@article{4bed86b0be6548fcbe05f2a59343d45f,
title = "Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads",
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 Rh 2 (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.",
author = "Ye Ding and Dengfeng Li and Chunyong Ding and Pingyuan Wang and Zhiqing Liu and Wold, {Eric A.} and Na Ye and Haiying Chen and White, {Mark A.} and Qiang Shen and Jia Zhou",
note = "Funding Information: This work was supported by Breast Cancer Research Program (BCRP) Breakthrough Award (grant nos. BC160038 and BC160038P1) from the Department of Defense (DoD) (to J.Z. and Q.S.), grant nos. P30 DA028821 and R01 DA038446 from the National Institutes of Health (to J.Z.), Sanofi Innovation Awards (iAward) Program (to J.Z.), the Cancer Prevention Research Institute of Texas (CPRIT) award (to J.Z.), Cancer Center Support grant no. P30 CA016672 from the United States National Institutes of Health (to The University of Texas MD Anderson Cancer Center), startup funds from MD Anderson Cancer Center (to Q.S.), and the Duncan Family Institute Seed Funding Research Program (to Q.S). We thank Dr. Lawrence C. Sowers at the Department of Pharmacology as well as Dr. Tianzhi Wang at the NMR core facility of UTMB for the NMR spectroscopy assistance and Dr. Xuemei Luo at UTMB mass spectrometry core with funding support from the UT system proteomics network for the HRMS analysis. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",
year = "2018",
month = apr,
day = "12",
doi = "10.1021/acs.jmedchem.7b01514",
language = "English (US)",
volume = "61",
pages = "2737--2752",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",
}