Thrombotic complications, such as heart attacks and strokes, are the major causes of cardiovascular associated mortality and morbidity events. Currently, platelet aggregation inhibitors constitute the largest class of antithrombotic drugs that are used to treat and manage cardiovascular complications. However, due to the limitations of existing antiplatelet drugs, new antiplatelet agents are continuously being developed.
Recently, Taniguchi et al. discovered four novel cyclodepsipeptides, namely YM-280193 (1), YM-254890 (2), YM-254891 (3) and YM-254892 (4) that exhibited platelet aggregation inhibitory activity, with IC50 values of 3.4, 0.26, 0.27 and 0.29 μM respectively. The four YM-compounds 1-4, share the common cyclic depsipeptide core of 1, which consists of a highly N-methylated backbone, depside bonds and unnatural residues, such as β-hydroxyleucine and an N-methylated dehydroalanine. In addition to the core backbone of 1, YM-compounds 2-4 possess an additional β-hydroxyleucine residue.
Importantly, further research proved YM-254890 (2) to be the first and currently only known selective inhibitor of Gαq/11, a G protein that is predominantly expressed in human platelets that is crucial to platelet activation and aggregation. Thus, in addition to the search for new antithrombotics, YM-254890 (2) is also an invaluable probe for understanding Gq-mediated biological processes. Despite its biological significance, none of these YM-molecules are commercially available to researchers, and thus the aim of this research was to develop a chemical synthetic route to YM-compounds 1-4.
We herein describe the first total synthesis of YM-280193 (1), the common cyclic core to YM-compounds 2-4, using a combination of conventional chemistry and Fmoc-solid-phase peptide synthesis (Fmoc-SPPS). Our synthetic strategy also featured a late-stage novel bis-alkylation–elimination of cysteine on-resin to introduce the unnatural N-methyldehydroalanine moiety. We envisaged that further side-chain esterification of cyclic 1 with an appropriately protected β-hydroxyleucine would afford the more potent YM-compounds 2-4.