|Salicylihalamide A SCH 351448 Psymberin||
Salicylihalamide A was first isolated in 1997 by NCI scientists from an unidentified species of the marine sponge Haliclona. Through the NCI 60-cell antitumor screen, it was found that this N-acyl-enamine appended macrolactone exhibited similar activity to the bafilomycins, which are vacuolar proton ATPase (V-ATPase) inhibitors. V-ATPases are located on membranes of vacuoles, lysosomes, and other organelles, as well as on certain specialized plasma membrane. These proton pumps are responsible for the pH regulation of intracellular compartments of eukaryotes, which is essential for many cellular processes. Irregular V-ATPase activity is thought to contribute to the development of a variety of diseases such as cancer and osteoporosis, making V-ATPase a potential target for the development of pharmacological agents.
In 1999, we initiated a synthetic program aimed at producing quantity of the natural product for pharmacology and SARs studies, which culminated in the first total synthesis of Salicylihalamide A as well as the revision of the absolute configuration.