A novel chalcone derivative as Nrf2 activator attenuates learning and memory impairment in a scopolamine-induced mouse model.

Alzheimer's disease is a common neurodegenerative disease characterized by progressive degeneration and neuronal cell death, resulting in neural network dysfunction. As the underlying mechanisms, oxidative damage and neuroinflammation have been reported to contribute to the onset and deterioration of Alzheimer's disease. The nuclear factor E2-related factor 2-antioxidant responsive element signaling pathway is a pivotal cellular defense mechanism against oxidative stress. Nrf2, a transcription factor, regulates the cellular redox balance and is primarily involved in anti-inflammatory responses. In this study, we synthesized novel chalcone derivatives and found a highly potent Nrf2 activator, compound 20a. Compound 20a confirmed to activate Nrf2 and induce expression of the Nrf2-dependent enzymes HO-1 and GCLC at both mRNA and protein levels. It also suppressed the production of nitric oxide and downregulated inflammatory mediators in BV-2 microglial cells. We found that compound 20a effectively increased the expression level and the activity of superoxide dismutase in both BV-2 microglial cells and brain hippocampus region of the scopolamine-induced mouse model. In addition, compound 20a effectively recovered the learning and memory impairment in a scopolamine-induced mouse model.

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer's disease treatment.

Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-ß. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 µM) results indicated safety of KMS80013.

Stereoselective synthesis of 2,6-trans-tetrahydropyran via primary diamine-catalyzed oxa-conjugate addition reaction of α,ß-unsaturated ketone: total synthesis of psymberin.

The total synthesis of psymberin was achieved employing a readily available chiral epoxide to prepare two of the three subunits in the natural product. The key reaction was a highly stereoselective organocatalytic oxa-conjugate addition reaction of α,ß-unsaturated ketone catalyzed by primary diamine for the synthesis of the 2,6-trans-tetrahydropyran embedded in psymberin.

In Vitro and In Vivo Osteogenic Activity of Largazole.

Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone diseases, including osteoporosis. We showed that the novel marine-derived HDAC inhibitor largazole exhibits in vitro and in vivo osteogenic activity. Largazole significantly induced the expression of ALP and OPN. The osteogenic activity of largazole was mediated through the increased expression of Runx2 and BMPs. Importantly, largazole showed in vivo bone-forming efficacy in the mouse calvarial bone formation assay and the rabbit calvarial bone fracture healing model. The dual action of largazole to stimulate bone formation and inhibit bone resorption would be a useful feature in drug development for bone-related disorders.

[(18)F]-labeled isoindol-1-one and isoindol-1,3-dione derivatives as potential PET imaging agents for detection of beta-amyloid fibrils.

In this study a novel series of isoindol-1-one and isoindol-1,3-dione derivatives for beta-amyloid-specific binding agents is described. Twelve compounds were synthesized and evaluated via a competitive binding assay with [(125)I]TZDM against beta-amyloid 1-42 (Abeta42) aggregates. Two new [(18)F]-labeled isoindole derivatives were synthesized and evaluated as potential beta-amyloid imaging probes based on the in vivo pharmacokinetic profiles. The preliminary results suggest that these [(18)F]18b and [(18)F]18c are promising positron emission tomography (PET) imaging probes for studying accumulation of Abeta fibrils in the brains of Alzheimer's disease (AD) patients.

Synthesis and activity of largazole analogues with linker and macrocycle modification.

To characterize largazole's structural requirements for histone deacetylase (HDAC) inhibitory and antiproliferative activities, a series of analogues with modifications to the side chain or 16-membered macrocycle were prepared and biologically evaluated. Structure-activity relationships suggested that the four-atom linker between the macrocycle and octanoyl group in the side chain and the (S)-configuration at the C17 position are critical to repression of HDAC activity. However, the valine residue in the macrocycle can be replaced with alanine without significant loss of activity.

Synthesis and evaluation of stilbenylbenzoxazole and stilbenylbenzothiazole derivatives for detecting beta-amyloid fibrils.

This paper describes a novel series of stilbenylbenzoxazole (SBO) and stilbenylbenzothiazole (SBT) derivatives for beta-amyloid specific binding probes. These 24 compounds were synthesized and evaluated by competitive binding assay against beta-amyloid 1-42 (Abeta42) aggregates using [(125)I]TZDM. All the derivatives displayed higher binding affinities with K(i) value in the subnanomolar range (0.10-0.74 nM) than Pittsburgh Compound-B (PIB) (0.77 nM). Among these derivatives, SBT-2, 5-fluoroethoxy-2-{4-[2-(4-methylaminophenyl)vinyl]phenyl}benzothiazole, showed lowest K(i) value (0.10 nM). In conclusion, the preliminary results suggest that these compounds are implying a possibility as a probe for detection of Abeta fibrils in Alzheimer's disease (AD) patients.

Ferulic acid and benzothiazole dimer derivatives with high binding affinity to beta-amyloid fibrils.

New ferulic acid and benzothiazole dimer derivatives were synthesized and evaluated by in vitro competition assay using [(125)I]TZDM for their specific binding affinities to Abeta fibrils. In particular, 4a showed the most excellent binding affinity (K(i)=0.53 nM), compared to PIB (K(i)=0.77 nM), for benzothiazole binding sites of Abeta(1-42) fibrils. This result suggests a possibility of a potential AD diagnostic probe for detection of Abeta fibrils.

Bis-styrylpyridine and bis-styrylbenzene derivatives as inhibitors for Abeta fibril formation.

New bis-styrylpyridine and bis-styrylbenzene derivatives were designed and synthesized. These 34 compounds were evaluated by Abeta fibril formation inhibitory assay using thioflavin T as a dye (named ThT assay). Most of them showed excellent inhibitory activities for Abeta fibril formation at IC50 of 0.1-2.7 microM which is comparable to curcumin (IC50 of 0.8 microM). Among them, nine compounds were screened for their cytotoxicities on HT-22 cell by MTT assay at 1, 10, and 50 microM. In particular, I-7 and II-2 exhibited the best combination of inhibitory activity and compound cytotoxicity.