Divergent Approach for the Synthesis of Gombamide A and Derivatives

Abstract

A synthesis of gombamide A (1) using N-terminal peptide extension, oxidative disulfide bond formation, and late-stage 4-hydroxystyrylamide installation has been achieved. This divergent method was also utilized to synthesize several gombamide A derivatives with modification to the 4-hydroxystyrylamide via cyclic peptide 2. The natural product and four derivatives were found to be devoid of Na(+)/K(+)-ATPase activity at 10 μM. In addition, the compounds were not cytotoxic at 10 μM against a panel of cancer cells.

Marine natural products

“…522 Plakilactone B, C, deshydroxyplakilactone B, 523 and des-hydroxygracilioether C 524 have been synthesised, 525 as has gracilioether E. 526,527 Peptides are common sponge metabolites and hence are targets of synthetic campaigns. Gombamide A, [528][529][530] stylissamide G, 531,532 and phakellistatin- 15 (ref. 533) were all synthesised in 2016, with the latter compound being inactive while the natural version inhibited the growth of several HTCLS, indicating the presence of a highly potent contaminant in the initial extract.…”

A Cross-Coupling Approach to Amide Bond Formation from Esters

“…The extension of efficient couplings to include these robust esters will be of particular importance in multistep chemical synthesis, where more easily hydrolyzed functional groups would not be tolerated. It also provides promising progress toward the ability to couple functional groups that would be typically considered protected acids, such as methyl, t -butyl, and benzyl esters, which often need to be deprotected prior to amidation of the free acid . The C­(acyl)–O bond of these aliphatic esters are considerably more robust, so even better catalytic systems need to be identified to enable their cleavage.…”

Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics

“…Macrocylization via disulfide bond often improves the potency, rigidity, target selectivity, and stability of proteases and also stabilizes the secondary structure of peptides . Disulfides are also a common structural motif in therapeutically active compunds and nonribosomal natural products , having interesting biological activities . For example, screening of disulfide-containing macrocyclic libraries has yielded potent inhibitors of the insulin-like growth factor-1 receptor .…”