Novel Aporphine- and Proaporphine-Clerodane Hybrids Identified from the Barks of Taiwanese <i>Polyalthia longifolia</i> (Sonn.) Thwaites var. <i>pendula</i> with Strong Anti-DENV2 Activity

• Main Authors: I-Wen Lo (Author), Geng-You Liao (Author), Jin-Ching Lee (Author), Chi-I Chang (Author), Yang-Chang Wu (Author), Yen-Yu Chen (Author), Shang-Pin Liu (Author), Huey-Jen Su (Author), Chih-I Liu (Author), Chia-Yi Kuo (Author), Zheng-Yu Lin (Author), Tsung-Lin Li (Author), Yun-Sheng Lin (Author), Chia-Ching Liaw (Author)
• Format: Book
• Published: MDPI AG, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Hybrid natural products produced via mixed biosynthetic pathways are unique and often surprise one with unexpected medicinal properties in addition to their fascinating structural complexity/diversity. In view of chemical structures, hybridization is a way of diversifying natural products usually through dimerization of two similar or dissimilar subcomponents through a C-C or N-C covalent linkage. Here, we report four structurally attractive diterpene-alkaloid conjugates polyalongarins A-D (<b>1</b>-<b>4</b>), clerodane-containing aporphine and proaporphine alkaloids, the first of its kind from the barks of Taiwanese <i>Polyalthia longifolia</i> (Sonn.) Thwaites var. <i>pendula</i>. In addition to conventional spectroscopic analysis, single crystal X-ray crystallography was employed to determine the chemical structures and stereo-configurations of <b>1</b>. Compounds <b>1</b>-<b>4</b> were subsequently subjected to in vitro antiviral examination against DENV2 by evaluating the expression level of the NS2B protein in DENV2-infected Huh-7 cells. These compounds display encouraging anti-DENV2 activity with superb EC₅₀ (2.8-6.4 μM) and CC₅₀ values (50.4-200 μM). The inhibitory mechanism of <b>1</b>-<b>4</b> on NS2B was further explored drawing on in-silico molecular docking analysis. Based on calculated binding affinities and predicted interactions between the functional groups of <b>1</b>-<b>4</b> and the allosteric-site residues of the DENV2 NS2B-NS3 protease, our analysis concludes that the clerodane-aporphine/proaporphine-type hybrids are novel and effective DENV NS2B-NS3 protease inhibitors.

Item Description

10.3390/ph15101218
1424-8247