2. Academic Validation
  3. Optimized synthesis of 5N-D and the exploration of its role as a promising anti-aging agent via AKR1B1 inhibition and PI3K/Akt/Nrf2 regulation

Optimized synthesis of 5N-D and the exploration of its role as a promising anti-aging agent via AKR1B1 inhibition and PI3K/Akt/Nrf2 regulation

  • Bioorg Chem. 2025 Sep:164:108886. doi: 10.1016/j.bioorg.2025.108886.
Lujie Liu 1,  Chanxi Wang 1,  Zhenqiang Chen 1,  Meili Yin 1,  Kun Zhang 1,  Chao Zhang 1,  Shuling Peng 1,  Mingyue Li 1,  Songshan Jiang 2,  Heru Chen 3
Affiliations

Affiliations

  • 1 Institute of Traditional Chinese Medicine and Natural Products; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, PR China.
  • 2 Department of Biology, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, PR China. Electronic address: jiangssh@mail.sysu.edu.cn.
  • 3 Institute of Traditional Chinese Medicine and Natural Products; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, PR China. Electronic address: thrchen@jnu.edu.cn.
PMID: 40850282 DOI: 10.1016/j.bioorg.2025.108886
Abstract

An optimized synthesis for (R,E)-N-(3-(2-acetamido-3-(benzyloxy) propanamido) propyl)-2-cyano-3-(3,4-dihydroxyphenyl)acrylamide (5N-D) was reported here. 5N-D has been identified as a promising agent for treating age problems. Through in vitro enzyme testing, 5N-D is verified as an effective ALR2 inhibitor showing an IC50 of 21.8 ± 1.5 nM, and excellent antioxidant showing an EC50 of 2.8 ± 0.2 μM. Its selectivity index over ALR1 is 241.6. All these indexes are far better than the positive Epalrestat (EPA). 5N-D alleviates hyperglycemia-induced oxidative stress (OS) via AKR1B1 inhibition. It is identified not only as a non-enzymatic antioxidant, which interacts directly with Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS) and interrupts the free radical chain reactions; but also as an endogenous enzymatic antioxidant regulator, which regulates enzyme functions of superoxide catalase (CAT) and dismutase (SOD). 5N-D regulates PI3K/Akt/Nrf2 pathway to attenuate hyperglycemia-mediated mitochondrial superoxide overproduction in vitro. It ameliorates CuSO4- and H2O2-induced OS in vivo. 5 N-D prolongs lifespan of C. elegans via the regulation of stress response genes such as PMK-1, DAF-16, AGE-1, AKT-1, AGE-1, SIR-2.1, and SKN-1. The results consistently support the potential of 5 N-D as an Anti-aging agent.

Keywords

Aldo-keto reductase (AKR) family 1 member B1 (AKR1B1) inhibitor; Anti-aging; Antioxidant; Nuclear factor-erythroid 2-related factor 2 (Nrf-2); Oxidative stress; Stress-response genes.

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