title: Synthesis and evaluation of N-aryl and N-alkenyl CBI derivatives.
abstract: The preparation of a novel series of N-aryl CBI derivatives in which an aryl substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue is detailed and its extension to a unique series of N-alkenyl derivatives is reported. The N-aryl derivatives were found to be exceptionally stable and to exhibit well-defined relationships between structure (X-ray), reactivity, and cytotoxic potency. When combined with the results of past investigations, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency. The parabolic relationship establishes that compounds in the series should possess sufficient stability to reach their biological target (DNA), yet maintain sufficient reactivity to effectively alkylate DNA upon reaching the biological target. Just as importantly, it defined this optimal balance of stability and reactivity that may be used for future design of related analogues. Notably, the duocarmycin SA and yatakemycin alkylation subunit lies at this optimal stability/reactivity position, whereas the CC-1065 and duocarmycin A alkylation subunits lie progressively and significantly to the left of this optimal position (too reactive).
authors.affiliation: Department of Chemistry and the Skaggs, Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Parrish
authors.forename: John D
authors.initials: JD
authors.lastname: Trzupek
authors.forename: Terry V
authors.initials: TV
authors.lastname: Hughes
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence / Q000235:genetics; D018360:Crystallography, X-Ray / Q000379:methods; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; D004247:DNA; C058289:duocarmycin A