Discovery of 2,3-seco-2,3-dioic acid type triterpene as lowing aβ-peptide compounds

Alzheimer's disease (AD) urgently requires novel potent inhibitors. Since roburic acid (RA, triterpene 3,4-seco-urs-4(23),12-diene-3-oic acid, known as an HIV-1 protease inhibitor) has been shown to be able to reduce amyloid-β (Aβ) protein levels, eight RA structural analogues 2,3-seco triterpenes (WY-1 to WY-8) were evaluated for their activity in lowering Aβ in HEK293/swAPP cells. The 2,3-seco-2,3-dioic acid triterpenes WY-3 to WY-6 (3.18-3.34 ng/mL) were more potent than RA (3.58 ng/mL) in reducing Aβ1-x peptide levels, and WY-2 to WY-6 (2.51-2.66 ng/mL) were more effective than RA (2.91 ng/mL) in decreasing Aβx-40 peptide levels. However, all analogues (0.36-0.45 ng/mL) were less effective than RA (0.18 ng/mL) towards the Aβx-42 peptide. Structure-activity relationship analysis indicated that the 2,3-seco-2,3-dioic acid moiety and a less polar C-28 methyl group in the pentacyclic triterpene enhanced efficacy against Aβ1-x and Aβx-40 peptides. This suggests that these 2,3-seco-2,3-dioic acid triterpenes could be promising dual-action inhibitors for AD and HIV-associated neurocognitive disorders.