Eduardo Ortega-Barria

Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp.

Coibamide A (1) is a new, potent antiproliferative depsipeptide which was isolated from a marine Leptolyngbya cyanobacterium collected from the Coiba National Park, Panama. The planar structure of 1 was elucidated by a combination of NMR spectroscopy and mass spectrometry. Exhaustive 1D and 2D NMR spectroscopy included natural abundance 15N and variable temperature experiments; mass spectrometry included TOF-ESI-MSn and FT-MSn experiments. Chemical degradation followed by chiral HPLC- and GC-MS analyses was used to assign the absolute configuration of 1. This highly methylated cyclized depsipeptide exhibited an unprecedented selectivity profile in the NCI 60 cancer cell line panel and appears to act via a novel mechanism.

Viridamides A and B, Lipodepsipeptides with Antiprotozoal Activity from the Marine Cyanobacterium Oscillatoria nigro-viridis

Parallel chemical and phylogenetic investigation of a marine cyanobacterium from Panama led to the isolation of two new PKS-NRPS-derived compounds, viridamides A and B. Their structures were determined by NMR and mass spectroscopic methods, and the absolute configurations assigned by Marfeys method and chiral HPLC analysis. In addition to six standard, N-methylated amino and hydroxy acids, these metabolites contained the structurally novel 5-methoxydec-9-ynoic acid moiety and an unusual proline methyl ester terminus. Morphologically, this cyanobacterium was identified as Oscillatoria nigro-viridis, and its 16S rDNA sequence is reported here for the first time. Phylogenetic analysis of these sequence data has identified O. nigro-viridis strain OSC3L to be closely related to two other marine cyanobacterial genera, Trichodesmium and Blennothrix. Viridamide A showed antitrypanosomal activity with an IC50 of 1.1 microM and antileishmanial activity with an IC50 of 1.5 microM.

Using ecological criteria to design plant collection strategies for drug discovery

Tropical forests are one of the most diverse and endangered habitats on earth. They have also been portrayed as a source of future pharmaceuticals, yet finding useful compounds can be both scientifically and politically challenging. Increasingly, over the past decade, the potential value of medicinal compounds derived from plants, microorganisms, and animals has been proposed as a tangible benefit of biodiversity, and therefore a basis for promoting its preservation. Ecological theories of plant defense can increase the probability of discovering compounds with activity in bioassays against human disease targets. In addition, conducting research in tropical countries with local scientists provides immediate and lasting benefits for the sustainable use of biodiversity. This new approach to drug discovery has been effective in identifying bioactive leads. It is both an important step towards understanding the medicinal value of biodiversity, and a practical way to link drug discovery with conservation.

Securing Economic Benefits and Promoting Conservation through Bioprospecting

ABSTRACT Bioprospecting has frequently been cited as a sustainable use of biodiversity. Nevertheless, the level of bioprospecting in biodiversity-rich tropical regions falls below its potential, with the result that bioprospecting has produced only limited economic benefits. We present a bioprospecting program that, in addition to promoting drug discovery, provides economic benefits to and promotes conservation in Panama through the sustainable use of biodiversity. The program was initiated using insights from 20 years of nonapplied ecological research to enhance the likelihood of finding treatments for human disease. Samples are not sent abroad; rather, most of the research is carried out in Panamanian laboratories. Panama has received immediate benefits for the use of its biodiversity in the form of research funding derived from sources outside Panama, training for young Panamanian scientists, and enhanced laboratory infrastructure. Over the long term, discoveries derived from bioprospecting may help to establish research-based industries in Panama.

Activity against Plasmodium falciparum of Lactones Isolated from the Endophytic Fungus Xylaria sp.

Three lactones were isolated from the culture medium of the endophytic fungus Xylaria sp. Grev. (Xylariaceae). The major compound, which showed weak activity (13 μ g/mL) against a chloroquine-resistant strain of Plasmodium falciparum, was identified as (+)-phomalactone (1). The others were 6-(1-propenyl)-3,4,5,6-tetrahydro-5-hydroxy-4H-pyran-2-one (2) and 5-hydroxymellein (3). Compounds 1 and 2 are reported for the first time as constituents of Xylaria. Also, this is the first report of the activity of the compounds 1–3 against a chloroquine-resistant Plasmodium falciparum strain.

Linking bioprospecting with sustainable development and conservation: the Panama case

The limited international resources for economic aid and conservation can only mitigate poverty and losses of biodiversity. Hence, developing nations must establish the capacity to resolve their problems. Additionally, policy-makers and donors need to obtain scientific input on issues such as global change and ecosystem services. We propose that for nations rich in biodiversity, ecosystem services derived from bioprospecting, or drug discovery, could contribute to economic development. In the case where unstudied samples are shipped abroad for research, the chances of obtaining royalties are infinitesimally small. Therefore developing nations will only realize benefits from bioprospecting through in-country research on their own biodiversity. Policy-makers and donors have failed to appreciate the value of this approach. In order to provide an example of the inherent links between conservation and sustainable economic development, we initiated a drug discovery effort in Panama that emphasizes local benefit. As much of the drug discovery process as possible is conducted in Panamanian laboratories, providing jobs dependent on intact biodiversity and enhancing local research and training. In short, research, plus the spin-offs from research, provide immediate and long-lasting benefits to Panama. The connection between conservation and development has been highlighted in publicity about the project in Panama’s urban media. This provides a constructive alternative to the perception the among the urban populace that economic development inevitably competes with conservation. In summary, our program uses biodiversity to promote human health as well as to support research capacity, economic development and conservation within Panama. The program provides an example of the widely recognized but little developed concept of bioprospecting research as an ecosystem service.

