Total synthesis of telomestatin and its analogues

Takayuki Doi, Masahito Yoshida, Kazuaki Shibata

Research output: Contribution to journalReview articlepeer-review

Abstract

We have achieved a total synthesis of telomestatin and determined it absolute configuration to be (R). During the synthetic study for its enantiomer, serious epimerization in the macrolactamization was observed. The problem was overcome under the reaction conditions utilizing DPPA/HOBt/DMAPO and the (S)-isomer was synthesized. Measurement of Tm values obtained from the CD melting curves indicated that (S)-isomer stabilizes the antiparallel G-quadruplex structure of telomea more strongly than telomestatin. The (S)-isomer exhibited more potent inhibitory activity against telomerase than telomestatin. We also synthesized telomestatin analogues that are heptaoxazole macrocycles including different numbers of methyloxazole moieties or containing a bromooxazole. The bromooxazole-containing heptaoxazole analogue underwent Suzuki-Miyaura coupling leading to aryl-substituted oxazole-containing heptaoxazole analogues. Although the substituents on the oxazole moieties in the heptaoxazole macrocyclic analogues did not affect telomerase inhibitory activity, one of amino-linked S-alkylated analogues exhibited potent inhibitory activity as telomestatin.

Original languageEnglish
Pages (from-to)3-13
Number of pages11
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume73
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

Keywords

  • G-quadruplex
  • Macrolactamization
  • Natural products
  • Oxazole
  • Telomerase inhibitor
  • Thiazoline
  • Total synthesis

ASJC Scopus subject areas

  • Organic Chemistry

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