title: Synthesis and neuroprotective action of xyloketal derivatives in Parkinson's disease models.
abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1-39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson's disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD.
authors.forename: Shichang
authors.initials: S
authors.lastname: Li
authors.forename: Cunzhou
authors.initials: C
authors.lastname: Shen
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Guo
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.forename: Shixin
authors.initials: S
authors.lastname: Liu
authors.forename: Fengyin
authors.initials: F
authors.lastname: Liang
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Xu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Pei
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-Sen University, No. 135 Xingangxi Road, Guangzhou 510275, China. yjhxhc@mail.sysu.edu.cn.
authors.forename: Huacan
authors.initials: H
authors.lastname: Song
authors.forename: Liqin
authors.initials: L
authors.lastname: Qiu
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: School of Chemistry & Chemical Engineering, Sun Yat-Sen University, No. 135 Xingangxi Road, Guangzhou 510275, China. cespjy@mail.sysu.edu.cn.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Pang
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism / Q000502:physiology
chemical_list: D018696:Neuroprotective Agents; D011714:Pyrans; D017382:Reactive Oxygen Species; C515343:xyloketal B; D004121:Dimethyl Sulfoxide