Intriguing steroid glycosides for cancer therapy by suppressing the DNA damage response and mTOR/S6K signaling pathways

Pei-Pei An; Hui Huang; Su-Jie Ru; Yuan Gao; Yu-Hao Ren; Kun Gao; Hu Zhou; Bin Zhou; Jian-Min Yue

doi:10.1016/j.bioorg.2024.107619

Intriguing steroid glycosides for cancer therapy by suppressing the DNA damage response and mTOR/S6K signaling pathways

Bioorg Chem. 2024 Oct:151:107619. doi: 10.1016/j.bioorg.2024.107619. Epub 2024 Jul 9.

Authors

Pei-Pei An¹, Hui Huang², Su-Jie Ru³, Yuan Gao³, Yu-Hao Ren³, Kun Gao⁴, Hu Zhou⁵, Bin Zhou⁶, Jian-Min Yue⁷

Affiliations

¹ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
⁷ State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].

PMID: 39024806
DOI: 10.1016/j.bioorg.2024.107619

Abstract

Two rare 8-hydroxysteroid glycosides (6-7), and their downstream metabolites (1-5) with an unprecedented 6/6/5/5/5-pentacyclic scaffold, together with seven known analogues (8-14) were isolated from the twigs and leaves of Strophanthus divaricatus. Their structures were fully assigned by analysis of the spectroscopic and ECD data, NMR calculations, X-ray crystallographic study, and chemical methods. In addition, the inhibitory effects of 1-14 on liver and lung cancer cell lines were evaluated, and preliminary structure-activity relationship was discussed. Data-independent acquisition (DIA)-based quantitative proteomic analysis and biological verification of H1299 cells suggested that this family of compounds may play an anticancer role by suppressing both DNA damage response (DDR) and mTOR/S6K signaling pathways.

Keywords: Anticancer mechanism; Steroid glycosides; Strophanthus divaricatus; Structural elucidation; Structure–activity relationship.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / isolation & purification
Antineoplastic Agents, Phytogenic / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Damage* / drug effects
Dose-Response Relationship, Drug*
Drug Screening Assays, Antitumor*
Glycosides* / chemistry
Glycosides* / isolation & purification
Glycosides* / pharmacology
Humans
Molecular Structure
Ribosomal Protein S6 Kinases / antagonists & inhibitors
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction* / drug effects
Steroids / chemistry
Steroids / isolation & purification
Steroids / pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases* / antagonists & inhibitors
TOR Serine-Threonine Kinases* / metabolism

Substances

TOR Serine-Threonine Kinases
Glycosides
MTOR protein, human
Steroids
Ribosomal Protein S6 Kinases
Antineoplastic Agents, Phytogenic
Antineoplastic Agents