Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: "Digging Their Graves with Their Forks".

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.

Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs.

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite's food vacuoles, our approach is summarized as "to dig its grave with its fork". However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

Design of a Targeting and Oxygen-Independent Platform to Improve Photodynamic Therapy: A Proof of Concept.

Photodynamic therapy (PDT) is a promising technique to treat different kinds of disease especially cancer. PDT requires three elements: molecular oxygen, a photoactivatable molecule called the photosensitizer (PS), and appropriate light. Under illumination, the PSs generate, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen, toxic, which then destroys the surrounding tissues. Even if PDT is used with success to treat actinic keratosis or prostate cancer for example, PDT suffers from two major drawbacks: the lack of selectivity of most of the PSs currently used clinically as well as the need for oxygen to be effective. To remedy the lack of selectivity, targeting the tumor neovessels is a promising approach to destroy the vascularization and cause asphyxia of the tumor. KDKPPR peptide affinity for the neuropilin-1 (NRP-1) receptor overexpressed on endothelial cells has already been proven. To compensate for the lack of oxygen, we focused on photoactivatable alkoxyamines (Alks), molecules capable of generating toxic radicals by light activation. In this article, we describe the synthesis of a multifunctional platform combining three units: a PS for an oxygen-dependent PDT, a peptide to target tumor neovessels, and an Alk for an oxygen-independent activity. The synthesis of the compound was successfully carried out, and the study of its photophysical properties showed that the PS retained its capacity to form singlet oxygen and the affinity tests confirmed the affinity of the compound for NRP-1. Thanks to the electron paramagnetic resonance spectroscopy, a technique of choice for radical investigation, the radicals generated by the illumination of the Alk could be detected. The proof of concept was thus successfully established.

Atypical Reaction Media and Organized Systems for the Synthesis of Low-Substitution Sugar Esters.

Sugar esters are non-ionic surfactants with amphiphilic properties of interest for the formulation of various products in the fields of detergents, foods, medicines, pharmaceuticals, agriculture, and cosmetics. The properties of sugar esters depend on their degree of substitution (we consider degrees of substitution between 1 and 3 here) which guides their use. Sugar esters are biodegradable and non-toxic, and the demand for these compounds is high and continuing to increase. Indeed, interest in these compounds stems from the natural origin of the raw materials, the synthetic processes involved and the performance of the final product. The choice of reaction medium is crucial, to facilitate contact between reactants and prevent hydrolysis of the products. In this review, we provide an overview of the processes and synthesis routes for sugar ester production, ionic liquids and deep eutectic solvent as non-usual media or with organized systems.

Detection of Bisphenol A in aqueous medium by screen printed carbon electrodes incorporating electrochemical molecularly imprinted polymers.

Electrochemical molecularly imprinted polymers (e-MIPs) were for the first time introduced in screen-printed carbon electrodes (SPCE) as the sensing element for the detection of an organic pollutant. To play this sensing role, a redox tracer was incorporated inside the binding cavities of a cross-linked MIP, as a functional monomer during the synthesis step. Ferrocenylmethyl methacrylate was used for this purpose. It was associated with 4-vinylpyridine as a co-functional monomer and ethylene glycol dimethacrylate as cross-linker for the recognition of the endocrine disruptor, Bisphenol A (BPA), as a target. Microbeads of e-MIP and e-NIP (corresponding non-imprinted polymer) were obtained via precipitation polymerization in acetonitrile. The presence of ferrocene inside the polymers was assessed via FTIR and elemental analysis and the polymers microstructure was characterized by SEM and nitrogen adsorption/desorption experiments. Binding isotherms and batch selectivity experiments evidenced the presence of binding cavities inside the e-MIP and its high affinity for BPA compared to carbamazepine and ketoprofen. e-MIP (and e-NIP) microbeads were then incorporated in a graphite-hydroxyethylcellulose composite paste to prepare SPCE. Electrochemical properties of e-MIP-SPCE revealed a high sensitivity in the presence of BPA in aqueous medium compared to e-NIP-SPCE with a limit of detection (LOD) of 0.06 nM. Selectivity towards carbamazepine and ketoprofen was also observed with the e-MIP-SPCE.

