Phakellistatins 7-9 respresent the first cancer cell growth inhibitory (P388 ED50 3.0, 2.9 and 4.1 Ixg/mL respectively) cyclic decapeptides. Each was isolated from the Federated States of Micronesia (Chunk) marine sponge Phakellia costata.
Animals, plants and microorganisms constitute a vast reservoir of peptides with potentially important medicinal properties that range from the partially understood higher animal hormones to the lower organism peptides of generally unknown natural function. Among the latter categories are the diverse series of marine shell-less mollusc antineoplastic 35 and cytotoxic 6-7 dolastatins, the cytotoxic marine ascidian peptides, s the Australian frog antimicrobal and antiviral coerin-type cyclic peptides, 9 higher plant (Aster tatoricus, Compositae) antineoplastic cyclic pentapeptides, lยฐ fungal antibioticsll and the streptomyces antineoplastic antibiotic himastatin. 12 Clearly, discovery and biological evaluation of such valuable naturally occurring peptides is only in a very early phase. 13 We herein report discovery of the first three cancer cell growth inhibitory cyclic decapeptides designated phakellistatins 7, 8 and 9 from a marine sponge and to our knowledge from any marine animal.
Earlier we summarized the isolation and structural elucidation of the cancer cell growth inhibitory cyclic heptapeptide phakellistatins 4-61 from the Western Pacific (Chunk, Micronesia) marine sponge Phakellia costata (class Demospongia). When the 1987 collection (500 kg wet wt.) of P. costata murine P388 lymphocytic leukemia (PS system) active fractions were examined further for trace PS cell line active components we discovered three cyclic decapeptides with significant cancer cell growth inhibitory properties.
The bioactive dichloromethane soluble fraction prepared from P. costata and used to obtain phakellistatins 1 and 4-6 by a solvent partitioning, gel permeation (Sephadex LH-20) and partition chromatographic (LH-20) sequence I led to a trace PS active fraction that was further separated (PS bioassay).
Continued column chromatographic (partition solvent system) separations on Sephadex LH-20 and final separation by reversed phase HPLC (Phenomenex C8 column and elution with CH3CN-CH3OH-H20, 10:10:13) afforded phakellistatin 7 (1, 6.5 mg, 1.3 x I0-6%), 8 (2, 69.8 mg, 1.4 x 105%) and 9 (3, 7.2 mg, 1.4 x 106%).