Antineoplastic Agents. 510. Isolation and Structure of Dolastatin 19 from the Gulf of California Sea Hare Dolabella auricularia

Abstract

The Gulf of California shell-less mollusc Dolabella auricularia has been found to contain a new 14-membered macrocyclic lactone linked to a 2,4-di-O-methyl-l-alpha-rhamnopyranoside, designated dolastatin 19 (1). The new cancer cell growth inhibitor (1, 8.33 x 10(-8)% yield) was obtained by bioassay (P388 lymphocytic leukemia and human cancer cell lines) directed isolation, accompanied by debromoaplysiatoxin (9.17 x 10(-7)% yield) and anhydrodebromoaplysiatoxin (2.0 x 10(-7)% yield). The structures were determined on the basis of analyses of high-resolution mass spectra and high-field NMR data. All the relative stereochemistry for the chiral centers was designated by utilizing NMR techniques.

Total Synthesis and Complete Stereostructure of a Marine Macrolide Glycoside, (−)‐Lyngbyaloside B

“…[23] Silylation of the alcohol 76 with TBSCl in the presence of AgNO 3 and pyridine [61] (91 %y ield) fol- www.chemeurj.org lowed by reductive removal of the superfluous chiral auxiliary gave rise to the alcohol 77 (79 %y ield). The alcohol 77 was deoxygenated by tosylation (85 %y ield) andL iEt 3 BH reduction [62] (92 %y ield) to deliver the olefin 78.D ihydroxylation of the olefin 78 and subsequent cleavageo fther esultant 1,2-diol with Pb(OAc) 4 gave the aldehyde 79 in 92 %y ield over the two steps, which was then reactedw ith the dienol silyl ether 64 under Mukaiyama conditions (BF 3 ·OEt 2 ,C H 2 Cl 2 , À95 8C) to afford the alcohol 80 in 87 %y ield, along with its C-5 epimer in 8% yield. These diastereoisomers were separated by flash columnc hromatography on silica gel.…”

“…Macrolide glycosides constitute a growing family of marine natural products with moderate to potent cytotoxic activity against human cancer cell lines. As exemplified by aurisides, callipeltosides, and dolastatin 19 (Figure ), these natural products were initially discovered from marine invertebrates, such as sea hares and sponges, but it is now speculated that these macrolide glycosides are actually the secondary metabolites of symbiotic microorganisms.…”

Marine natural products

“…391 Mooreamide A 640 is a cannabinomimetic lipid obtained from Moorea bouillonii and is the most potent marine-derived inhibitor of the neuroreceptor CB 1 reported to date. 392 Two new aplysiatoxin analogues, 3-methoxyaplysiatoxin 641 and 3methoxydebromoaplysiatoxin 642 were isolated from Trichodesmium erythraeum and 642, along with the co-isolated known debromo analogues debromoaplysiatoxin 393 and anhydrodebromoaplysiatoxin, 394 were inhibitors of the Chikungunya virus. 395 Other new metabolites 643-655 were obtained from the genera Anabaena, Lyngbya, Moorea, Oscillatoria and Symploca.…”

Integrated approaches to the configurational assignment of marine natural products

“…are recent additions to a group of cytotoxic glycosidic 14-membered ring macrolides from various marine organisms; others include aurisides A ( 161 ) clxxxix and B and dolastatin 19 ( 162 ) cxc from the sea slug Dolabella auricularia , callipeltoside A ( 163 ) from the sponge Callipelta sp., cxci and lyngbyaboulloside ( 164 ) from the cyanobacteria Lyngbya bouillonii . cxcii Configurational assignment of auriside A ( 161 ) by combined J coupling and NOESY analysis which established the complete RC.…”