How intramolecular hydrogen bonding (IHB) controls the C-ON bond homolysis in alkoxyamines.

Recent amazing results (Nkolo et al., Org. Biomol. Chem., 2017, 6167) on the effect of solvents and polarity on the C-ON bond homolysis rate constants kd of alkoxyamine R1R2NOR3 led us to re-investigate the antagonistic effect of intramolecular hydrogen-bonding (IHB) on kd. Here, IHB is investigated both in the nitroxyl fragment R1R2NO and in the alkyl fragment R3, as well as between fragments, that is, the donating group on the alkyl fragment and the accepting group on the nitroxyl fragment, and conversely. It appears that IHB between fragments (inter IHB) strikingly decreases the homolysis rate constant kd, whereas IHB within the fragment (intra IHB) moderately increases kd. For one alkoxyamine, the simultaneous occurrence of IHB within the nitroxyl fragment and between fragments is reported. The protonation effect is weaker in the presence than in the absence of IHB. A moderate solvent effect is also observed.

C-ON bond homolysis of alkoxyamines: when too high polarity is detrimental.

Throughout the last decade, the effect of electron withdrawing groups (EWGs) has been known to play a role - minor or moderate depending on the nitroxyl fragment R1R2NO - in the change in the homolysis rate constant (kd) for C-ON bond homolysis in alkoxyamines (R1R2NOR). It has been shown that the effect of EWGs on kd is described by a linear relationship with the electrical Hammett constant σI. Since then, linear multi-parameter relationships f(σRS,ν,σI) have been developed to account for the effects involved in the changes in kd, which are the stabilization of the released radical (σRS) and the bulkiness (ν) and polarity (σI) of the alkyl fragment. Since a decade ago, new results have been published highlighting the limits of such correlations. In this article, previous multi-parameter linear relationships are amended using a parabolic model, i.e. (σI,nitroxide - σI,alkyl)2, to describe the effect of EWGs in the alkyl fragment on kd. In contrast to previous studies, these improved linear multi-parameter relationships f(σRS,ν,ΔσI2) are able to account for the presence of several EWGs on the alkyl fragment, R. An unexpectedly strong solvent effect - a ca. 1500-fold increase in kd - from tert-butylbenzene to the water/methanol mixture is also observed for 3-((2,2,6,6-tetramethylpiperidin-1-yl)oxyl)pentane-2,4-dione 1b in comparison to a ca. 5-fold increase in kd that is generally observed.

Normal, Leveled, and Enhanced Steric Effects in Alkoxyamines Carrying a ß-Phosphorylated Nitroxyl Fragment.

The design of new R1R2NOR3 alkoxyamines for various applications relies on the accurate prediction of two kinetic parameters, the C-ON bond homolysis rate constant (kd) and its re-formation rate constant (kc). Relationships to describe the steric and polar effects of the R1R2NO fragment ruling kd have been developed. For all cyclic nitroxyl fragments, the steric effect is described as the sum of the bulkiness of the R1 and R2 groups (i.e., normal steric effect), while for the noncyclic nitroxyl fragment (except for one case), a leveled steric effect is assumed. In this work, we show that the normal steric effect also applies to noncyclic nitroxyl fragments and that for one case an enhanced steric effect is also observed, i.e., experimental kd >5-fold larger than the predicted value.

A New Benzophenanthridine Alkaloid from Caloncoba glauca.

Three alkaloids including a new one, N-formyldihydrochelerythrine (1), together with four other known compounds were isolated from the stem bark of Caloncoba glauca. The structure of the new compound was elucidated from spectroscopic and mass spectrometric evidence. This is the first report of alkaloids from the genus Caloncoba. Sesamin (4) [MIC = 256 µg/mL (Candida albicans) and dihydrochelerythrine (2) [MIC = 32 (C. albicans and C. parapsilosis), and 128 µg/mL (C. krusei)] had moderate to weak antifungal activity.

