Cycloartane-type triterpenoids from Combretum quadrangulare Kurz with PCSK9 secretion inhibitory activities

Chae-Yeong An; Pisey Pel; Mingoo Bae; Chan-Woong Park; Haeun Kwon; Hyun Suk Lee; Luong Van Dung; Changmu Kim; Dongho Lee; Young Hee Choi; Young-Won Chin

doi:10.1016/j.phytochem.2024.114330

Cycloartane-type triterpenoids from Combretum quadrangulare Kurz with PCSK9 secretion inhibitory activities

Phytochemistry. 2024 Nov 14:230:114330. doi: 10.1016/j.phytochem.2024.114330. Online ahead of print.

Authors

Affiliations

¹ Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
² College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
³ Department of Plant Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
⁴ Dalat University, Center for Biodiversity and Climate Change Research, Phu Dong Thien Vuong 01, Dalat City, Lam Dong Province, Viet Nam.
⁵ Species Diversity Research Division, National Institute of Biological Resources, Incheon, 22689, Republic of Korea.
⁶ Natural Product Research Institute and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: ywchin@snu.ac.kr.

PMID: 39547492
DOI: 10.1016/j.phytochem.2024.114330

Abstract

Nine previously undescribed (1-9) and seven known (10-16) cycloartane-type triterpenoids were isolated and characterized from Combretum quadrangulare Kurz using physicochemical and spectroscopic methods. The absolute configurations of these compounds were determined through modified Mosher's method and quantum chemical calculation of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Their inhibitory activities against PCSK9 secretion were assessed, and a plausible structure-activity relationship was delineated. Compounds 2, 14, and 15 exhibited notable inhibitory effects on PCSK9 mRNA and protein levels, and significant PCSK9 mRNA inhibition was observed when co-treated with atorvastatin. Compound 15 showed the most potent activity, markedly enhancing LDL uptake compared to the negative control. In vivo pharmacokinetic studies confirmed that compound 15 exhibited higher distribution in the liver than plasma, where PCSK9 is predominantly synthesized. These findings emphasize the potential significance of the cycloartane-type triterpenoid scaffold in discovering PCSK9 inhibitors.

Keywords: Combretaceae; Combretum quadrangulare; Cycloartane; Hypercholesterolemia; LDL; PCSK9; Triterpenoid; VCD.