Synthesis and biological evaluation of novel gigantol derivatives as potential agents in prevention of diabetic cataract

Authors: WU, JIE - Guangzhou University; LU, CHUANJUN - Zhejiang University; LI, XUE - Guangzhou University; FANG, HUA - Guangzhou University; WAN, WENCHENG - Guangzhou University; YANG, QIAOHONG - Guangzhou University; SUN, XIAOSHENG - Guangzhou University; WANG, MEILING - Guangzhou University; HU, XIAOHONG - Guangzhou University; CHEN, CHUNG-YEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WEI, XIAOYONG - Guangzhou University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/5/2015
Publication Date: 10/30/2015
Citation: Wu, J., Lu, C., Li, X., Fang, H., Wan, W., Yang, Q., Sun, X., Wang, M., Hu, X., Chen, C., Wei, X. 2015. Synthesis and biological evaluation of novel gigantol derivatives as potential agents in prevention of diabetic cataract. PLoS One. 10(10):e0141092. doi: 10.1371/journal.pone.0141092.

Interpretive Summary: Polyphenols are nutrients commonly found in fruits, vegetables, whole grains, and spices. Further, their consumptions have been linked to reduced risk for chronic diseases, such as heart disease and cancers, via actions to clean up free radicals and reduce inflammation. Gigantol is a naturally occurring polyphenol discovered in a Chinese herb, Herba dendrobii. It has been found that gigantol displays an array of actions, e.g. anticancer, free radical removal, and anti-inflammation. Cataracts are the leading cause of visual impairment and blindness worldwide. Development and progression of cataracts are attributed to a wide range of risk factors, e.g. age, gene, radiation, and diseases. Among these factors, high blood glucose is well appreciated to increase risk for cataracts in people with the diabetes because this condition increases damages in lenses partially through the activation of 2 enzymes, aldose reductase and inducible nitric oxide synthase. Our previous studies have shown that gigantol extracted from Herba dendrobii inhibited the development of diabetic cataracts through its inhibitory effect on the activity of these enzymes. To continue investigating the applicability of gigantol as a therapeutic agent for diabetic cataracts, chemical synthesis of gigantol and its analogs becomes essential. Thus, the main objective of the study was to synthesize gigantol and its analogs and then assess their therapeutic effect on diabetic cataract through modulation of aldose reductase and inducible nitric oxide synthase. We successfully synthesized 25 gingantol analogs and identified one compound displaying the highest inhibition on the activity of the 2 enzymes.

Technical 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 micro-M. Compounds 5, 10, 14b, and 14f inhibited iNOS activity with IC50 ranging from 432.6 to 1188.7 micro-M. 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.