Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads

Ye Ding, Dengfeng Li, Chunyong Ding, Pingyuan Wang, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark White, Qiang Shen, Jia Zhou

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure-activity relationship (SAR) and the structure-reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in vivo while displaying lower toxicity to normal human mammary epithelial cells in comparison to oridonin.

Original languageEnglish (US)
Pages (from-to)2737-2752
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number7
DOIs
StatePublished - Apr 12 2018

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Triple Negative Breast Neoplasms
Structure-Activity Relationship
Drug Discovery
Biological Products
Breast
Epithelial Cells
Pharmacology
Apoptosis
Inflammation
Pharmaceutical Preparations
Neoplasms
oridonin
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads. / Ding, Ye; Li, Dengfeng; Ding, Chunyong; Wang, Pingyuan; Liu, Zhiqing; Wold, Eric A.; Ye, Na; Chen, Haiying; White, Mark; Shen, Qiang; Zhou, Jia.

In: Journal of Medicinal Chemistry, Vol. 61, No. 7, 12.04.2018, p. 2737-2752.

Research output: Contribution to journalArticle

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