Cedric Stephan Graebin

Synthesis and in vitro activity of limonene derivatives against Leishmania and Trypanosoma

The synthesis and in vitro activity of R(+)-Limonene derivatives against Leishmania and Trypanosoma cruzi strains are reported. Seven compounds have shown better in vitro activity against Leishmania (V.)braziliensis than the standard drug pentamidine. Additionally, we have identified two promising new anti-T. cruzi limonene derivatives.

Two series of new semisynthetic triterpene derivatives: differences in anti-malarial activity, cytotoxicity and mechanism of action

BackgroundThe discovery and development of anti-malarial compounds of plant origin and semisynthetic derivatives thereof, such as quinine (QN) and chloroquine (CQ), has highlighted the importance of these compounds in the treatment of malaria. Ursolic acid analogues bearing an acetyl group at C-3 have demonstrated significant anti-malarial activity. With this in mind, two new series of betulinic acid (BA) and ursolic acid (UA) derivatives with ester groups at C-3 were synthesized in an attempt to improve anti-malarial activity, reduce cytotoxicity, and search for new targets. In vitro activity against CQ-sensitive Plasmodium falciparum 3D7 and an evaluation of cytotoxicity in a mammalian cell line (HEK293T) are reported. Furthermore, two possible mechanisms of action of anti-malarial compounds have been evaluated: effects on mitochondrial membrane potential (ΔΨm) and inhibition of β-haematin formation.ResultsAmong the 18 derivatives synthesized, those having shorter side chains were most effective against CQ-sensitive P. falciparum 3D7, and were non-cytotoxic. These derivatives were three to five times more active than BA and UA. A DiOC6(3) ΔΨm assay showed that mitochondria are not involved in their mechanism of action. Inhibition of β-haematin formation by the active derivatives was weaker than with CQ. Compounds of the BA series were generally more active against P. falciparum 3D7 than those of the UA series.ConclusionsThree new anti-malarial prototypes were obtained from natural sources through an easy and relatively inexpensive synthesis. They represent an alternative for new lead compounds for anti-malarial chemotherapy.

Highlights in the solid-phase organic synthesis of natural products and analogues

In this manuscript, we disclose solid-phase organic syntheses (SPOS) of small-molecules of some secondary metabolites, such as alkaloids, polyamines, steroids, terpenes, and flavonoids, described in the literature since 2000. A number of elegant, efficient and challenging syntheses on solid support will be presented.

Synthesis and mechanism of novel fluorescent coumarin–dihydropyrimidinone dyads obtained by the Biginelli multicomponent reaction

The optimization of a Biginelli Multicomponent Reaction (MCR) protocol for obtaining a collection of 3,4-dihydropyrimidin-2(1H)-one/thione, with UV absorption and blue fluorescent properties, from synthetic coumarin beta-ketoester derivatives is described. This is the first report of Biginelli adducts bearing a coumarin nucleus in the β-ketoester moiety and their MCR mechanism seems to pass through a Knoevenagel intermediate, which was considered as unlikely before. A chemical library was obtained and the dihydropyrimidin-2(1H)-one nucleus formation confirmed by X-ray diffraction. Photophysical analyses of representative compounds in different solvents show good Stokes shifts in water that are associated to a postulated ICT process and pKa determination make these compounds a good start point for new chemical and biological probes as well as useful pH indicators.

Synthesis of limonene β-amino alcohol derivatives in support of new antileishmanial therapies

A series of seven limonene beta-amino alcohol derivatives has been regioselectively synthesised in moderate to good yields. Two of these compounds were found to be significantly effective against in vitro cultures of the Leishmania (Viannia) braziliensis promastigote form in the micromolar range. The activities found for 3b and 3f were about 100-fold more potent than the standard drug, Pentamidine, in the same test, while limonene did not display any activity. This is the first report of antileishmanial activity by limonene beta-amino alcohol derivatives.

