Synthesis of Jasplakinolide Analogues Containing a Novel ω‐Amino Acid

Abstract

The synthesis of the omega-amino acid 4 is described utilizing a two-dimensional synthesis strategy combined with an enzymatic differentiation of homotopic ester groups. The amino acid 4 features two non-bonded interactions that result in conformational constraints on a cyclic construct. This amino acid was incorporated into the four macrolactams 17, 22, 31, and 37. The ring in 17 and 22 is 18-membered, whereas 31 and 37 have a 19-membered ring. The pairs with the same ring size differ in a N-methyl group. For the larger macrolactams (31 and 37) conformational analysis showed that the macrocyclic rings are somewhat more rigid than in the natural lead, the depsipeptide jasplakinolide. Nevertheless, their conformations are comparable to the natural product. There are no intramolecular hydrogen bonds, neither is the cis-rotamer populated in the N-methyl compound 37. Due to the increased flexibility of the smaller macrolactams 17 and 22 and signal overlap, a distinct solution structure could not be obtained for these compounds. The amino acid 4 should be useful for restricting the conformation of other small peptides.

Cyclodepsipeptides from Marine Sponges: Natural Agents for Drug Research

“…It is difficult to explain the similar effects of these metabolites on actin in the absence of a receptor map and additional structural details. Previous investigations on jasplakinolide have indicated that the two structural elements of the molecule, the tripeptidic portion and the polyketide fragment, play a cooperative role in creating the bioactive shape of the compound [97,98]. In fact, it seems that the tripeptide moiety, in the macrocycle, is forced to adopt a preferential β-turn conformation, indicating that the polyketide fragment plays a decisive role in generating geometric constrains and inducing a selective conformation [68].…”

The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity

“…Numerous structure-activity relationship studies conducted with jaspamide analogs indicate that actin disruption plays a role in the cytotoxic effect of jaspamide (Tannert et al, 2010; Gala et al, 2007, 2008, 2009; Marimganti et al, 2005). The inactivity of jaspamide analogs is possibly due to structural modifications on jaspamide at the actin binding site (Tannert et al, 2010; Waldmann et al, 2008; Gala et al 2007, 2008, 2009; Marimganti et al, 2005). We found that the cell index IC 50 (1 M) for jaspamide-exposed cardiomyocytes after 72 h exposure was well above the jaspamide concentration (80 nM) required for maximal actin disruption in PC-3 cells.…”

Concise route to defined stereoisomers of the hydroxy acid of the chondramides

“…This fact also stimulated the design of simpler analogs of acid 6. 15 Typical routes to acid 6 are based on aldehyde 8. Extension is done either by reaction with 2-propenyl-magnesium bromide followed by Claisen rearrangement or by the sequence Wittig reaction, conversion to an allylic halide and asymmetric alkylation.…”