title: Synthesis-enabled probing of mitosene structural space leads to improved IC₅₀ over mitomycin C.
abstract: A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesis-driven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA (USA) http://www.chem.ucsb.edu/∼zhang/index.html.
authors.forename: Zhitong
authors.initials: Z
authors.lastname: Zheng
authors.forename: Mollie
authors.initials: M
authors.lastname: Touve
authors.forename: Josue
authors.initials: J
authors.lastname: Barnes
authors.forename: Norbert
authors.initials: N
authors.lastname: Reich
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D016685:Mitomycin / Q000737:chemistry / Q000494:pharmacology*; D008937:Mitomycins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D008937:Mitomycins; C046001:mitosene; D016685:Mitomycin
keywords: DNA; cancer; drug design; medicinal chemistry; synthetic methods