Antiprotozoal Activity Against Plasmodium falciparum and Trypanosoma cruzi of Xanthones Isolated from Chrysochlamys tenuis

Abstract One new prenylated xanthone, 1,5-dihydroxy-3-methoxy-4-isoprenylxanthone (1), along with four previously known prenylated xanthones, ananixanthone (2), 1,3,7-trihydroxy-2,4-diisoprenylaxnthone (3), 8-desoxygartanin (4), and toxyloxanthone A (5), have been isolated from Chrysochlamys tenuis. (Hammel) (Clusiaceae). Compound 1 showed moderate activity (31 ± 9 µM) against a chloroquine-resistant strain of Plasmodium falciparum., and compounds 3 and 5 showed the highest antimalarial potency, IC50 = 20 ± 2 and 16 ± 4 µM, respectively. Evaluated against Trypanosoma cruzi., compound 1 presented negligible activity, but compounds 2, 3, and 4 showed mild antitrypanosomal activity with IC50 values of 23 ± 4, 21 ± 5, and 24 ± 3 µM, respectively. All structures were elucidated by NMR spectroscopy in combination with UV, IR, and MS spectral data.

Evaluation of Larvicidal and in Vitro. Antiparasitic Activities of Plants in a Biodiversity Plot in the Altos de Campana National Park, Panama

Abstract This TDR/WHO project was carried out from 2003 to 2005 in an 0.1-ha biodiversity plot in the Altos de Campana National Park to discover novel active antiparasitic and larvicidal compounds in Panamanian plants. One-hundred-fifty organic plant extracts representing 43 families, 73 genera, and 93 species were tested in a panel of antimalarial (Plasmodium falciparum. W2, chloroquine resistant), antileishmanial (Leishmania mexicana. amastigotes), antitrypanosomal (Trypanosoma cruzi. trypomastigotes), and larvicidal (Aedes aegypti.) screens. Of these 150 plant extracts, two (1.3%) (Talisia nervosa. and Topobea parasitica.) showed significant antimalarial activity (IC50 values < 10 µg/ml), two (1.3%) (Cestrum megalophyllum. and Zanthoxylum acuminatum.) weak antileishmanial activity (IC50 values ranging from 10 to 20 µg/ml), one (0.6%) (Zanthoxylum acuminatum.) weak antitrypanosomal activity (IC50 values ranging from 10 to 20 µg/ml), and one (0.6%) (Piper fimbriulatum.) larvicidal activity (LC100 values < 30 µg/ml). Ethyl gallate (1) and methyl gallate (2) were isolated from stems of Talisia nervosa. by bioassay-guided fractionation. Both (1) and (2) showed weak in vitro. antiplasmodial activity against P. falciparum. (IC50 35.3 µM and IC50 38.0 µM, respectively), but both compounds were less active than chloroquine (IC50 0.088 µM). Moreover, compounds (1) (IC50 33.1 µM) and (2) (IC50 33.6 µM) showed weakly antileishmanial activity (miltefosine: IC50 0.5 µM), but they were not cytotoxic to Vero mammalian cells.

Screening of Latin American plants for antiparasitic activities against malaria, Chagas disease, and leishmaniasis.

In order to explore rationally the medical potential of the plant biodiversity of the Central and South American region as a source of novel antiparasitic molecules, a multinational Organization of American States (OAS) project, which included the participation of multidisciplinary research centers from Argentina, Bolivia, Colombia, Costa Rica, Guatemala, Nicaragua and Panama, was carried out during the period 2001-2004. This project aimed at screening organic plant extracts for antitrypanosomal, antileishmanial and antimalarial activities and subsequently isolating and characterizing bioactive molecules. Plants for antiparasitic screening were selected from a database of ethnomedical uses of Latin American plants (PlanMedia) based on the amount of biological and chemical information available in the literature. We report here the evaluation of 452 extracts from 311 plant species in vitro screens against Plasmodium falciparum, Leishmania mexicana, and Trypanosoma cruzi. Out of 311 species tested, 17 plants (5.4%) showed antiparasitic activities at IC50 values ≤ 10 µg/mL. The most active plants were Acnistus arborescens (L.) Schltdl. (Solanaceae) (leaf, EtOH, IC50: 4 µg/mL) Monochaetum myrtoideum Naudin (Melastomataceae) (leaf, MeOH, IC50: 5 µg/mL) and Bourreria huanita (Lex.) Hemsl. (Boraginaceae) (branch, EtOH, IC50: 6 µg/mL). These were selectively active against P. falciparum, L. mexicana and T. cruzi, respectively.

Antiprotozoal Activity of Flavonoid Glycosides Isolated from Clidemia sericea. and Mosquitoxylon jamaicense.

Abstract A new O.-galloyl-C-glycosylflavone, 2″,6″-O.-digalloylvitexin (1), along with four known glycosylflavones (2–5) have been isolated from Clidemia sericea. D. Don (Melastomataceae), and four other known glycosylflavones (6–9) have been isolated from Mosquitoxylon jamaicense. Krug & Urb. (Anacardiaceae). Compound 1, 3, and 6 showed mild antimalarial activity (24 ± 1, 38 ± 2, and 44 ± 1 µM, respectively) against a chloroquine-resistant P. falciparum. strain. Additionally, tests against leishmaniasis and Trypanosoma cruzi. were made. These compounds were identified by MS, UV, IR, and 1D and 2D NMR data and by comparison with the literature data.