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Novel enantiomers and diastereoisomers structurally related to σ ligand (+)-MR200 were synthesized to improve σ1/σ2subtype selectivity. The selective σ1ligand (–)-8showed an antagonist profile determined by phenytoin differential modulation of binding affinity in vitro, confirmed in vivo by an increase of κ opioid analgesia. The σ2ligand (–)-9displayed agonist properties in an in vitro isolated organ bath assay and antiproliferative effects on LNCaP and PC3 prostate cancer cell lines.

The enantiomers of cis-(±)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (±)-PPCC], a selective σ ligand, were synthesized. The (+)- and (−)-enantiomers bind predominantly to σ1receptors and have a reduced σ2affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on κ opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly σ1agonist activity and that they have neuroprotective effects.

Background: The evolution of the pandemic has burdened the national healthcare systems worldwide and at present, there is no preferred antiviral treatment for COVID-19. Recently, the SARS-Cov-2 protease structure was released that may be exploited in in-silico studies in order to conduct molecular docking analysis. Methods: In particular, we compared the binding of twoantimalarial drugs, already in use, (i.e. chloroquine and hydroxychloroquine), which showed some potential clinical effects on COVID-19 patients, using ritonavir, lopinavir and darunavir as positive control tree antiviral recognized compounds. Results: Our results showed that hydroxychloroquine but not chloroquine exhibited a significant binding activity to the main protease similar to that possessed by protease inhibitors tested for other viral infections. Conclusion: Our data suggest that hydroxychloroquine may exert additional direct antiviral activity compared to chloroquine. In the absence of clinical studies comparing the efficacy of these two compounds, hydroxychloroquine may offer additional effects and may be considered as the first choice.

Functional antitumor vaccine constructs are the basis for active tumor immunotherapy, which is useful in the treatment of many types of cancers. MUC1 is one key glycoprotein for targeting and designing new strategies for multicomponent vaccines. Two self-adjuvant tetravalent vaccine candidates were prepared by clustering four or eight PDTRP MUC1 core epitope sequences on calixarene scaffolds. In this work, the different activities of two molecules with calix[4]arene and calix[8]arene skeleton are rationalized. Quantum mechanics, docking, and molecular dynamics structural optimization were first carried out followed by metadynamics to calculate the energy profiles. Further insights were obtained by complementarity studies of molecular fields. The molecular modeling results are in strong agreement with the experimental in vivoimmunogenicity data. In conclusion, the overall data shows that, in the designing of anticancer vaccines, scaffold flexibility has a pivotal role in obtaining a suitable electrostatic, hydrophobic, and steric complementarity with the biological target.

5-Arylidene-2-oxo-4-thiazolidinones and 2-phenylimino analogues were evaluated for their antidegenerative activity on human chondrocyte cultures stimulated by IL-1 and for their inhibitory capability against matrix metalloproteinase- 13. Our results indicated that 5-arylidene-4-thiazolidinone derivatives 1-9 exhibit antidegenerative activity and could block multiple cartilage destruction during the osteoarthritic process. Out of the selected compounds, (5-arylidene- 2,4-dioxothiazolidin-3-yl)acetic acids 7-9 showed significant effectiveness in reducing NO release and restoring normal levels of GAGs in chondrocytes treated with IL-1. Moreover, benzoic acids 1, 5 and 6 proved to be effective MMP-13 inhibitors and were able to restore normal levels of GAGs.

Starting with 5‐iodo N,O‐nucleosides, prepared by 1,3‐dipolar cycloaddition of nitrones with vinyliodouracil, or vinyl acetate followed by coupling with silylated iodouracil, a series of 5‐alkynyl N,O‐nucleosides were synthesized via a palladium‐catalyzed (Sonogashira) coupling reaction. The cytotoxic activity of modified nucleosides against HEp‐2 cell lines was determined in vitro. The 5‐ethynyl N,O‐nucleoside, the only compound in the series containing a terminal acetylene unit, was found to be the most active compound.

Treatment of 3‐alkoxycarbonyl‐4‐acyl‐ or 3,4‐dialkoxycarbonyl‐substituted isoxazolidines with a mild base, such as tetrabutylammonium fluoride, affords β‐enaminones and/or 3‐methylamino‐2(5H)‐furanones according to the nature of the substituents at C4and C5. Two alternative mechanisms (lactonization and retro‐aldolization) have been rationalized by DFT quantum chemical methods. Any realistic theoretical modeling requires the explicit inclusion of countercation and solvent effects.

MRJF4 (I) inhibits cell growth in the prostate cancer cell lines LNCaP and PC3.

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