Synthesis of the marine sponge cycloheptapeptide phakellistatin 51

George Pettit, Brian E. Toki, Jun-Ping Xu, Daniel C. Brune

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Abstract

Phakellistatin 5 (1), a constituent of The Federated States of Micronesia (Chuuk) marine sponge Phakellia costada, was synthesized by solution-phase and solid-phase techniques. Because the linear peptide bearing (R)-Asn resisted cyclization, the synthesis of this peptide was repeated using the PAL resin attachment proceeding from N-Fmoc-D-Asp-α-OCH2CH=CH2. After addition of the final unit (Ala), the allyl ester was removed under neutral conditions with Pd°[P(C6H5)3l4. Removal of the final Fmoc- protecting group and cyclization with PyAOP provided (R)-Asn-phakellistatin 5 (2) in 28% overall yield. The same synthetic route from (S)-Asp led to natural phakellistatin 5 (1) in 15% overall recovery. The solution-phase and solid-phase synthetic products derived from (S)-Asp were found to be chemically but not biologically identical with natural phakellistatin 5 (1). This important fact suggested that a trace, albeit highly cancer-cell growth inhibitory, constituent accompanied the natural product or that there is a subtle conformational difference between the synthetic and natural cyclic peptides.

Original languageEnglish (US)
Pages (from-to)22-28
Number of pages7
JournalJournal of Natural Products
Volume63
Issue number1
DOIs
StatePublished - Feb 14 2000

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ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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