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Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are useful as selective chemical tools in pharmacological studies of the three β-AR subtypes, or lead compounds for drug development is still a highly challenging task. This is mainly due to the intrinsic plasticity of β-ARs as G protein-coupled receptors in conjunction with the requirement for functional receptor subtype selectivity, tissue specificity and minimal off-target effects. With the aim to provide insight into structure-activity relationships for the three β-AR subtypes, we have synthesized and obtained the pharmacological profile of a series of structurally diverse compounds (named MC) that were designed based on the aryloxy-propanolamine scaffold of SR59230A. Comparative analysis of their predicted binding mode within the active and inactive states of the receptors in combination with their pharmacological profile revealed key structural elements that control their activity as agonists or antagonists, in addition to clues about substituents that mediate selectivity for one receptor subtype over the others. We anticipate that these results will facilitate selective β-AR drug development efforts.

The engineering of the surface of nanomaterials with bioactive molecules allows controlling their biological identity thus accessing functional materials with tuned physicochemical and biological profiles suited for specific applications. Then, the manufacturing process, by which the nanomaterial surface is grafted, has a significant impact on their development and innovation. In this regard, we report herein the grafting of sugar headgroups on a graphene oxide (GO) surface by exploiting a green manufacturing process that relies on the use of vibrational ball mills, a grinding apparatus in which the energy is transferred to the reacting species through collision with agate spheres inside a closed and vibrating vessel. The chemical composition and the morphology of the resulting glyco-graphene oxide conjugates (glyco-GO) are assessed by the combination of a series of complementary advanced techniques (

Sugar headgroups have been grafted on the surface of graphene oxide (GO) by exploiting vibrational ball mills. The resulting glyco-GO conjugates significantly disrupt an already established P. aeruginosa biofilm.

The ability to custom-modify cell surface glycans holds great promise for treatment of a variety of diseases. We propose a glycomimetic ofl-fucose that markedly inhibits the creation of sLeXby FTVI and FTVII, but has no effect on creation of LeXby FTIX. Our findings thus indicate that selective suppression of sLex display can be achieved, and STD-NMR studies surprisingly reveal that the mimetic does not compete with GDP-fucose at the enzymatic binding site.

[Image: see text] Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis, and cancer. Therefore, therapeutic approaches that control S1P production have focused on the development of SK1/2 inhibitors. In this framework, we designed a series of natural monosaccharide-based compounds to enhance anchoring of the known SK1 inhibitor PF-543 at the polar head of the J-shaped substrate-binding channel. Herein, we describe the structure-based design and synthesis of new glycan-containing PF-543 analogues and we demonstrate their efficiency in a TGFβ1-induced pro-fibrotic assay.

Colorectal cancer (CRC) is a global health problem being the fourth most common cause of death due to cancer worldwide. Oxaliplatin plays a key role in current CRC treatment but shows serious drawbacks, such as a high systemic toxicity and the frequent insurgence of Pt resistance. In search of novel and more efficacious Pt-based drugs for CRC treatment, we synthesized and characterised PtI2(DACH), an oxaliplatin analogue. PtI2(DACH) was obtained through the replacement of bidentate oxalate with two iodides. PtI2(DACH) turned out to be more lipophilic than oxaliplatin, a fact that led to an enhancement of its cellular uptake. In contrast to oxaliplatin, PtI2(DACH) showed a scarce reactivity towards model proteins, while maintaining affinity for a standard DNA oligo. Notably, PtI2(DACH) induced cytotoxicities roughly comparable to those of oxaliplatin in three representative CRC cell lines. Moreover, it was able to trigger cell apoptosis, to an extent even better than cisplatin and oxaliplatin. Overall, a rather promising picture emerges for this novel Pt drug that merits, in our opinion, a deeper and more extensive preclinical evaluation.