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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The pyrrolo[2,1-c][1,4]benzodiazepine (PBD) family of antitumor agents is based on the natural product anthramycin, which was the first member to be isolated from Streptomyces refuineus var. thermotolerans in the early 1960s (Figure 5.9). Other well-known members of the family include tomaymycin, sibiromycin, and neothramycin. Structure of the pyrrolobenzodiazepine (PBD) anthramycin showing the interconvertible electrophilic N10-C11 carbinolamine, carbinolamine methyl ether, and imine forms which allow covalent interaction with DNA.
Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer
Published in mAbs, 2019
Jason B. White, Ryan Fleming, Luke Masterson, Ben T. Ruddle, Haihong Zhong, Christine Fazenbaker, Patrick Strout, Kim Rosenthal, Molly Reed, Vanessa Muniz-Medina, Philip Howard, Rakesh Dixit, Herren Wu, Mary Jane Hinrichs, Changshou Gao, Nazzareno Dimasi
Although pyrrolobenzodiazepines (PBDs) such as anthramycin and sibiromycin were shown to be potent antitumor agents over 50 years ago, they have only recently emerged as cytotoxic warheads for antibody-drug conjugates (ADCs),1-3 which are a class of targeted therapeutics for the treatment of cancers.4-6 In their monomeric form, PBDs derive their cytotoxic activity by selectively binding to the minor groove of DNA and forming covalent bonds with the C2-NH2 group of guanine bases.7-10 Efforts to enhance this cytotoxic activity led to the synthesis of dimeric PBDs,11,12 which have two alkylating imine functions that allow the formation of minor groove DNA adducts, resulting in greater interference with DNA replication than monomeric PBDs.13-15