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Challenges and Opportunities to Develop Enediyne Natural Products as Payloads for Antibody-Drug Conjugates.
Antib Ther
January 2021
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.
Calicheamicin, the payload of the antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa), belongs to the class of enediyne natural products. Since the isolation and structural determination of the neocarzinostatin chromophore in 1985, the enediynes have attracted considerable attention for their value as DNA damaging agents in cancer chemotherapy. Due to their non-discriminatory cytotoxicity towards both cancer and healthy cells, the clinical utilization of enediyne natural products relies on conjugation to an appropriate delivery system, such as an antibody.
View Article and Find Full Text PDF2-Naphthol Moiety of Neocarzinostatin Chromophore as a Novel Protein-Photodegrading Agent and Its Application as a H O -Activatable Photosensitizer.
Chemistry
November 2020
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
A 2-naphthol derivative 2 corresponding to the aromatic ring moiety of neocarzinostatin chromophore was found to degrade proteins under photo-irradiation with long-wavelength UV light without any additives under neutral conditions. Structure-activity relationship studies of the derivative revealed that methylation of the hydroxyl group at the C2 position of 2 significantly suppressed its photodegradation ability. Furthermore, a purpose-designed synthetic tumor-related biomarker, a H O -activatable photosensitizer 8 possessing a H O -responsive arylboronic ester moiety conjugated to the hydroxyl group at the C2 position of 2, showed significantly lower photodegradation ability compared to 2.
View Article and Find Full Text PDFCharacterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay.
J Am Chem Soc
March 2016
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, are potent inhibitors of DNA double-strand break (DSB) repair. Our data suggest that cardiac glycosides interact with phosphorylated mediator of DNA damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger protein 8 (RNF8), two factors involved in DSB repair, and inhibit the retention of p53 binding protein 1 (53BP1) at the site of DSBs.
View Article and Find Full Text PDFNeocarzinostatin as a probe for DNA protection activity--molecular interaction with caffeine.
Mol Carcinog
April 2012
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan, Republic of China.
Neocarzinostatin (NCS), a potent mutagen and carcinogen, consists of an enediyne prodrug and a protein carrier. It has a unique double role in that it intercalates into DNA and imposes radical-mediated damage after thiol activation. Here we employed NCS as a probe to examine the DNA-protection capability of caffeine, one of common dietary phytochemicals with potential cancer-chemopreventive activity.
View Article and Find Full Text PDFIn vivo characterization of NcsB3 to establish the complete biosynthesis of the naphthoic acid moiety of the neocarzinostatin chromophore.
FEMS Microbiol Lett
October 2010
Department of Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, Asansi, Chungnam, Korea.
Neocarzinostatin (NCS) is an enediyne antibiotic produced by Streptomyces carzinostaticus. The NCS chromophore consists of an enediyne core, a sugar moiety, and a naphthoic acid (NA) moiety. The latter plays a key role in binding the NCS chromophore to its apoprotein to protect and stabilize the bioactive NCS chromophore.
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