The ß-phosphorus hyperfine coupling constant in nitroxides: 6. Solvent effects in non-cyclic nitroxides.

In two recent articles (Org. Biomol. Chem., 2015 and 2016), we showed that changes in the phosphorus hyperfine coupling constant aP at position ß in ß-phosphorylated nitroxides can be dramatic. Such changes were applied to the titration of water in organic solvents and conversely of organic solvents in water. One of the molecules tested was a non-cyclic nitroxide meaning that a thorough investigation of the solvent effect on the EPR hyperfine coupling constant is timely due. In this article, we show that the aP of persistent non-cyclic ß-phosphorylated nitroxides decrease with the normalized polarity Reichardt's constant E(N)T. The Koppel-Palm and Kalmet-Abboud-Taft relationships were applied to gain deeper insight into the effects influencing aN and aP: polarity/polarizability, hydrogen bond donor properties, and the structuredness of the cybotactic region.

Essential oil of Plectranthus tenuicaulis leaves from Gabon, source of (R),(E)-6,7-epoxyocimene. An unusual chemical composition within the genus Plectranthus.

Water distilled essential oils from leaves of Plectranthus tenuicaulis (Hook. f.) J. K. Morton collected in Gabon were analyzed using GC-FID and GC-MS. The main constituent, unusual within the genus Plectranthus, was isolated and formally identified as being the (+)-(R)-enantiomer of (E)-6,7-epoxyocimene [(E)-myroxide]. This enantiomer, which represents about 75% of the essential oil, has been previously identified as a pheromone emitted by the male fruit-spotting bug Amblypelta nitida; this insect is responsible of destruction of most fruit crops in tropical and subtropical areas. The potential application of P. tenuicaulis essential oil in crop protection programs is discussed and the atypical chemical profile of the gabonese essential oil is compared with those previously reported in the genus Plectranthus (or Coleus).

Chemical composition and biological activities of Santiria trimera (Burseraceae) essential oils from Gabon.

Water-distilled essential oils from leaves and bark of Santiria trimera (Oliv.) Aubrév. (Burseraceae) collected in Gabon were analyzed using capillary GC-FID and GC-MS. The leaf essential oil, which is described for the first time, was dominated by sesquiterpenes (76.5%), among which alpha-humulene (34.6%) and beta-caryophyllene (14.9%) were the major components. The bark essential oil was almost exclusively monoterpenic, with alpha-pinene (51.5%) and alpha-terpineol (16.8%) as main constituents. The antimicrobial activities of both essential oils were tested against eight Gram-positive and three Gram-negative bacteria by using agar disc diffusion and broth microdilution methods; anticandidal effect was also tested on different strains of Candida albica. The Gram-negative bacteria were the less sensitive to the leaf essential oil, which was effective against Bacillus cereus and Enterococcus faecalis. The bark essential oil was more active and, in particular, exhibited significant antimicrobial activity against Proteus mirabilis, which was resistant to the leaf oil. A weak anticandidal effect of both essential oils was observed.

Chemical composition and antimicrobial activity of the essential oils of leaves, roots and bark of Glossocalyx staudtii.

The chemical composition of the essential oils obtained by hydrodistillation from air dried leaves, bark and roots of Glossocalyx staudtii Engl. grown in Gabon was analyzed by GC and GC-MS. The essential oil content was 0.84% (w/w), 0.28% (w/w), and 0.74% (w/w), respectively. The leaf oil was characterized by a high content of monoterpene hydrocarbons (64.8%), with beta-pinene (30.6%) and alpha-pinene (22.6%) as the major constituents. The oil obtained from the bark contained 30.5% of oxygenated monoterpenes with cryptone as the main constituent (11.5%) and 28.9% of aliphatic compounds, with 9.3% of 2-tridecanone; in the roots oil, the main component was 2-tridecanone (55.2%). The antimicrobial activity of the oils was studied by means of the agar disc diffusion and broth microdilution methods. The Gram positive bacteria were the most sensitive to the essential oils. A significant anticandidal effect of the bark essential oil was observed.