New Antiinfective and Human 5-HT2 Receptor Binding Natural and Semisynthetic Compounds from the Jamaican Sponge Smenospongia aurea

Abstract

In addition to the sesquiterpene-phenol aureols (1), 6'-chloroaureol (2), and aureol acetate (3), eight indole alkaloids including the new N-3'-ethylaplysinopsin (9) have been isolated from the Jamaican sponge Smenospongia aurea. Makaluvamine O (10), a new member of the pyrroloiminoquinone class, was also isolated. The structures were characterized by spectroscopic methods, and two new derivatives of aureol were prepared to optimize the biological activity. Aureol N,N-dimethyl thiocarbamate (1a) and 6-bromoaplysinopsin (7) exhibit significant antimalarial and antimycobacterial activity in vitro. Compound 6 showed activity against the Plasmodium enzyme plasmepsin II. The 6-bromo-2'-de-N-methylaplysinopsin (6), 6-bromoaplysinopsin (7), and N-3'-ethylaplysinopsin (9) displaced high-affinity [(3)H]antagonist ligands from cloned human serotonin 5-HT(2) receptor subtypes, whereas the other compounds tested did not. Remarkably, the 6-bromo-2'-de-N-methylaplysinopsin (6) showed a > 40-fold selectivity for the 5-HT(2C) subtype over the 5-HT(2A) subtype.

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“…These monomeric aplysinopsins were evaluated against Plasmodium falciparum and On evaluation against human serotonin receptor subtype 5-HT 2A and 5-HT 2C , half of the six monomeric aplysinopsins were active against the receptors including 6-bromo-2(-demethylaplysinopsin (5.6), ethylaplysinopsin (5.9) and 6-bromo aplysinopsin (5.14). Although these three compounds showed high affinity antagonist binding towards 5-HT 2C receptor subtype, only 5.9 and 5.14 showed potent activity against receptor 5-HT 2A subtype 150 . Of these, 5.14 showed the highest affinity against 5-HT 2C receptor subtype resembling the equilibrium affinity constant (K i ) value of the indigenous receptor, K I = 0.13 µM and 0.33 µM for serotonin and 5.14 respectively.…”

“…Compound 5.14 revealed strong antimalarial activity at 0.34 µg/mL with a selectivity index of 14 while isoplysin (5.32) and 6-bromo-2(-demethylaplysinopsin (5.6) exhibited moderate activity at 0.97 and 1.1 µg/mL and with a selectivity index of >4.9 and >43 respectively. It was also proven that compound 5.6 inhibited the antimalarial target plasmepsin II enzyme with IC 50 values of 53 µM (FRET) and 66 µM (FP) 150 .…”

“…In contrast, many biological activities have been reported for the monomeric aplysinopsin including antibacterial, antiplasmodial, anticancer and antidepressant agents with anticancer and antidepressant being the most interesting feature. Apart from bromination, methylation also plays a key role in dictating the bioactivity of the monomeric aplysinopsins [149][150][151] (see Table 5.1 for detail).…”

“…6-bromo-aplysinopsin (5.14) and isoplysin (5.32) were active against the D6 clone of Plasmodium falciparum 150 . Compound 5.14 revealed strong antimalarial activity at 0.34 µg/mL with a selectivity index of 14 while isoplysin (5.32) and 6-bromo-2(-demethylaplysinopsin (5.6) exhibited moderate activity at 0.97 and 1.1 µg/mL and with a selectivity index of >4.9 and >43 respectively.…”

“…From several marine taxa such as sponge [140][141][142][143] , scleractinian coral [144][145][146][147] , anemone 148 and mollusc 149 , dozen monomeric aplysinopsins have been reported featuring a diverse pattern of bromination and methylation as well as different levels of oxidation and geometry (E vs. Z) 146,149 . Monomeric aplysinopsins are known to exert a range of biological activities particularly as anticancer and antidepressant agents [150][151][152] , inspiring numerous total syntheses [153][154][155][156] . More recently, the discovery of asymmetric and symmetric dimers has generated renewed interest in this structure class.…”