Synthesis and Biological Evaluation of Novel Gigantol Derivatives as Potential Agents in Prevention of Diabetic Cataract.

Abstract

As a continuation of our efforts directed towards the development of natural anti-diabetic cataract agents, gigantol was isolated from Herba dendrobii and was found to inhibit both aldose reductase (AR) and inducible nitric oxide synthase (iNOS) activity, which play a significant role in the development and progression of diabetic cataracts. To improve its bioefficacy and facilitate use as a therapeutic agent, gigantol (compound 14f) and a series of novel analogs were designed and synthesized. Analogs were formulated to have different substituents on the phenyl ring (compounds 4, 5, 8, 14a-e), substitute the phenyl ring with a larger steric hindrance ring (compounds 10, 17c) or modify the carbon chain (compounds 17a, 17b, 21, 23, 25). All of the analogs were tested for their effect on AR and iNOS activities and on D-galactose-induced apoptosis in cultured human lens epithelial cells. Compounds 5, 10, 14a, 14b, 14d, 14e, 14f, 17b, 17c, 23, and 25 inhibited AR activity, with IC50 values ranging from 5.02 to 288.8 μM. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 μM. Compounds 5, 8, 10, 14b, 14f, and 17c protected the cells from D-galactose induced apoptosis with viability ranging from 55.2 to 76.26%. Of gigantol and its analogs, compound 10 showed the greatest bioefficacy and is warranted to be developed as a therapeutic agent for diabetic cataracts.

• Authors: Jie Wu, Chuanjun Lu, Xue Li, Hua Fang, Wencheng Wan, Qiaohong Yang, Xiaosheng Sun, Meiling Wang, Xiaohong Hu, C-Y Oliver Chen, Xiaoyong Wei
• Journal: PloS one (PLoS One) Vol. 10 Issue 10 Pg. e0141092 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26517726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bibenzyls
• Enzyme Inhibitors
• Hypoglycemic Agents
• gigantol
• Guaiacol
• Aldehyde Reductase
• Nitric Oxide Synthase Type II

Topics

• Aldehyde Reductase (antagonists & inhibitors)
• Apoptosis
• Bibenzyls (chemical synthesis, chemistry, pharmacology)
• Cataract (enzymology, etiology, prevention & control)
• Cell Survival (drug effects)
• Cells, Cultured
• Diabetes Complications (enzymology, prevention & control)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Epithelial Cells (cytology, drug effects, enzymology)
• Guaiacol (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Humans
• Hypoglycemic Agents (chemical synthesis, chemistry, pharmacology)
• Lens, Crystalline (cytology, drug effects)
• Molecular Structure
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Structure-Activity Relationship