Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice.

Histone acetylation is a prominent epigenetic modification linked to the memory loss symptoms associated with neurodegenerative disease. The use of existing histone deacetylase inhibitor (HDACi) drugs for treatment is precluded by their weak blood-brain barrier (BBB) permeability and undesirable toxicity. Here, we address these shortcomings by developing a new class of disulfide-based compounds, inspired by the scaffold of the FDA-approved HDACi romidepsin (FK288). Our findings indicate that our novel compound MJM-1 increases the overall level of histone 3 (H3) acetylation in a prostate cancer cell line. In mice, MJM-1 injected intraperitoneally (i.p.) crossed the BBB and could be detected in the hippocampus, a brain region that mediates memory. Consistent with this finding, we found that the post-training i.p. administration of MJM-1 enhanced hippocampus-dependent spatial memory consolidation in male mice. Therefore, MJM-1 represents a potential lead for further optimization as a therapeutic strategy for ameliorating cognitive deficits in aging and neurodegenerative diseases.

Aqueous complexes for efficient size-based separation of americium from curium.

Complexation of the adjacent actinide ions americium(III) and curium(III) by the ligand N,N'-bis[(6-carboxy-2-pyridyl)methyl]-1,10-diaza-18-crown-6 (H2bp18c6) in aqueous solution was studied to quantify and characterize its americium/curium selectivity. Liquid-liquid extraction and spectrophotometric titration indicated the presence of both fully deprotonated and monoprotonated complexes, An(bp18c6)(+) and An(Hbp18c6)(2+) (An = Am or Cm), at the acidities that would be encountered when treating nuclear wastes. The stability constants of the complexes in 1 M NaNO3 determined using competitive complexation were log ß101 = 15.49 ± 0.06 for Am and 14.88 ± 0.03 for Cm, indicating a reversal of the usual order of complex stability, where ligands bind the smaller Cm(III) ion more tightly than Am(III). The Am/Cm selectivity of bp18c6(2-) that is defined by the ratio of the Am and Cm stability constants (ß101 Am/ß101 Cm = 4.1) is the largest reported so far for binary An(III)-ligand complexes. Theoretical density functional theory calculations using the B3LYP functional suggest that the ligand's size-selectivity for larger 4f- and 5f-element cations arises from steric constraints in the crown ether ring. Enhanced 5f character in molecular orbitals involving actinide-nitrogen interactions is predicted to favor actinide(III) complexation by bp18c6(2-) over the complexation of similarly sized lanthanide(III) cations.