Novel azoles as potent and selective cannabinoid CB2 receptor agonists.

Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.

A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells.

Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen-androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects' importance in modulating drug activity in vivo.

Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein.

Stapled-peptides have emerged as an exciting class of molecules which can modulate protein-protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.

Calpain inhibitors and antioxidants act synergistically to prevent cell necrosis: effects of the novel dual inhibitors (cysteine protease inhibitor and antioxidant) BN 82204 and its pro-drug BN 82270.

Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.

Novel dual inhibitors of calpain and lipid peroxidation with enhanced cellular activity.

A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.

Novel dual inhibitors of calpain and lipid peroxidation.

A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.

Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties.

A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.