Design, synthesis, and examination of neuron protective properties of alkenylated and amidated dehydro-silybin derivatives.
A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe(2+) chelation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether at C7-OH and C20-OH as well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe(2+) chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H(2)O(2)-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
Yang
Lei Xiang
LX
Key Laboratory of Southern Zhejiang TCM R&D, Pharmacy School of Wenzhou Medical College, Wenzhou 325035, China.
Huang
Ke Xin
KX
Li
Hai Bo
HB
Gong
Jing Xu
JX
Wang
Feng
F
Feng
Yu Bing
YB
Tao
Qiao Feng
QF
Wu
Yi Hang
YH
Li
Xiao Kun
XK
Wu
Xiu Mei
XM
Zeng
Su
S
Spencer
Shawn
S
Zhao
Yu
Y
Qu
Jia
J
D000475:Alkenes / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D000577:Amides / Q000737:chemistry*; D000818:Animals; D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D012838:Silymarin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000475:Alkenes; D000577:Amides; D016166:Free Radical Scavengers; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D012838:Silymarin; C515097:dehydrosilybin; D014969:Xanthine Oxidase