Short synthesis of piperizinohydroisoquinoline ring by selective Pictet-Spengler cyclization and evaluation of antitumor activity

Yu An Chang, Tsung Hsien Sun, Michael Y. Chiang, Pei Jung Lu, Yi Ting Huang, Li Ching Liang, Chi Wi Ong

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

A rapid access to the piperizinohydroisoquinoline motif, which has feature of the saframycins and related pentacyclic antitumor alkaloids is described. The key features of the synthetic strategy include (1) a controlled mono-Pictet-Spengler cyclization of the symmetrical 3,6-bis-[(2,5-dimethoxy-phenyl)methyl]piperizine-2,5-dione (1), with aldehydes to give 2, under a critically controlled ratio of acetic acid and trifluoroacetic acid as solvent and (2) reduction of the activated amide to the hemiaminal, which then undergoes an unexpected dehydrogenation reaction to remove the steric hindrance for the second Pictet-Spengler cyclization to form the pentacyclic piperizinohydroisoquinoline 6. The in vitro antitumor activity of these compounds was tested against five human cancer cell lines (A549 lung, HeLa cervical, SAS oral, SKHep1 hepatoma and PC-3 prostate carcinoma). The pentacyclic saframycin analogues 6, 7 and 9 showed only weak activities. Interestingly, compound 6, having a closer relation to cribrostatin IV, is selective towards oral cancer.

Original languageEnglish
Pages (from-to)8781-8787
Number of pages7
JournalTetrahedron
Volume63
Issue number36
DOIs
Publication statusPublished - 2007 Sep 3

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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