Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 7, Pages 2737-2752Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01514
Keywords
-
Categories
Funding
- Breast Cancer Research Program (BCRP) Breakthrough Award from the Department of Defense (DoD) [BC160038, BC160038P1]
- National Institutes of Health [P30 DA028821, R01 DA038446]
- Sanofi Innovation Awards (iAward) Program
- Cancer Prevention Research Institute of Texas (CPRIT) award
- Cancer Center Support grant from the United States National Institutes of Health [P30 CA016672]
- MD Anderson Cancer Center
- Duncan Family Institute Seed Funding Research Program
- UT system proteomics network for the HRMS analysis
- NATIONAL CANCER INSTITUTE [P30CA016672] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [T32DA007287, R01DA038446, F31DA045511] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 moredruglike 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available