Bioactive compounds from the Thai sea hare, Bursatella leachii

Abstract

Chemical investigation of the extract from the Thai sea hare, Bursatella leachii (family Aplysiidae, phylum Mollusca), led to the isolation of one known and three new compounds. Bioassay-guided isolation from the first collection of the sea hare afforded a new malyngamide X, the first tripeptide malyngamide (0.71% yield of the crude extract). The second collection of the sea hare provided a potent stimulator of actin assembly, hectochlorin, and its new derivative, deacetylhectochlorin, together with a new structurally unrelated molecule, syn-3-isopropyl-6-(4-methoxy-benzyl)-4-methyl-morpholine-2,5-dione, in 0.25, 0.08, and 0.007% yield of the crude extract, respectively. Malyngamide X exhibited moderate cytotoxicity against KB, NCI-H187, and BC cancer cell lines with ED50's of 8.20, 4.12, and 7.03 M, respectively; anitimalaria with ED[subscript50]'s of 5.44 micrometre; and antituberculosis with MIC's of 50 microgram/ml. Hectochlorin showed strong cytotoxicity against KB and NCI-H187 with ED[subscript50]'s of 0.86 and 1.20 micrometre, while deacetylhectochlorin exhibited more potent cytotoxicity with ED[subscript50]'s of 0.31 and 0.32 micrometre, respectively. However, the small amount of the new morpholine-2,5-dione derivative precluded biological evaluation. Non-hydrolytic degradation methods were developed as an exemplary study for assigning absolute stereochemistry of malyngamide X having conformationally flexible system as 2(S), 5(S), 7(S), 8(R), 14(S), and 7'(S). The current strategy comprised of the NMR applications of the NMR chiral solvating agent (CSA) employing 2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE, Pirkle's alcohol), the modified Mosher's method, and partly NOEs correlations in conjunction with the conformational calculations and the biogenetic considerations. In addition, we have demonstrated the proposed solvation models that lead to stereochemical determination at some chiral carbons within the molecules of malyngamide X and several synthetic model compounds including alkaline degradation product of tautomycin and enantiomers of deta[superscript 3]-pyrrolin-2-one derivatives. The solvation models extend the use of TFAE and allow one to employ the current strategy to other natural compounds without chemical modification of the compounds as well.