Kahalalides V–Y Isolated from a Hawaiian Collection of the Sacoglossan Mollusk Elysia rufescens

Abstract

Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-L-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an L configuration. Kahalalide Y (4) was found to have an L-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.Sacoglossan mollusks are a group of marine invertebrates found within the subclass Opisthobranchia and have been extensively studied for their notable production of bioactive secondary metabolites. 1 They are considered to be specialists both in the manner in which they feed and the organisms that they feed upon. Many species are herbivores feeding primarily on green algae, from which they are able to sequester functioning chloroplasts. In some cases, these organelles are used as a source of photosynthetic energy, as shown by 14 C experiments establishing the conversion of carbonate to a variety of carbohydrates, which can then in turn be used to biosynthesize secondary metabolites, with the majority of these being associated with ecological functions, including chemical defense. 16 In addition, KF and its semisynthetic derivatives were found to have in vitro antifungal activity against various AIDS opportunistic infectious strains, which expands the therapeutic indications for this novel drug lead. 8,17 Due to the potential therapeutic value of KF, we have renewed investigations for kahalalide derivatives from E. rufescens. To date, little is known about the life cycle of E. rufescens. It can be speculated that the life span and growth rate of the species is rapid and the mollusk must reproduce and grow quickly due to the fact that the mollusk is not found during the month of January but can be found easily in the tens to hundreds of thousands during the months of March, April, and May at this location. To evaluate the bioactivity of KF and to prepare semisynthetic analogues, we collected aroun...

Biosynthetic Products from a Nearshore-Derived Gram-Negative Bacterium Enable Reassessment of the Kailuin Depsipeptides

“…However, similar to the situation with the kailuins, no assignments have been made for other members of this list including ngercheumicins D and E, 20 halobacillin, 37 and kahalalides Y and W (W was assigned only by biosynthetic analogy). 33 To date, no natural products of this type have been reported with an S configuration at the β -acyloxy carbon, although NMR properties for the peptidolipin B have been predicted via DFT calculations (see Figure 4). 35 …”

“…Unfortunately, no useful Δ δ data were observed for the nine-carbon side chain flanking the CO-MPTA group because the resonances of 12a/12b appeared as unresolved multiplets. This same situation also confounded the Mosher approach to the peptidolipins, possessing a 23-carbon side chain, 35 but it was not a problem for the three five-carbon side chain containing compounds 19,21,33 (Figure S32, Supporting Information). The only remaining useful data were minimal and consisted of Δ δ S − R = −0.059 at C-2, suggesting an R β -acyloxy configuration.…”

“…Important benchmark information is contained in the first three entries, which present experimental R -peptiolipin B 13 C shifts ( δ C β 72.6, δ C γ 32.5) 35 alongside those from DFT calculations for R -peptiolipin B ( δ C β 74.1, δ C γ 35.7) and S -peptiolipin B ( δ C β 77.5, δ C γ 40.6). 35 Other diagnostic insights can be derived from the data available for an additional five compounds definitively assigned with an R - β -acyloxy configuration (solonamide A, 19 unnarmicin A, 21 serratiomycin, 36 triopeptin, 34 and kahalalide V 33 ), whose shift values are δ C β 71–73 and δ C γ 34–36. Thus, our proposed analysis framework consists of (a) assigning an R configuration when δ C β ≤ 74/ δ C γ ≤ 36 and (b) assigning an S configuration when δ C β ≥77/ δ C γ ≥ 40.…”

“…Extending this analysis allows an R configuration to also be assigned, based on literature data (δ Cβ 73.0, δ C γ 35.3), 24 for kailuin A ( 1 ). Employing this same logic allows four other compounds to now be assigned as R including kahalalides W and Y, 33 halobacillin, 37 and ngercheumicin D 20 (Figure 4). …”

Chemistry and Biology of Kahalalides

“…In 2008, four new kahalalide peptides from the mollusk E. rufescens were reported. 22 Kahalalide V ( 18 ) was identified as an acyclic derivative of kahalalide D ( 4 ), while kahalalide W ( 19 ) was determined to have a 4-hydroxy- L -Pro residue instead of the proline in kahalalide D ( 4 ). Kahalalide X ( 20 ) was an acyclic derivative of kahalalide C ( 3 ), and kahalalide Y ( 21 ) was found to have an L -proline residue instead of the hydroxyproline in kahalalide K ( 10 ).…”