Synthesis of the marine sponge cycloheptapeptide phakellistatin 5(1).
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-alpha-OCH(2)CH=CH(2). After addition of the final unit (Ala), the allyl ester was removed under neutral conditions with Pd(o) [P(C(6)H(5))(3)](4). 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.
Pettit
G R
GR
Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Box 872404, Tempe, Arizona 87287-2404, USA.
Toki
B E
BE
Xu
J P
JP
Brune
D C
DC
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011161:Porifera / Q000737:chemistry*; D013057:Spectrum Analysis
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C404712:phakellistatin 5