title: Efficacious cyclic N-acyl O-amino phenol duocarmycin prodrugs.
abstract: Two novel cyclic N-acyl O-amino phenol prodrugs are reported as new members of a unique class of reductively cleaved prodrugs of the duocarmycin family of natural products. These prodrugs were explored with the expectation that they may be cleaved selectively within hypoxic tumor environments that have intrinsically higher concentrations of reducing nucleophiles and were designed to liberate the free drug without the release of an extraneous group. In vivo evaluation of the prodrug 6 showed that it exhibits extraordinary efficacy (T/C > 1500, L1210; 6/10 one year survivors), substantially exceeding that of the free drug, that its therapeutic window of activity is much larger, permitting a dosing ≥ 40-fold higher than the free drug, and yet that it displays a potency in vivo that approaches the free drug (within 3-fold). Clearly, the prodrug 6 benefits from either its controlled slow release of the free drug or its preferential intracellular reductive cleavage.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Wolfe
authors.forename: Katharine K
authors.initials: KK
authors.lastname: Duncan
authors.forename: Nikhil K
authors.initials: NK
authors.lastname: Parelkar
authors.forename: Douglas
authors.initials: D
authors.lastname: Brown
authors.forename: George A
authors.initials: GA
authors.lastname: Vielhauer
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry; D003692:Delayed-Action Preparations; D000080890:Duocarmycins; D007202:Indicators and Reagents; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D011355:Prodrugs; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D000080890:Duocarmycins; D007202:Indicators and Reagents; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; D004247:DNA; C058289:duocarmycin A