Improving the Thrombin Inhibitory Activity of Glycyrrhizin, a Triterpenic Saponin, Through a Molecular Simplification of the Carbohydrate Moiety

Glycyrrhizin, a saponin, and its aglycone glycyrrhetinic acid are natural products found in the Liquorice (Glycyrrhiza glabra L.) root extract. This saponin is known for its in vitro and in vivo thrombin inhibitory activity. The design and synthesis of five glycyrrhizin derivatives were carried out to improve the natural product activity. Compound 3b, a phthalic ester derivative of glycyrrhizin, presented a more pronounced thrombin inhibition (IC50 = 114.4 ± 1.3 μm) than the saponin (IC50 = 235.7 ± 1.4 μm). Molecular docking simulations performed to investigate the molecular interaction between compound 3b and the enzyme indicate that this product is, as previously determined for glycyrrhizin, an allosteric thrombin inhibitor.

An efficient monitoring technique for solid-phase reactions by KBr pellets/FT-IR using methyl p-aminobenzoate synthesis assisted by microwave radiation on merrifield resin

The use of KBr pellets in infrared spectroscopy has been investigated for monitoring solid-phase reactions. Synthesis of the methyl p-aminobenzoate on Merrifield resin (MR) is described as a model for this technique, which allows the progress of its three on-bead reaction steps to be monitored throughout their duration.

Discovery of a Series of Acridinones as Mechanism-Based Tubulin Assembly Inhibitors with Anticancer Activity

Microtubules play critical roles in vital cell processes, including cell growth, division, and migration. Microtubule-targeting small molecules are chemotherapeutic agents that are widely used in the treatment of cancer. Many of these compounds are structurally complex natural products (e.g., paclitaxel, vinblastine, and vincristine) with multiple stereogenic centers. Because of the scarcity of their natural sources and the difficulty of their partial or total synthesis, as well as problems related to their bioavailability, toxicity, and resistance, there is an urgent need for novel microtubule binding agents that are effective for treating cancer but do not have these disadvantages. In the present work, our lead discovery effort toward less structurally complex synthetic compounds led to the discovery of a series of acridinones inspired by the structure of podophyllotoxin, a natural product with important microtubule assembly inhibitory activity, as novel mechanism-based tubulin assembly inhibitors with potent anticancer properties and low toxicity. The compounds were evaluated in vitro by wound healing assays employing the metastatic and triple negative breast cancer cell line MDA-MB-231. Four compounds with IC50 values between 0.294 and 1.7 μM were identified. These compounds showed selective cytotoxicity against MDA-MB-231 and DU-145 cancer cell lines and promoted cell cycle arrest in G2/M phase and apoptosis. Consistent with molecular modeling results, the acridinones inhibited tubulin assembly in in vitro polymerization assays with IC50 values between 0.9 and 13 μM. Their binding to the colchicine-binding site of tubulin was confirmed through competitive assays.

O uso do forno de microondas na síntese orgânica em fase sólida

Solid-phase organic synthesis (SPOS) has been considered the main strategy for the construction of combinatorial libraries, because its simplicity leads to faster synthetic procedures. In addition to that, a series of reports in the specialized literature show great advantages in the use of microwave activation, when compared to classical heating, for instance: shorter reaction times, in some cases from several hours to a few minutes, increase of selectivity and product yields, energy economy and reduction and/or elimination of solvent. This review describes the use of microwave ovens/reactors in solid phase organic synthesis, describing the advantages, equipment and reactions using both techniques.

Multicomponent Reactions: A Brief History and their Versatility for the Synthesis of Biologically Active Molecules

Multicomponent reactions (MCRs) are reactions that start from three or more reagents in order to obtain only one final product that has all or most of the carbon atoms from its starting materials. Regarding the Green Chemistry goals, MCRs emerge as ideal processes, with its atomic economy and less waste, as well as being tools for the creation of wide ranges of compounds with potential biological activity. These reactions represent, in the Medicinal Chemistry context, a great potential in the research for new drug candidates, since their products can present great structural complexity. The aim of this review is to present the main multicomponent reactions since its inception, and especially its evolution, emphasizing the synthetic, biological and pharmaceutical importance of the same.