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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Synthesis and Evaluation of Halogenated Vinyl Sulfones as Nrf2 Activators

2019년 8월 29일 13시 39분 04초
MEDI.P-280 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 17일 (목요일) 11:00~12:30
Medicinal Chemistry
저자 및
Jong Seok Yoo, Ki Duk Park*
Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by abnormalities in motor control and muscle rigidity. Recent studies suggest that oxidative stress causes the striatal dopamine (DA) deficiency by neuronal loss in the substantia nigra (SN). The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of various antioxidant enzyme genes. In previous work, we have synthesized novel vinyl sulfone derivatives as Nrf2 activator. The lead compound KDS4048 was confirmed to activate Nrf2 and to induce expression of the Nrf2 dependent antioxidant enzymes such as HO-1, GCLM, GCLC, and NQO1 at both mRNA and protein levels in dopaminergic neuronal cells. In this work, we have optimized the lead compound KDS4048 (EC50=530 nM) to increase potency of Nrf2 activation. Compounds containing halogens and pyridine moieties into the vinyl sulfones were synthesized. Then, we compared potency and drug-like properties between the synthesized vinyl sulfone derivatives isomers. Among the synthesized compounds, KDS4105 exhibited potent effect on Nrf2 activation (KDS4105 EC50=26 nM) in cell-based assay. We also confirmed its ability to induce the expression of anti-oxidant response genes HO-1, GCLM, GCLC, and NQO1 at both mRNA and protein levels and attenuate the PD-like motor dysfunctions in the MPTP-induced mice model of PD.