title: 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.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014, China; Institute of Drug Synthesis and Pharmaceutical Processing, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
authors.forename: Chuanjun
authors.initials: C
authors.lastname: Lu
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Fang
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Wan
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Sun
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Hu
authors.affiliation: Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, United States of America.
authors.forename: C-Y Oliver
authors.initials: CY
authors.lastname: Chen
authors.affiliation: School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, United States of America.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Wei
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D017209:Apoptosis; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002386:Cataract / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000201:enzymology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007908:Lens, Crystalline / Q000166:cytology / Q000187:drug effects*; D015394:Molecular Structure; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D001632:Bibenzyls; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C478099:gigantol; D006139:Guaiacol; D000449:Aldehyde Reductase; D052247:Nitric Oxide Synthase Type II