title: Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene.
abstract: The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT 06520-8107 (USA) http://www.chem.yale.edu/herzongroup.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Woo
authors.forename: Nihar
authors.initials: N
authors.lastname: Ranjan
authors.forename: Dev P
authors.initials: DP
authors.lastname: Arya
authors.forename: Seth B
authors.initials: SB
authors.lastname: Herzon
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D053837:DNA Cleavage / Q000187:drug effects*; D004249:DNA Damage; D003979:Diazonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D003979:Diazonium Compounds; D005449:Fluorenes; D004247:DNA; C427203:calf thymus DNA
keywords: DNA cleavage; DNA damage; cancer; natural products