Antimalarial Linear Lipopeptides from a Panamanian Strain of the Marine Cyanobacterium Lyngbya majuscula

Abstract

As part of the Panama International Cooperative Biodiversity Groups (ICBG) project, two new (2, 4) and two known (1, 3) linear alkynoic lipopeptides have been isolated from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula. Carmabin A (1), dragomabin (2), and dragonamide A (3) showed good antimalarial activity (IC 50 4.3, 6.0, and 7.7 μM, respectively) whereas the non-aromatic analog, dragonamide B (4), was inactive. The planar structures of all four compounds were determined by NMR spectroscopy in combination with mass spectrometry, and their stereoconfigurations were established by chiral HPLC and by comparison of their optical rotations and NMR data with literature values.Artemisinin Combination Treatments (ACTs) for falciparum malaria are currently the only first-line antimalarial drugs amenable to widespread use against all chloroquine-resistant malaria parasites. 1 However, their effective distribution to combat malaria in economically disadvantaged regions could require an annual global subsidy of $300-500 million. 2 Furthermore, in the event of successful widespread use of the artemisinins, the development of resistance to these drugs before effective replacements or alternatives are at hand is a cause for profound concern. Therefore, the development of new classes of antimalarial drugs remains an enormous challenge and is a focus of many collaborative research efforts, including the International Cooperative Biodiversity Groups project in Panama, which investigates Panamanian terrestrial plants, endophytes and marine organisms as sources of tropical disease treatments. 3 As part of this program, we have been investigating marine cyanobacteria as a source of antimalarial agents, and found that the organic extracts of a red Panamanian strain of the marine cyanobacterium Lyngbya majuscula were active against chloroquine-resistant Plasmodium falciparum. To the best of our knowledge, there are only three reports of marine cyanobacterial metabolites isolated with antimalarial activity. Most recently, members of our * To whom correspondence should be addressed. Tel: 541 737 5808. Fax: 541 737 3999. E-mail: kerry.mcphail@oregonstate.edu. Supporting Information Available: 1 H and 13 C NMR spectra in CDCl 3 for carmabin A (1), dragomabin (2), dragonamide A (3) and dragonamide B (4). Results and DiscussionThe organic extracts of two collections of L. majuscula from different sites in Bocas del Toro, Panama (2002 and2003) showed significant activity against chloroquine-resistant Plasmodium falciparum (IC 50 = 6 and 26 μg/mL). Crude fractionation by normal-phase vacuum-liquid chromatography (NP-VLC) of the most active collection from Isla Bastimentos (Bocas del Toro, 2002) produced two relatively polar fractions (100% EtOAc and 25% MeOH-EtOAc) with good antimalarial activity (<2 and 1 μg/mL, respectively). Solid-phase extraction (SPE) and reversed-phase HPLC of the 25% MeOH-EtOAc NP-VLC fraction yielded carmabin A (1) and dragomabin (2) as the active components.Structure elucidation of li...

Biosynthesis and function of polyacetylenes and allied natural products

“…Apramides A-B (44A-B) and D-E contained variably methylated 7-octanoic acid termini and had negligible bioactivity [435]. The related planar metabolites dragomabin (44C) [436], carmabin (44D) [437], and dragonamides A-B (44E-F) [436,438] are also known; 44A-C were isolated with 7-alkenoate and 42-keto lipid modifications, respectively. α-Methylation of the fatty amide group was (S) in each case (the original assignment for 44E was corrected by total synthesis).…”

“…α-Methylation of the fatty amide group was (S) in each case (the original assignment for 44E was corrected by total synthesis). Amides 44C-E inhibited the W2 chloroquine-resistant strain of P. falciparum but 44F was inactive, which suggested that an aromatic amino acid was required for antimalarial activity [436].…”

A Cytotoxic Fellutamide Analogue from the Sponge-Derived Fungus Aspergillus versicolor

“…These lipopeptides were found to have interesting bioactivities, including, anti-inflammatory, antimalarial properties, antimicrobial, antileishmanial, cytotoxic and neurotoxic activities. [1][2][3][4][5][6][7][8][9] Fellutamides A and B are lipopeptides first isolated from the fish-derived fungus Penicillium fellutanum. Fellutamides exhibit cytotoxic properties, 10 and fellutamide A has been shown to stimulate the synthesis and secretion of nerve growth factor (NGF) in vitro.…”

Antiplasmodial activity of extracts of 25 cyanobacterial species from coastal regions of Tamil Nadu

“…from coastal regions of Panama. Likewise, crude organic extracts of Lyngbya majuscula from different sites of coastal regions of Panama exhibited promising antiplasmodial activities (IC 50 ¼ 6 and 26 mg mL À1 ) against CQ-resistant P. falciparum (McPhail et al, 2007). It is interesting that, in our study, the organic extract of in vitro grown L. aestuarii CNP 1005 has shown promising antiplasmodial activity against both CQ-sensitive (IC 50 ¼ 18 mg mL À1 ) and resistant strains (IC 50 ¼ 34 mg mL À1 ) of P. falciparum.…”

“…More interestingly, marine Moorea producens (earlier known as Lyngbya majuscula Harvey in Hooker ex Gomont) has been found to exhibit potent antimalarial activity against Plasmodium falciparum and a number of antimalarial compounds such as lagunamides (Tripathi et al, 2010a), dragomabin (McPhail et al, 2007), and malyngolide (Gutiérrez et al, 2010) have been isolated from it. Likewise, antimalarial screening of 18 cyanobacterial strains showed that the methylene dichloride extract of Phormidium ectocarpi inhibited the malaria parasite (IC 50 ¼ 2.1 mg mL À1 ) (Papendorf et al, 1998).…”