Bioactivity Focus of α-Cyano-4-hydroxycinnamic acid (CHCA) Leads to Effective Multifunctional Aldose Reductase Inhibitors.
Bioactivity focus on α-cyano-4-hydroxycinnamic acid (CHCA) scaffold results in a small library of novel multifunctional aldose reductase (ALR2) inhibitors. All the entities displayed good to excellent inhibition with IC50 72-405 nM. (R,E)-N-(3-(2-acetamido-3-(benzyloxy)propanamido)propyl)-2-cyano-3-(4-hydroxy phenyl)acrylamide (5f) was confirmed as the most active inhibitor (IC50 72.7 ± 1.6 nM), and the best antioxidant. 5f bound to ALR2 with new mode without affecting the aldehyde reductase (ALR1) activity, implicating high selectivity to ALR2. 5f was demonstrated as both an effective ALR2 inhibitor (ARI) and antioxidant in a chick embryo model of hyperglycemia. It attenuated hyperglycemia-induced incidence of neural tube defects (NTD) and death rate, and significantly improved the body weight and morphology of the embryos. 5f restored the expression of paired box type 3 transcription factor (Pax3), and reduced the hyperglycemia-induced increase of ALR2 activity, sorbitol accumulation, and the generation of ROS and MDA to normal levels. All the evidences support that 5f may be a potential agent to treat diabetic complications.
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
Laitao
L
Zhang
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.|Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, P. R. China.
Yi-Fang
YF
Li
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
Sheng
S
Yuan
Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
Shijie
S
Zhang
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
Huanhuan
H
Zheng
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
Jie
J
Liu
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.
Pinghua
P
Sun
National Center for Protein Science Shanghai, Shanghai 201210, P. R. China.
Yijun
Y
Gu
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.|Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, P. R. China.
Hiroshi
H
Kurihara
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.|Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, P. R. China.
Rong-Rong
RR
He
Institute of Traditional Chinese Medicine and Natural Product, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China.|Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Guangzhou 510632, P. R. China.|State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
Heru
H
Chen
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D002642:Chick Embryo; D003373:Coumaric Acids / Q000737:chemistry / Q000378:metabolism*; D048909:Diabetes Complications / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D011485:Protein Binding
D000975:Antioxidants; D003373:Coumaric Acids; D004791:Enzyme Inhibitors; C007175:alpha-cyano-4-hydroxycinnamate; D000449:Aldehyde Reductase