry was assigned as being 1,2-anti by using chiral HPLC method. To this end, an authentic sample already described in the literature was prepared in order the retention time. In general, for the first time, a method more general to perform a diastereoselective dessymetrization of dbas in presence of azlactones by using a Brønsted acid as catalyst was described.