Unusual antimalarial meroditerpenes from tropical red macroalgae

Abstract

Three antimalarial meroditerpenes have been isolated from two Fijian red macroalgae. The absolute stereochemistry of callophycolide A (1), a unique macrolide from Callophycus serratus, was determined using a combination of Mosher's ester analysis, circular dichroism analysis with a dimolybdenum tetraacetate complex, and conformational analysis using NOEs. In addition, two known tocopherols, β-tocopherylhydroquinone (4) and δ-tocopherylhydroquinone (5), were isolated from Amphiroa crassa. By oxidizing 5 to the corresponding δ-tocopherylquinone (6), antimalarial activity against the human malaria parasite Plasmodium falciparum was increased by more than 20-fold.© 2010 Elsevier Ltd. All rights reserved. * Corresponding author. Mailing address: 310 Ferst Drive NW, Atlanta, GA 30332-0230, USA, Phone: (404) Fax: (404) 385-4440, julia.kubanek@biology.gatech.edu. Publisher'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. Supplementary DataExperimental details and 1 and 2-D NMR spectroscopic data for 1 and 4-5 are available free of charge via the Internet. The design and development of many synthetic antimalarial drugs has largely been inspired by these and other antimalarial natural products. 1 Thus, the discovery of novel chemistry from natural sources could provide new scaffolds for the development of much needed antimalarial treatments. We previously discovered a structurally-novel class of brominated diterpenoid macrolides, called bromophycolides, from the Fijian red macroalga Callophycus serratus ,3-4 and several bromophycolides exhibited submicromolar activity against the human malaria parasite Plasmodium falciparum. [5][6] Our continued efforts to uncover antimalarial natural products from understudied tropical red macroalgae led us to explore potent activity from two red algae in our library, thus leading to the identification of an unusual non-brominated macrolide we named callophycolide A (1) and two known tocopherols, β-tocopherylhydroquinone (4) and δ-tocopherylhydroquinone (5) from the coralline alga Amphiroa crassa. Compound dataCallophycus serratus (family Solieriaceae, order Gigartinales, class Rhodophyceae, phylum Rhodophyta) was collected at depths of 2-3 m from Yanuca in the Fiji Islands (18° 23' 57" S, 177° 57' 59" E), and Amphiroa crassa (family Corallinaceae, order Corallinales, class Florideophyceae, phylum Rhodophyta) was collected at a depth of 20 m from the Coral Coast, Fiji (18° 12' 15" S, 177° 39' 35" W). Frozen C. serratus and A. crassa were each extracted with MeOH and MeOH:DCM (1:1, 1:2) and subjected to liquid partitioning between MeOH:H 2 O (9:1) ...

Diterpenes as lead molecules against neglected tropical diseases

“…On the other hand, otostegindiol (25, 50, and 100 mg/kg) against Plasmodium berghei exhibited a significant chemosuppression effect (Endale et al, 2013). It should be mentioned that, till date, a number of promising diterpenes and their derivatives have been isolated from natural sources (Pouvelle et al, 1994;Uys et al, 2002;Riel et al, 2002;Kuria et al, 2002;Köhler et al, 2002;Clarkson et al, 2003;Wei et al, 2004;Loyola et al, 2004;Ospina et al, 2005;Kalauni et al, 2006;Ojo-Amaize et al, 2007;Koka et al, 2009;Lane et al, 2009;Wei et al, 2010;Lin et al, 2010;Wangchuk et al, 2010;Stout et al, 2010;Sebisubi et al, 2010;Stout et al, 2011;Cocquyt et al, 2011;Alasbahi and Melzig, 2012;Ebrahimi et al, 2013;Ehrhardt et al, 2013;Walter et al, 2013;Batista et al, 2013;González et al, 2014;Ma et al, 2014;Avilés et al, 2015;Gbedema et al, 2015;Annan et al, 2015;Sadashiva et al, 2015;Namukobe et al, 2015;Ahmad et al, 2016).…”

Seaweed Phenolics: From Extraction to Applications

“…Davyt et al [174] isolated 11 sesquiterpenes from Laurencia dendroidea (formerly known as Laurencia scoparia) and studied the anthelmintic activity with moderate results against the parasite stage of Nippostrongylus brasiliensis. Meroditerpenes of the Callophycus serratus and Amphiroa crassa had been demonstrated in the initial stages of studying antimalarial activity [175].…”

Antiplasmodial natural products: an update

“…The macrolide ring appears to improve bioactivity, considering that non-macrocyclic diterpene-benzoic acids and diterpene-phenols were less active. Furthermore, isolation of the less active 14-membered ring callophycolide A (IC 50 = 5.4 µM), which lacked the bromine atoms and a cyclohexane ring, showed that these features are not essential but improve the potency [259, 261]. Some bromophycolides target haem crystallization, suggesting that the mechanism of action involves the inhibition of haemozoin formation [262].…”