ABSTRACT
Dominicin, a macrocyclic peptide isolated from the marine sponge Eurypon laughlini, has been synthesized for the first time by solid-phase peptide synthesis. The strategy uses oxime resin and takes advantage of the nucleophile susceptibility of the oxime ester bond. The synthesis relies on the preparation of a linear precursor followed by on-resin head-to-tail concomitant cyclization-cleavage. This is the first report of the use of a Boc/OtBu biorthogonal protection strategy on oxime resin to facilitate concomitant N-terminal and side-chain tert-butyl ether deprotection cyclization of unprotected peptides. Also, we report the first antimalarial investigation of dominicin. Interestingly, the natural macrocyclic peptide demonstrates effective low micromolar activity (1.8 µM) against the chloroquine-mefloquine-pyrimethamine-resistant Dd2 strain of Plasmodium falciparum.
Subject(s)
Antimalarials/chemical synthesis , Peptides, Cyclic/chemical synthesis , Porifera/drug effects , Pyrroles/chemical synthesis , Animals , Antimalarials/pharmacology , Cyclization , Drug Resistance , Hemolysis/drug effects , Humans , In Vitro Techniques , Molecular Structure , Peptides/chemical synthesis , Peptides/pharmacology , Peptides, Cyclic/pharmacology , Plasmodium falciparum/drug effects , Pyrroles/pharmacologyABSTRACT
Mortiamides A-D (1-4) are head-to-tail cyclic heptapeptides that were identified from a novel Mortierella sp. isolate obtained from marine sediments from Northern Canada. Herein we report the first total synthesis of mortiamides A-D (1-4) on a solid support by concomitant cyclization/cleavage without any oligomerization side reactions, and overall yields up to 48%. We also report on the antiplasmodial activity of mortiamides A-D (1-4). We show that three out of the four tested mortiamides (A, B and D) have moderate antiplasmodial activity, while mortiamide D (4) exhibits low micromolar activity.
Subject(s)
Antimalarials/chemical synthesis , Peptides, Cyclic/chemical synthesis , Antimalarials/pharmacology , Cyclization , Peptides, Cyclic/pharmacology , Plasmodium falciparum/drug effects , PolymerizationABSTRACT
Two anabaenopeptins, Schizopeptin 791 and anabaenopeptin NZ825, have similar structural features and have been synthesized via a novel acid-catalyzed head-to-side-chain concomitant cyclization/cleavage reaction on oxime resin. The methodology gave rapid access to the anabaenopeptin scaffold by taking advantage of a combined solid-phase/solution-phase synthetic strategy. Also, as side-products of the synthesis, large C2-symmetric 38-member cyclic peptides ring bearing two endocyclic lysine side-chains were isolated, constituting a novel cyclic peptide scaffold.
