CKD-504

Dodecanedioic acid (DC₁₂) is mainly prepared via microbial synthesis in industrial production, however, the refined products have many drawbacks, such as low purity, poor crystal size distribution (CSD), and heavily agglomerated character, to name a few. Therefore, the refining process is a crucial step in DC₁₂ preparation by microbial production. In this study, a novel pneumatically agitated crystallizer for DC₁₂ refinery by gassing crystallization was developed. A batch cooling crystallization process was developed, providing the final crystal in 82.0% yield and purity increment to 99.20% at the end of crystallization process. Optimized conditions were determined as the initial supersaturation ratio of 300:3000 (g/mL) and gassing air flow rate of 4 L/min with solution preparation temperature of 85 °C. The crystal products with significantly better morphology characteristics than the starting crude feedstocks, including crystal uniformity and color brightness, were harvested. These obtained results indicated that the pneumatically agitated crystallizer-based crystallization process without any mechanical agitation was a robust and economically feasible technique. To our knowledge, this is also the first DC₁₂ crystallization process with sole gassing agitation for unseeded batch cooling crystallization.

Huntington's disease (HD) is a neurodegenerative disorder, of which pathogenesis is caused by a polyglutamine expansion in the amino-terminus of huntingtin gene that resulted in the aggregation of mutant HTT proteins. HD is characterized by progressive motor dysfunction, cognitive impairment and neuropsychiatric disturbances. Histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase, has been shown to induce transport- and release-defect phenotypes in HD models, whilst treatment with HDAC6 inhibitors ameliorates the phenotypic effects of HD by increasing the levels of α-tubulin acetylation, as well as decreasing the accumulation of mutant huntingtin (mHTT) aggregates, suggesting HDAC6 inhibitor as a HD therapeutics. In this study, we employed in vitro neural stem cell (NSC) model and in vivo YAC128 transgenic (TG) mouse model of HD to test the effect of a novel HDAC6 selective inhibitor, CKD-504, developed by Chong Kun Dang (CKD Pharmaceutical Corp., Korea). We found that treatment of CKD-504 increased tubulin acetylation, microtubule stabilization, axonal transport, and the decrease of mutant huntingtin protein in vitro. From in vivo study, we observed CKD-504 improved the pathology of Huntington's disease: alleviated behavioral deficits, increased axonal transport and number of neurons, restored synaptic function in corticostriatal (CS) circuit, reduced mHTT accumulation, inflammation and tau hyperphosphorylation in YAC128 TG mouse model. These novel results highlight CKD-504 as a potential therapeutic strategy in HD. [BMB Reports 2023; 56(3): 178-183].