Saturday, July 4, 2015
Dragmacidolide A, A New Oxysterol Metabolite from the Dragmacidon Genus of Marine Sponges
Deep-water sponges of the Dragmacidon genus typically yield structurally complex bis-indole alkaloid compounds such as dragmacidins D, E and F. Some Dragmacidon alkaloids have been shown to be potent inhibitors of the serine/threonine phosphatases PP1 and PP2A. In addition, the dragmacidins exhibit antiviral, antibacterial and antifungal bioactivities, as well as cytotoxicity towards various cancer cell lines. Very recently, a Dragmacidon australe specimen, collected by SCUBA off the coast of the Whitsunday Islands in Queensland, Australia, was investigated to gain a better understanding of the chemistry of this poorly investigated genus. Surprisingly, a new steroidal secondary metabolite, dragmacidolide A, was isolated and characterized using 1D/2D NMR and MS data. The isolation of a steroid from this sponge genus is unusual given that previous reports of Dragmacidon metabolites were comprised exclusively of indole and b-carboline alkaloids (with the unique exception of the nucleoside, dragmacidoside). At this time, it cannot be ruled out that a microbial symbiont could be responsible for the biosynthetic production of the oxysterol, within the microenvironment of the sponge.
In order to obtain a small sample of dragmacidolide A, the methanol/dichloromethane extract of a freeze-dried and ground specimen of sponge was subjected to RP-HPLC purification and analysis of the purified fraction suggested the presence of a steroid. Unfortunately, the relative configuration of C20 and C22 could not be assigned on the basis of the 2D NMR data. Both H21, as well as H20, showed ROESY cross-peaks to protons on the angular methylene projecting from the C/D ring junction (H18), indicating that free-rotation about the C17-C20 bond was operative. The C20 configuration depicted in the structure shown above is based solely on analogy to the stereogenic disposition of the side chains of other archetypal cholestane-type steroids (e.g. lanosterol or OSW-1). The limited availability from natural sources and highly oxidized nature of the dragmacidolide A skeletal framework makes it an ideal target for chemical synthesis. New synthetic technologies that provide access to large quantities of molecules like dragmacidolide A are likely to lead to the discovery of new biological targets and properties of pharmacotherapeutic significance.