DEVELOPMENT OF NEW COOPERATIVE METAL-ORGANO-CATALYSED TRANSFORMATIONS BASED ON DIRHODIUMII COMPLEXES.

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3-Hydroxy-quinolin-2(1H)-ones, a useful scaffold : synthesis and biological evaluation

Publication . Paterna, Roberta 1985-; Góis, Pedro Miguel Pimenta; Moreira, Rui, 1960-

The quinolin-2(1H)-ones ring establish the core structure of many natural and synthetic molecules and a broad spectrum of biological properties like, antimicrobial, enzymatic and neuro protective activities, have been attributed to these molecules. Additionally, 4-hydroxyquinolin-2-ones (4HQs) and 3-hydroxyquinolin-2-ones (3HQs), derivatives of quinolin-2-one, have also been reported with promising biological properties, and have attracted much attention from the medicinal chemist community. The 3HQ core is present in the structure of naturally occurring products viridicatin, viridicatol and 3-O-methyl viridicatin first isolated from the mycelium of Penicillium viridicatum. Although, due to the reduced knowledge about 3HQs, from a synthetic and biological perspective, in the last years, the development of new methodologies for their synthesis has been stimulated and strategies based on condensations, intramolecular cyclization and ring expansions have been applied. Recently reported has nonclassical bioisosteres of α-glycine, 3HQs derivatives are potent inhibitors of the Human D-amino acid oxidase (DAAO) and due to their ability to chelates metal centres, 3HQs are counted as inhibitors of HIV-1 reserve transcriptase associated RNase H activity and as inhibitors of influenza A endonuclease. In view of the present stat-of-the-art, 3HQs new derivatives were synthetized using a new efficient methodology centered on the emergent metal-organo-catalysed (MOC) concept. A one-pot protocol using the MOC system NHCdirhodium( II)/DBU catalyzed Eistert ring expansion reaction of isatins with ethyl diazoacetate to afford the 3-hydroxy-4 ethylesterquinolin-2(1H)-ones core. The reaction provides the final products regioselectively and with yields ranging from good to excellent. Furthermore, DFT calculations were performed on this system and support a mechanism in which the key step is the metallocarbene formation between the 3-hydroxyindole-diazo intermediate and the dirhodium(II) complex. After the above mentioned optimized methodology the second part of this work is dedicated to the biological activity of 3HQ and its derivatives. Various synthetic modifications have been made to introduce specific chemical group keeping the 3HQs core structure. Several compounds with different properties were synthesized and important biological studies were performed on 4-carboxamide-3HQ derivatives showed interesting biological activity as a potential anticancer lead molecule. Additionally, based on the that 3HQs can complex metallic centers and been an isoster of glycine, we hypothesized that 3HQ derivatives could be a useful platform to design new modulators of human phenylalanine hydroxylase (hPAH), the enzyme responsible by the genetic disease phenylketonuria. The new hPAH modulators were simply prepared based on ring-expansion reaction of isatins with NHS-diazoacetate catalysed by di-rhodium(II) complexes yielding 4-Carboxamide-3HQs in good-toexcellent yields. The 7-trifluoromethyl-4-carboxamide-3HQs 134, was identified as the most efficient hPAH modulator, with an apparent binding affinity nearly identical to the natural allosteric activator L-Phenylalanine. Therefore, as 3 hydroxyquinolies have demonstrated to be good scaffolds for the design and development of compounds with activity over phenylalanine hydroxylase and an excellent starting point for the development of novel therapeutics for a phenylketonuria.

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/78301/2011