(-)-Oleocanthal (OC), a phenolic compound present in extra-virgin olive oil (EVOO), has been implicated in the health benefits associated with diets rich in EVOO. We investigated the effect of OC on human cancer cell lines in culture and found that OC induced cell death in all cancer cells examined as rapidly as 30 minutes after treatment in the absence of serum. OC treatment of non-transformed cells suppressed their proliferation but did not cause cell death. OC induced both primary necrotic and apoptotic cell death via induction of lysosomal membrane permeabilization (LMP). We provide evidence that OC promotes LMP by inhibiting acid sphingomyelinase (ASM) activity, which destabilizes the interaction between proteins required for lysosomal membrane stability. The data presented here indicate that cancer cells, which tend to have fragile lysosomal membranes compared to non-cancerous cells, are susceptible to cell death induced by lysosomotropic agents. Therefore, targeting lysosomal membrane stability represents a novel approach for the induction of cancer-specific cell death.
C1 and flexible analogs of (±)-nantenine were synthesized and evaluated for antagonist activity at human 5-HT 2A receptors in a calcium mobilization assay. This work has resulted in the identification of the most potent 5-HT 2A antagonist known based on an aporphine. Our results also suggest that the C1 position may be a key site for increasing 5-HT 2A antagonist activity in this compound series. In addition, the structural rigidity of the aporphine core appears to be required for nantenine to function as a 5-HT 2A antagonist.The monoamine neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT, 1) is known to play a significant role in the central nervous system (CNS) modulation of appetite, mood, body temperature and sleep in humans. 1 There are fourteen serotonin receptors presently known, of which all except one (5-HT 3 ) are G-protein coupled receptors. 2 Ligands for the 5-HT 2A receptor are constantly being developed as chemical tools to study the functional role of this receptor in hallucinations, depression, anxiety and psychosis. 3-7 The role of 5-HT 2A receptor blockade in the neuropharmacological processes of addiction is also of growing interest. 8-13Aporphines are a diverse group of tetracyclic alkaloids found in several plant species and have been found to show a range of interesting biological activities such as antiplasmoidal, antihelminthic and antitumor activities. 14-18 As a result of their biological activities, new and facile synthetic methodologies to prepare these compounds are always being explored. 19,20 Others have reported the 5-HT 2A antagonist properties of the aporphine alkaloid nantenine (2). 21, 22 This pharmacodynamic property seems to be relevant to it's in vivo activity as an antagonist of the designer drug MDMA (methylenedioxymethamphetamine, "Ecstasy"). 23 Although aporphines have been evaluated as 5-HT 1A , α-adrenergic, and dopaminergic D1 and D2 ligands, very little SAR work has been performed on aporphines as 5-HT 2A antagonists. 21, 24-28 Part of our program is geared towards understanding the importance of selective receptor blockade as well as multi-potent antagonism involving 5-HT 2A receptors in the antagonism of MDMA-induced effects. Aporphines may be a valuable structural template for such a study, given the apparent promiscuity of these compounds across various CNS targets including 5-HT subtypes. As such, we have embarked on a study to evaluate the 5-HT 2APublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. antagonist activity of aporphines using 2 as a lead molecule. In this communication, we report results on the synth...
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