Computationally-Assisted Discovery and Assignment of a New Class of 6/6/5/5 Fused-Ring Diterpene Acting as Pregnane X Receptor Ligands from Isodon serra

Bian Z 1 , Liu X 1 , Hu S 1 , Li H 2 , Wood JS 3 , Williamson RT 3 Show all authors , Liu J 4 , Chen Y 5 , Shi J 6 , Cummins CL 6 , Ferreira D 7 , Choo YM 8 , Wang S 2 , Hamann MT 9 , Wang X 1

Affiliations 

  • 1 School of Pharmacy, Lanzhou University, Lanzhou 730000, Gansu, P. R. China
  • 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, P. R. China
  • 3 Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, North Carolina 28403, United States
  • 4 Department of Chemistry, The Donnelly Centre, University of Toronto, Toronto M5S 3E1, Canada
  • 5 Department of Biology, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada
  • 6 Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
  • 7 Department of Biomolecular Sciences, Division of Pharmacognosy, and National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, Mississippi 38677, United States
  • 8 Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
  • 9 Drug Discovery, Biomedical Sciences and Public Health, Medical University of South Carolina, Charleston, South Carolina 29425, United States
J Nat Prod, 2024 Oct 25;87(10):2459-2467.
PMID: 39315450 DOI: 10.1021/acs.jnatprod.4c00759

Abstract

We report here the orchestration of molecular ion networking (MoIN) and a set of computationally assisted structural elucidation approaches in the discovery and assignment of a new class of rearranged 4,5-seco-abietane diterpenoids including serra A (1), which possesses an unusual 6/6/5/5 fused-ring skeleton system, together with two previously unreported diterpenoids serras B-C (2-3) and five known compounds were isolated from Isodon serra (I. serra). The structures were elucidated by spectroscopic analysis in conjunction with computationally assisted structure elucidation tools. In silico, serras A-C (1-3) bind well to PXR, suggesting their potential role in reducing inflammation. The results of serra A (1) with hPXR demonstrated agonist activity with an EC50 value of 15 μM. Serra A (1), graciliflorin F (4), gerardianin C (5), 11,12,15-trihydroxy-8,11,13-abietatrien-7-one (6), rabdosin D (7), and 15-hydroxysalprionin (8) exhibited promising anti-inflammatory activities in lipopolysaccharide (LPS)-induced RAW 267.4 cells, and their inhibition rates on NO production were more than 65% at 10 μM.

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