Diterpenoids with an unusual tricyclo[10.3.0.02,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators

Lan-Jun Zhang; Pei-Zhi Huang; Ke-Jing Li; Yue-Yang Cao; Yue Sun; Wei-Jiao Feng; Yu-Xian Wang; Yi-Lin He; Le-Yuan Mi; Yan-Li Wei; Qi-Zhong Lai; Jian-Jun Chen; Kun Gao

doi:10.1016/j.bioorg.2023.106619

Diterpenoids with an unusual tricyclo[10.3.0.0^2,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators

Bioorg Chem. 2023 Sep:138:106619. doi: 10.1016/j.bioorg.2023.106619. Epub 2023 May 20.

Authors

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China.
² The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China.
³ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China; Research Institute, Lanzhou Jiaotong University, Lanzhou 730070, People's Republic of China.
⁴ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People's Republic of China. Electronic address: npchem@lzu.edu.cn.

PMID: 37253310
DOI: 10.1016/j.bioorg.2023.106619

Abstract

Three new diterpenoids with an unusual carbon skeleton, pedilanins A-C (1-3), and nine new jatrophane diterpenoids, pedilanins D-L (4-12), along with five known ones (13-17), were isolated from Pedilanthus tithymaloides. Compounds 1-3 characterize an unprecedented tricyclo[10.3.0.0^2,9]pentadecane skeleton. Compounds 4-8 are rare examples of the jatrophanes bearing a cyclic hemiketal substructure. Their structures were determined by an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. In the bioassay, compounds 1-12 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.9 to 396.8 at the noncytotoxic concentration of 10 μM. The mechanism results indicated that compounds 2 and 3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

Keywords: Diterpenoids; Jatrophanes; Multidrug resistance modulators; Pedilanins A-L; Pedilanthus tithymaloides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diterpenes* / chemistry
Diterpenes* / pharmacology
Drug Resistance, Multiple
Euphorbia* / chemistry
Molecular Structure
Radiopharmaceuticals / pharmacology

Substances

pentadecane
Radiopharmaceuticals
Diterpenes