Novel designed enediynes: Molecular design, chemical synthesis, mode of cycloaromatization and guanine-specific DNA cleavage

• Published in: Bioorganic & medicinal chemistry Vol. 4; no. 1; pp. 105 - 113
• Main Authors: Toshima, Kazunobu, Ohta, Kazumi, Kano, Takaaki, Nakamura, Takatsugu, Nakata, Masaya, Kinoshita, Mitsuhiro, Matsumura, Shuichi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 1996
• Subjects: Alkynes; Anti-Bacterial Agents - chemistry; Antibiotics, Antineoplastic; Benzoates - chemical synthesis; Benzoates - chemistry; DNA - chemistry; DNA - metabolism; Drug Design; Enediynes; Guanine - chemistry; Peptides; Structure-Activity Relationship; Zinostatin - analogs & derivatives; Zinostatin - chemical synthesis; Zinostatin - chemistry
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(95)00170-0

The molecular design and chemical synthesis of novel enediyne molecules related to the neocarzinostatin chromophore (1), and their chemical and DNA cleaving properties are described. The 10-membered enediyne triols 16–18 were effectively synthesized from xylitol ( 10) in a short step, and found to be quite stable when handled at room temperature. The representative and acylated enediyne 16 was cycloaromatized by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in cyclohexa-1,4-diene-benzene to give the benzenoid product 21 through a radical pathway. On the other hand, the enediyne 16 was cycloaromatized by diethylamine in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer to afford another benzenoid product 22 as a diethylamine adduct through a polar pathway. Furthermore, the enediynes 16–18 were found to exhibit guanine-specific DNA cleavage under weakly basic conditions with no additive.