18 抗腫瘍性抗生物質カプリマイシンA_3アナログの合成とDNAとの反応の解析(口頭発表の部)

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Kapurimycin A_3 (1) having anthra-γ-pyron ring system with vinyl epoxide side chain is an antitumor antibiotic isolated from culture broth of Streptomyces sp. DO-115. The reaction of 1 with DNA is shown to occur at the C16 epoxide carbon to preferentially form guanine adduct. To get insight into the extraordinary reactivity and selectivity of 1 toward guanine base in DNA synthesis of analogs of 1 and the reaction with DNA were examined. The key step for the synthesis of kapurimycin analogs is 6-endo-digonal cyclization of o-hydroxyarylethynylketone. It was found that under thermodynamic conditions employing KF and 18-crown-6 the cyclization preferentially gave the desired pyrone derivatives. Optically active epoxide segment was prepared from commercially available acetylenic alcohol by asymmetric dihydroxylation using AD-mix-β. Coupling of acetylenic epoxide with aromatic aldehyde followed by oxidation with MnO_2 produced ethynylketone. Treatment of the ethynylketoene under the reaction conditions we developed gave optically active kapurimycin analog. To examine DNA-cleaving activity for those analogs DNA transformation assays were performed using supercoiled pBR322 plasmid DNA. The reaction of kapurimycin analogs with pBR322 was carried out at 37℃ for 5h and unbound agents were removed by ethanol precipitation. The recovered DNA was dissolved and incubated for 24h at the same temperature. Agarose gel electrophoresis clearly showed that the DNA-cleaving activity was highly dependent on the structure of analogs and the presence of epoxide, double bond adjacent to epoxide, and the ring system in 2 was essential for the remarkable DNA cleavage for 1.
天然有機化合物討論会の論文
1995-09-01

18 抗腫瘍性抗生物質カプリマイシンA_3アナログの合成とDNAとの反応の解析(口頭発表の部)

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