Tau protein dysfunction lies at the core of several neurodegenerative disorders, including Alzheimer’s disease and frontotemporal dementia. The misfolding and aggregation of tau into insoluble filaments disrupt neuronal function and contribute to cell death. A key cellular mechanism for maintaining tau homeostasis involves molecular chaperones, particularly Heat Shock Protein 70 (Hsp70), which regulate the fate of misfolded tau by either promoting its refolding or targeting it for degradation. Among the Hsp70 isoforms, Hsc70 and Hsp72 are most implicated in tau turnover, with Hsp72 playing a dominant role in facilitating proteasomal clearance. Targeting Hsp70 allosterically—by stabilizing a conformation that enhances substrate degradation—has emerged as a promising therapeutic strategy.60940-34-3 IUPAC Name
In this study, we developed a series of novel Hsp70 inhibitors based on the rhodacyanine scaffold, aiming to improve metabolic stability while retaining potent activity in reducing tau levels. Our lead compound, YM-08, demonstrated brain penetration and efficacy in lowering tau levels in HeLaC3 cells but suffered from rapid metabolism due to oxidative cleavage at the benzothiazole ring by CYP3A4 enzymes. To overcome this limitation, we systematically introduced halogen atoms—fluorine and chlorine—at the 3-, 4-, 5-, and 6-positions of the benzothiazole moiety. Additionally, we altered the position of the pyridine nitrogen from ortho to para to investigate potential electronic effects on metabolic susceptibility.
Seventeen analogs were synthesized using a reliable multi-step route involving cyclization of substituted anilines with potassium ethyl xanthate, followed by methylation, condensation with 3-ethylrhodanine, and final deprotection under mild conditions. All compounds were purified via flash chromatography and confirmed by LC-MS and NMR spectroscopy, achieving high purity (>97%) and moderate yields (20–30%). Microsome stability assays revealed that halogenation significantly enhanced resistance to metabolism. Compound JG-23, bearing a 4-chloro substitution and para-pyridine configuration, exhibited the highest stability, with 52% of the parent compound remaining after 30 minutes—12-fold greater than YM-08.17397-89-6 site
Functional evaluation showed that JG-23 effectively reduced total tau levels in both HeLaC3 and SH-SY5Y cell models. In HeLaC3 cells, treatment with JG-23 led to a significant dose-dependent decrease in tau protein levels after 24 hours, with maximal effect observed at concentrations above 10 µM. Similarly, in SH-SY5Y cells expressing physiological levels of tau, JG-23 reduced tau by approximately 80%, without inducing upregulation of stress-responsive chaperones such as Hsp72 or Hsp90.PMID:30944121 This indicates that JG-23 promotes tau degradation specifically through Hsp70 modulation rather than general proteotoxic stress.
These findings highlight the importance of targeted chemical modification in improving drug-like properties of Hsp70 modulators. The structural changes not only enhance metabolic stability but also preserve biological activity, making JG-23 a valuable tool for probing tau dynamics in neurodegenerative contexts. Future work will focus on optimizing brain exposure, potency, and in vivo efficacy to advance this class of compounds toward preclinical testing for tauopathies.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
