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Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity.

Reported is an enantiodivergent approach for the synthesis of both enantiomers of sulforaphane (SFN) homologues with different chain lengths between the sulfinyl sulfur and the isothiocyanate groups and different substituents on the sulfinyl sulfur. The homologues were designed in order to unravel the effect of all the diversity elements included in sulforaphanes structure. The key step of the approach is the diastereoselective synthesis of both sulfinate ester epimers at sulfur, using as single chiral auxiliary the sugar derived diacetone-d-glucose. The approach allows the first synthesis of both enantiomers of 5-methylsulfinylpentyl isothiocyanate, and the biologically important 6-methylsulfinylhexyl isothiocyanate (6-HITC) found in Japanese horseradish, wasabi (Wasabia japonica). The ability of the synthesized compounds as inductors of phase II detoxifying enzymes has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2. The cytotoxic activity of all the synthesized compounds against human lung adenocarcinoma (A549) and foetal lung fibroblasts (MRC-5) is also reported.

Sulfinamide Phosphinates as Chiral Catalysts for the Enantioselective Organocatalytic Reduction of Imines

A new type of chiral sulfinamide phosphinate catalysts with up to three stereogenic centers, readily accessible from commercially available starting materials, is reported. The naphthyl derivative SulPhos proved to be highly efficient in the organocatalytic asymmetric imine reduction, leading to a wide range of arylmethylamines in high yields with up to 99% ee under 10% catalyst loading. The synthetic utility of this method was demonstrated by the expeditious enantioselective synthesis of the calcimimetic NPS-R568.

Pseudo enantiomeric mixed S/P ligands derived from carbohydrates for the 1,4-addition of phenyl boronic acid to cyclohexenone

The application of phosphinite–thioglycosides and phosphine–thioglycosides ligands in Rh(I)-catalyzed 1,4-addition of phenylboronic acid to cyclohexenone is reported. Among the ligands tested, phosphinite–thioglycoside 3 and phosphine–thioglycoside 10, bearing a 1,2-cis arrangement of the two heteroatoms, have exhibited the best results in terms of reactivity and enantioselectivity. Interestingly, ligands 3 and 10, both derived from a D-sugar are able to generate the addition product of the phenylboronic acid to the cyclohexenone with opposite configurations, behaving thus as enantiomers.

Design, synthesis and biological studies of a library of NK1-Receptor Ligands Based on a 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyran core: Switch from antagonist to agonist effect by chemical modification

A library of 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyrans has been synthesized as a new family of non-peptide NK1 receptor ligands by a one-pot cascade process. Their biological effects via interaction with the NK1 receptor were experimentally determined as percentage of inhibition (for antagonists) and percentage of activation (for agonists), compared to the substance P (SP) effect, in IPone assay. A set of these amino compounds was found to inhibit the action of SP, and therefore can be considered as a new family of SP-antagonists. Interestingly, the acylation of the 2-amino position causes a switch from antagonist to agonist activity. The 5-phenylsulfonyl-2-amino derivative 17 showed the highest antagonist activity, while the 5-p-tolylsulfenyl-2-trifluoroacetamide derivative 20R showed the highest agonist effect. As expected, in the case of the 5-sulfinylderivatives, there was an enantiomeric discrimination in favor of one of the two enantiomers, specifically those with (SS,RC) configuration. The anticancer activity studies assessed by using human A-549 lung cancer cells and MRC-5 non-malignant lung fibroblasts, revealed a statistically significant selective cytotoxic effect of some of these 2-amino-4H-pyran derivatives toward the lung cancer cells. These studies demonstrated that the newly synthesized 4H-pyran derivatives can be used as a starting point for the synthesis of novel SP-antagonists with higher anticancer activity in the future.

Chapter 6 - Biologically Active Isothiocyanates: Protecting Plants and Healing Humans

Abstract Organic isothiocyanates (ITCs) are a very important group of biologically active compounds. They do not occur as a free form in nature, but they are liberated from glucosinolates in plant tissues by enzymatic degradation. In this group are compounds with very different structural features, ranging from the simplest methyl isothiocyanate, contained in the caper plant, to the structurally complex welwitindolinone isothiocyanate, which comes from the broth of a blue-green algae, which has a bridge ring system and numerous stereogenic centers including quaternary carbons and many heteroatoms. A key feature of all these compounds is the role of the isothiocyanate function on their biological activity. Over the past several years, numerous comprehensive reviews have been published on the biological activities of natural ITCs in general, and sulforaphane (SFN), a constituent of broccoli that is considered to be one of the most important antitumor compounds, in particular. However, with the discovery of important new therapeutic applications, this field continues to evolve and remains an active area of research. In fact, the vast majority of the reviews focus on ITC biological activities and omits other important aspects as synthesis and structure-activity relationship. The aim of this paper is to fill this gap by describing all the natural biologically active ITCs known to date and covering aspects related to the mechanism of action and biological activities of these compounds, with a particular emphasis on the methodologies developed for their synthesis. In the case of chiral derivatives, we will describe the procedures developed for their asymmetric synthesis as well as the studies related to the influence of the chirality on activity. Finally, based on the exceptional biological activity of SFN, we will also highlight the concepts of functional and epigenetic foods and discuss the importance of diet for human health.

NMR study on the stabilization and chiral discrimination of sulforaphane enantiomers and analogues by cyclodextrins

Sulforaphane (SFN), a phytochemical isolated from broccoli, is an important antitumoral compound with additional beneficial effect on other important diseases. However, the chemical instability of SFN has hampered its clinical use. In order to circumvent this problem, we report the first comparative study on the inclusion complexes of SFN and SFN homologues with different cyclodextrins by NMR spectroscopy. From this study it has been shown that α-CD is the most indicated cyclodextrin for the stabilization of SFN and SFN homologues, and that the highest affinity constant is that of the isothiocyanate obtained from the wasabi. Furthermore, the study of the inclusion complexes of α-CD and the non-natural SFN and analogues with S absolute configuration at sulfur shows for the first time that α-CD is able to discriminate between the two enantiomers, with the natural R enantiomers forming the inclusion complexes with higher affinity.