Synthesis of phakellistatin 11: a micronesia (Chuuk) marine sponge cyclooctapeptide.
The cyclic octapeptide phakellistatin 11 (1), a constituent of The Federated States of Micronesia (Chuuk) marine sponge Phakellia sp., was synthesized using solid-phase techniques. An initial solution-phase synthesis proved to be inadequate owing to spontaneous deprotection of the Fmoc group at the heptapeptide stage. Using the PAL resin attachment and proceeding from Fmoc-Glu-alpha-allyl ester, linear elongation of the octapeptide was performed until the final unit Pro was added. The allyl ester was removed using Pd(0)[P(C(6)H(5))(3)](4). Cleavage of the final Fmoc group and cyclization with PyAOP provided phakellistatin 11 (1) in 17% overall yield. The synthetic specimen of phakellistatin 11 (1) was found to be chemically but not biologically (cancer cell lines) identical to the natural product. The result suggested a conformational difference or more likely the presence of a trace amount of a highly active antineoplastic agent that binds noncovalently to the natural cyclic octapeptide 1.
Pettit
G R
GR
Cancer Research Institute and Department of Biochemistry, Arizona State University, Tempe, Arizona 85287-2404, USA.
Lippert
J W
JW
Taylor
S R
SR
Tan
R
R
Williams
M D
MD
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C095626:phakellistatin 11; C119157:phakellistatin 2; C404712:phakellistatin 5; C086904:axinastatin 2