Cytotoxicity Studies of Fijianolide (a.k.a. Laulimalide) Acetylated Derivatives Against Pancreatic Cancer Cell lines to Investigate New Paths For Therapeutic Development

Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. The Mu (µ), Delta (δ) and Kappa (MOR, DOR, KOR) opioid receptors are particularly intriguing members of this receptor family as they are the targets involved in many neurobiological diseases such as addiction, pain, stress, anxiety, and depression. To date few marine natural products have been investigated for their neurobiological activities.1 One noteworthy example involves ziconotide (1) from the cone snail Conus magnus.2 Compound 1 was the first marine natural product approved by the FDA and is used for the treatment of pain, marketed under the trade name Prialt® (2004).3 More recently Hamman reported that aaptamine (2) is the first marine natural product to show in vivo anti-depressant activity, however no mechanism of action was proposed.1,4 During a separate collaborative screening project we profiled 96 sponge-derived extracts and discovered that demethyl–aaptamine (3) and demethyl (oxy)–aaptamine (4) were selective DOR agonists using an LC-MS based library of an active methanolic extract coll. no. 92553 FM as shown in Fig. 1. We speculated that the in vivo activity for 2 could thus be linked to the DOR target and to test this hypothesis we conducted the following experiments below.