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During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams.

Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC50 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections.

Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds ( i.e. , flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV–RNA complexes.

Multiple Sclerosis (MS) is a disabling immune-mediated neurological disease, affecting more than 2.5 million people worldwide. Regardless of the broad arena of pharmaceutical strategies against MS, up to now a concrete cure is still missing. The drugs against MS currently used in the clinical practice are mainly biological immunomodulatory therapeutics, which are effective and safe during the short-term treatment. Nevertheless, they are suitable only for systemic administration and fairly expensive, hence academic and industrial environments are still addressing their efforts towards the development of new drugsChamberlain et al. (2016). Considering that neurodegeneration is a contributory factor in the onset of MS, Sigma 1 Receptor (S1R) could play a crucial role in MSCollina et al. (2013), Peviani et al. (2014). During the years, our interdisciplinary research group identified compound (R )-RC-33, as a new selective S1R agonist with an excellent S1R affinity (Ki = 1.8 nM) along with high selectivity over other receptors, including S2R, and good in vitro metabolic stabilityRossi et al. (2010), Rossi et al. (2013), Marra et al. (2016). On the bases of these results, (R )-RC-33has been selected as lead compound for MS preliminary biological assay. A pilot study was performed to evaluate the effect of the S1R agonist (R )-RC33 on rat Dorsal Root Ganglia (DRG) experimental model. Our encouraging results support the idea that S1R represents a novel appealing target for the treatment of neurodegeneration and a promising protein for the development of new drugs against MS.

RNA-protein interactions are pivotal in the regulation of biological systems and they are implicated in gene expression defect. In fact, RNAs in cells are in complex with RNA-binding proteins (RBPs) which influence every aspect of their biogenesis and function. Recent works have highlighted the involvement of these complexes in various pathological pathways and their potential as drug targets, suggesting a fascinating route for discovering new drugs able to inhibit or enhance gene expressionCampos-Melo et al. (2014). Among the most studied and better characterized RBPs are ELAV (Embryonic Lethal Abnormal Vision) or Hu proteins whose complexes with various RNAs are of great relevance in the etiology of different dysfunctions such as cancer, inflammation and neurodegenerative diseases. Recent studies have unearthed the concept of druggability of ELAV proteins and NMR has been proposed as a useful tool for investigating “protein-RNA” interactions (Nasti et al. 2017, Rossi et al. 2009). Here we present our recent efforts to follow up with a rational investigation on ELAV subtype HuR. Given the described attitude of certain natural compounds to interfere with ELAV-RNA complexesKwak et al. (2009), we studied the interaction between HuR protein and a number of natural structurally-related compounds, including flavones, flavonols and coumarins. These results constitute the starting point to define the features of the “ideal ligand”.

Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing.

Hematopoietic stem/progenitor cell (HSPC) aging studies have been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across human aging is lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis across the lifespan. Although primitive HSPC numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had superior repopulating frequency than younger counterparts in xenografts; yet aged HSPC displayed epigenetic dysregulation of cell cycle, inflammatory signatures, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This phenotype was recapitulated by enforcing proliferative stress in vivo on cord blood (CB) HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes CB xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.