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Funding Information: We are grateful to Cristina Leit?o (ITQB-NOVA) for expert technical assistance on the HPLC assays. We thank the Diamond Light Source for access to beamline B21 (proposal mx20161) and the technical support from Katsuaki Inoue, that contributed to the results presented here.This work was supported by FEDER and Funda??o para a Ci?ncia e a Tecnologia, I. P. through national funds (Projects UIDB/04138/2020 and UIDP/04138/2020 and research project PTDC/MED-QUI/29712/2017). This work has received funding from the European Union?s Horizon 2020 research and innovation programme under the Marie-Sklodowska Curie grant agreement No [675007], LISBOA-01-0145-FEDER-029967 and PTDC/QUI-QOR/29967/2017. Principal Researcher grant CEECIND/03143/2017 (Funda??o para a Ci?ncia e a Tecnologia) is acknowledged by L.M.D.G. European Union?s Horizon 2020 research and innovation programme (grant agreement No 810856) is acknowledged by M.T. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged by J.B.V. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human pheny-lalanine hydroxylase (hPAH) that, when untreated, can lead to severe psychomotor impairment. Protein misfolding is recognized as the main underlying pathogenic mechanism of PKU. Therefore, the use of stabilizers of protein structure and/or activity is an attractive therapeutic strategy for this condition. Here, we report that 3-hydroxyquinolin-2(1H)-one derivatives can act as protectors of hPAH enzyme activity. Electron paramagnetic resonance spectroscopy demonstrated that the 3-hydroxyquinolin-2(1H)-one compounds affect the coordination of the non-heme ferric center at the enzyme active-site. Moreover, surface plasmon resonance studies showed that these stabilizing compounds can be outcompeted by the natural substrate L-phenylalanine. Two of the designed compounds functionally stabilized hPAH by maintaining protein activity. This effect was observed on the recombinant purified protein and in a cellular model. Besides interacting with the catalytic iron, one of the compounds also binds to the N-terminal regulatory domain, although to a different location from the allosteric L-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering. publishersversion published

This review covers the addition of diazo compounds to ketones to afford homologated ketones, either in the presence or in the absence of promoters or catalysts. Reactions with diazoalkanes, aryldiazomethanes, trimethylsilyldiazomethane, α-diazo esters, and disubstituted diazo compounds are covered, commenting on the complex regiochemistry of the reaction and the nature of the catalysts and promoters. The recent reports on the enantioselective version of ketone homologation reactions are gathered in one section, followed by reports on the use of cyclic ketones ring expansion in total synthesis. Although the first reports of this reaction appeared in the literature almost one century ago, the recent achievements, in particular, for the asymmetric version, forecast the development of new breakthroughs in the synthetically valuable field of diazo chemistry.

Herein we show that the 3-hydroxyquinolin-2(1H)-one (3HQ) core is a suitable platform to develop new compounds with anticancer activity against MCF-7 (IC50 up to 4.82 μM) and NCI–H460 (IC50 up to 1.8 μM) cancer cell lines. The ring-expansion reaction of isatins with diazo esters catalysed by di-rhodium (II) complexes proved to be a simple and effective strategy to synthesize 4-carboxylate-3HQs (yields up to 92%). 4-Carboxamide-3HQs were more efficiently prepared using NHS-diazoacetate in yields up to 88%. This innovative methodology enabled the construction of “peptidic-like” 3HQs, with several amino acid substituents. Among this series, the L-leucine derivative induced the cell death of MCF-7 (IC50 of 15.1 μM) and NCI–H460 (IC50 of 2.7 μM) cancer cell lines without causing any appreciable cytotoxicity against the non-cancer cell model (CHOK1).