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

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

The strategy of chiral switches in drug discovery

The chirality of drugs has become a major theme in the design, discovery, development, patenting and marketing of new drugs1. There are two principal scenarios in chiral drug development: the de novo development of an enantiomerically pure drug, or a switch from an existing racemic drug to one of its enantiomers1,2. For many years, the pharmacopoeias were dominated by racemates. This trend was inverted in the mid-1980s: most of the chiral new molecular entity (NME) drugs were developed and marketed as single enantiomers. A chiral switch is the development of a single enantiomer from a chiral drug that has been developed (and often approved and marketed) previously as a racemate or as a mixture of diastereomers. The essential criterion of a chiral switch is a change in the status of chirality3. A list of chiral drugs that have successfully undergone a chiral switch will be presented, together with considerations on patentability and regulatory exclusivities of chiral-switch drugs. A special focus will be given to the antimalarial racemic drugs chloroquine (CQ) phosphate and hydroxychloroquine (HCQ) sulphate4 (Figure 1) which were repurposed for hospitalized patients affected by COVID-19 under an Emergency Use Authorization (EUA) by FDA in 2020 (later withdrawn). We called for adopting a variant of the repurposing strategy by developing the more-promising single enantiomers (S)-CQ and/or (S)-HCQ for the cure of COVID-19. Finally, deuterium-enabled chiral switches (DECS)5 of teratogenic racemic thalidomide and analogs which undergo racemization in vivo will be analyzed, in light of the finding that deuteration can stabilize hydrogen-containing chiral centers