Synthesis and DNA cleavage reaction characteristics of enediyne prodrugs activated via an allylic rearrangement by base or UV irradiation.
A number of enediyne prodrugs 1-5 possessing an (E)-3-hydroxy-4-(2'-hydroxy-1'-phenylethylidene)cyclodeca-1,5-diyne scaffold have been synthesized via the Sonogashira coupling and an intramolecular Nozaki-Hiyama-Kishi reaction as the key steps. Upon incubation with enediyne prodrugs 4 and 5 possessing a free hydroxymethyl group on the exocyclic double bond, circular supercoiled DNA (Form I) underwent single strand cleavage into circular relaxed DNA (Form II) in buffer solution at pH 8.5, while the silylated analogs 1-3 showed very weak DNA cleavage activity. Alternatively, the silylated analogs 1-3 could be activated by UV irradiation via a photochemical alkene isomerization followed by an allylic rearrangement to form the putative epoxy enediyne, resulting in efficient DNA cleavage similar to the level observed with the prodrugs 4 and 5.
Tachi
Yukihiro
Y
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan.
Dai
Wei-Min
WM
Tanabe
Kazuhito
K
Nishimoto
Sei-ichi
S
D000598:Amino Acids, Cyclic / Q000737:chemistry*; D004247:DNA / Q000235:genetics*; D053281:Enediynes; D007477:Ions / Q000737:chemistry; D013058:Mass Spectrometry; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014466:Ultraviolet Rays
D000598:Amino Acids, Cyclic; D053281:Enediynes; D007477:Ions; D011355:Prodrugs; D004247:DNA