Aplysinopsins as Promising Marine Natural Product Drug Leads: Recent Developments

Marine natural products represent a rich source of bioactive secondary metabolites, one of which is the marine indole alkaloids aplysinopsins. Aplysinopsins were first described in 1977 from the extracts of Indo-Pacific sponge species. Since that initial description, they have been isolated from a wide range of marine sources: sponges, corals, mollusks, and sea anemones. Aplysinopsins are composed of an indole coupled with an imidazolidinone moiety. The structural variation of naturally occurring aplysinopsin analogs occurs in the bromination pattern on the indole moiety as well as the pattern of N-methylations on the imidazolidinone ring. There are multiple synthetic strategies used to access the aplysinopsin scaffold. The majority of them are convergent routes that begin with synthesis of the desired indole moiety followed by the imidazolidinone synthesis and, ultimately, coupling of the two systems via several different methodologies. Aplysinopsins possess a wide variety of biological activities, from antimicrobial and antimalarial to antitumor activity seen in mice. However, their neuromodulatory activities have generated the most recent interest in their bioactivity. Both natural and synthetic aplysinopsin analogs have been found to act on both the serotonin receptor and the monoamine oxidase system. This chapter will review recently published synthetic strategies used to construct aplysinopsin analogs. It will also highlight significant and promising biological activities displayed by aplysinopsins, with an emphasis of neuromodulatory activities.