Sunday, June 14, 2015
Secosterols as Chemical Defense Weapons Derived from Marine Invertebrates
Certain benthic marine organisms have served as an abundant source of architecturally diverse secondary metabolites for natural products chemists. Structural classes derived from marine sources include various types of peptides, neurotoxic alkaloids and halogenated sesquiterpenes, to name a few. The most common explanation for this phenomenon of chemical ecology is that marine invertebrates such as mollusks and sponges, which are shell-less and have soft, unprotected body tissues, rely on chemical defense substances to deter potential predators. Other postulated roles for co-occurring chemical defense molecules include prevention of fouling, inhibition of overgrowth and protection from ultraviolet radiation. An alternate hypothesis is that some secondary metabolites serve no function at all and are simply representative of accumulations of enzymatic side products or have served as deterrents toward ancient predators that have since gone extinct. Regardless, marine invertebrates have provided a vast supply of bioactive molecules for the eventual discovery and development of new pharmacological tools and therapeutic agents.
Recently, in the journal Angewandte Chemie International Edition (ACIE), Hideo Kigoshi and co-workers reported the structural assignment of a new ‘seco-’ (defined as ring-fragmented) steroid, isolated from a type of marine gastropod mollusk commonly referred to as a ‘sea hare.’ Interestingly, certain sea hares are known for the unique ability to discharge a colorful, sticky ink when threatened. The defensive ink’s chemical composition induces sensory inactivation in predators such as spiny lobsters. Kigoshi’s team at the University of Tsukuba in Japan disclosed the chemical structure of aplysiasecosterol A (see Table above, top panel), a 9,11-secosteroid isolated from the marine sea hare Aplysia kurodai. The tricyclic g-diketone skeletal framework of aplysiasecosterol A is unprecedented and a compelling biosynthetic pathway starting from a derivative of cholesterol was proposed by the authors. The new degraded steroid exhibits modest cytotoxicity against the human myelomonocytic leukemia cell line HL-60 (IC50 = 16 uM). The eastern substructure of aplysiasecosterol A, encompassed by the characteristic steroid D-ring and cholestane-type side chain, is reminiscent of the long-known polyhydroxylated sponge-derived 9,11-secosterol, herbasterol. The fascinating and ornate structure of herbasterol was characterized in 1985 by Capon and Faulkner (Scripps Institute of Oceanography) and, to my knowledge, has never been synthesized by chemical means. Aplykurodinone-1 is another marine secosteroid that has generated intense interest (for a leading reference, see here) amongst synthetic chemists, dating back to its prominent inaugural total synthesis in 2010 by Sam Danishefsky’s group. Aplykurodinone-1 was isolated from the sea hare Syphonota geographica from the Mediterranean Sea off the Greek coast and can be broadly classified as an oxidatively degraded steroid with cytotoxic bioactivity against a range of human cancer cell lines. The related aplykurodins (Table above, bottom panel) are a group of ichthyotoxic lactones that were isolated from marine mollusks of the genus Aplysia in the late 1980s to early ‘90s. Additional biochemical screening efforts will likely uncover new pharmacological properties and cellular targets for marine secosterols that may be pertinent to drug discovery programs.