Cannabis through the looking glass: chemo- and enantio-selective separation of phytocannabinoids by enantioselective ultra high performance supercritical fluid chromatography

By using the Inverted Chirality Columns Approach (ICCA) we have developed an enantioselective UHPSFC method to determine the enantiomeric excess (ee) of (-)-Δ(9)-THC in medicinal marijuana (Bedrocan®). The ee was high (99.73%), but the concentration of the (+)-enantiomer (0.135%) was not negligible, and it is worth a systematic evaluation of bioactivity

Dynamic HPLC on chiral stationary phases: a powerful tool for the investigation of stereomutation processes

Dynamic HPLC on enantioselective stationary phases has become a well-established technique to investigate chiral molecules with internal motions that result in stereoinversion and occur on the time scale of the separation process. Kinetic parameters for the on-column interconversion phenomena can be extracted from experimental peak profiles by computer simulation or by direct calculation methods. The technique has been used in a wide range of temperatures and is complementary in scope to dynamic NMR spectroscopy

Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype

Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance

Chirality effects on the IRMPD spectra of basket resorcinarene/nucleoside complexes

The IRMPD spectra of the ESI-formed proton-bound complexes of the R,R,R,R- and S,S,S,S-enantiomers of a bis(diamido)-bridged basket resorcin[4]arene (R and S) with cytosine (1), cytidine (2), and cytarabine (3) were measured in the region 2800– 3600 cm1. Comparison of the IRMPD spectra with the corresponding ONIOM (B3LYP/6-31(d):UFF)-calculated absorption frequencies allowed the assessment of the vibrational modes that are responsible for the observed spectroscopic features. All of the complexes investigated, apart from [R·H·3]+, showed similar IRMPD spectra, which points to similar structural and conformational landscapes. Their IRMPD spectra agree with the formation of several isomeric structures in the ESI source, wherein the N(3)-protonated guest establishes noncovalent interactions with the host amidocarbonyl groups that are either oriented inside the host cavity or outside it between one of the bridged side-chains and the upper aromatic nucleus. The IRMPD spectrum of the [R·H·3]+ complex was clearly different from the others. This difference is attributed to the effect of intramolecular hydrogen bonding interactions between the C(2’)-OH group and the aglycone oxygen atom of the nucleosidic guest upon repulsive interactions between the same oxygen atom and the aromatic rings of the host

Enantioseparation on Riboflavin Derivatives Chemically Bonded to Silica Gel as Chiral Stationary Phases for HPLC

International audienceAcetylated and/or 3,5-dimethylphenylcarbamated riboflavins were prepared and the resulting riboflavin derivatives as well as natural riboflavin were regioselectively immobilized on silica gel through chemical bonding at the 5’-O- or 3-N-position of the riboflavin to develop novel chiral stationary phases (CSPs) for enantioseparation by high-performance liquid chromatography (HPLC). The chiral recognition abilities of the obtained CSPs were significantly dependent on the structures of the riboflavin derivatives, the position of the chemical bonding on the silica gel, and the structures of the racemic compounds. The CSPs bonded at the 5’-O-position on the silica gel tended to well separate helicene derivatives, while the CSPs bonded at the 3-N-position composed of acetylated and 3,5-dimethylphenylcarbamated riboflavins showed a better resolving ability toward helicene derivatives and bulky aromatic racemic alcohols, respectively, and some of them were completely separated into the enantiomers. The observed difference in the chiral recognition abilities of these riboflavin-based CSPs is discussed based on the difference in their structures, including the substituents of riboflavin and the positions immobilized on the silica gel

Phytochemical studies and antioxidant activity of two South African medicinal plants traditionally used for the management of opportunistic fungal infections in HIV/AIDS patients

<p>Abstract</p> <p>Background</p> <p>It has been observed that perturbations in the antioxidant defense systems, and consequently redox imbalance, are present in many tissues of HIV-infected patients. Hence, the exogenous supply of antioxidants, as natural compounds that scavenge free radicals, might represent an important additional strategy for the treatment of HIV infection. The aim of this study was therefore to analyse the phytochemical constituents and antioxidant potential of <it>Gasteria bicolor </it>Haw and <it>Pittosporum viridiflorum </it>Sims., two South African plants traditionally used for the management of opportunistic fungal infections (OFIs) in AIDS patients.</p> <p>Methods</p> <p>The <it>in vitro </it>antioxidant properties of the two plants were screened through DPPH (1,1-diphenyl-2-picrylhydrazyl), NO (nitric oxide), H₂O₂(hydrogen peroxide) radical scavenging effects and reducing power assays. Phytochemical studies were done by spectrophotometric techniques.</p> <p>Results</p> <p>There were no significant differences in the flavonoid and proanthocyanidins contents between the leaves and bark extracts of <it>Gasteria bicolor </it>and <it>Pittosporum viridiflorum </it>respectively, while the total phenolic content of the bark extract of <it>P. viridiflorum </it>was significantly higher than that of <it>G. bicolor </it>leaf. The acetone extracts of both plants indicated strong antioxidant activities.</p> <p>Conclusion</p> <p>The results from this study indicate that the leaves and stem extracts of <it>Gasteria bicolor </it>and <it>Pittosporum viridiflorum </it>respectively possess antioxidant properties and could serve as free radical inhibitors, acting possibly as primary antioxidants. Since reactive oxygen species are thought to be associated with the pathogenesis of AIDS, and HIV-infected individuals often have impaired antioxidant defenses, the inhibitory effect of the extracts on free radicals may partially justify the traditional use of these plants in the management of OFIs in HIV patients in South Africa.</p

Il ruolo della cromatografia enantioselettiva nello sviluppo di farmaci chirali

Farmaci chirali - racemati e singoli enantiomer

New synthetic strategies for the preparation of novel chiral stationary phases for high-performance liquid chromatography containing natural pool selectors

Twelve new chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) were generally prepared starting from the macrocyclic glycopeptide antibiotic teicoplanin, according to novel and efficient ‘one-pot’ synthetic strategies. Their chiral recognition abilities were evaluated under polar-organic mode HPLC, towards a variety of biopharmacological interesting racemates, such as b-amino acids and quaternary ammonium salts (e.g. carnitine and its derivatives). All materials were prepared by two different synthetic strategies, both leading to the formation of one or two stable ureidic functions on the CSP structure. The influence of the different spacers and of the silica matrix nature on the chiral performances was investigated. The obtained results suggested that the optimal synthetic strategy was that leading to the formation of two ureidic functions on the CSP structure, spaced-out by a six-carbon atoms aliphatic chain; the best chromatographic results were reached with the use of the spherical LiChrospher silica gel. Enantioselectivity factors (a) particularly high and short-time analyses characterised the analytical procedures; in addition, analytes lacking in chromophore groups were easily detected by evaporative light scattering (ELS) with no need of preliminary derivatization