RESUMO
Fractionation of the extract of the marine cyanobacterium Lyngbya majuscula collected from Panama led to the isolation of malyngolide dimer (1). The planar structure of 1 was determined using 1D and 2D NMR spectroscopy and HRESI-TOFMS. The absolute configuration was established by chemical degradation followed by chiral GC-MS analyses and comparisons with an authentic sample of malyngolide seco-acid (4). Compound 1 showed moderate in vitro antimalarial activity against chloroquine-resistant Plasmodium falciparum (W2) (IC(50) = 19 microM) but roughly equivalent toxicity against H-460 human lung cell lines. Furthermore, because the closely related cyanobacterial natural product tanikolide dimer (5) was a potent SIRT2 inhibitor, compound 1 was evaluated in this assay but found to be essentially inactive.
Assuntos
Cianobactérias/química , Éteres Cíclicos/isolamento & purificação , Éteres Cíclicos/farmacologia , Toxinas de Lyngbya/química , Toxinas de Lyngbya/isolamento & purificação , Plasmodium falciparum/efeitos dos fármacos , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Éteres Cíclicos/química , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Toxinas de Lyngbya/farmacologia , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Panamá , Testes de Sensibilidade Parasitária , Pironas/química , Pironas/isolamento & purificação , Pironas/farmacologia , Relação Estrutura-AtividadeRESUMO
The jamaicamides are natural product sodium channel blockers derived from the cyanobacterium Lyngbya majuscula. The carboxylic acid fragment of jamaicamide C contains a methyl stereocenter and a trisubstituted E chloroolefin. Herein, we present the nonracemic synthesis of the aliphatic chain of jamaicamide C. The methyl stereocenter was installed using Evans' oxazolidinone methodology, and the trisubstituted chloroolefin was set by silylstannylation of a triple bond.
Assuntos
Amidas/síntese química , Produtos Biológicos/síntese química , Ácidos Carboxílicos/síntese química , Lipopeptídeos/síntese química , Toxinas de Lyngbya/síntese química , Pirrolidinonas/síntese química , Bloqueadores dos Canais de Sódio/síntese química , Amidas/química , Amidas/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ácidos Carboxílicos/química , Lipopeptídeos/química , Lipopeptídeos/farmacologia , Toxinas de Lyngbya/química , Toxinas de Lyngbya/farmacologia , Estrutura Molecular , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , EstereoisomerismoRESUMO
Hectochlorin (1) was isolated from marine isolates of Lyngbya majuscula collected from Hector Bay, Jamaica, and Boca del Drago Beach, Bocas del Toro, Panama. The planar structure was deduced by one- and two-dimensional NMR spectroscopy. X-ray crystallography was used to determine the absolute stereochemistry of hectochlorin as 2S,3S,14S,22S. Hectochlorin is equipotent to jasplakinolide (5) in its ability to promote actin polymerization, but unlike jasplakinolide, is unable to displace a fluorescent phalloidin analogue from polymerized actin. In addition, hectochlorin shows both a unique profile of cytotoxicity by the COMPARE algorithm and potent inhibitory activity toward the fungus Candida albicans. Structurally, hectochlorin resembles dolabellin and the recently reported lyngbyabellin class of compounds.
Assuntos
Actinas/efeitos dos fármacos , Actinas/metabolismo , Antibacterianos/isolamento & purificação , Antifúngicos/isolamento & purificação , Cianobactérias/química , Depsipeptídeos , Lactonas/isolamento & purificação , Tiazóis/isolamento & purificação , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cristalografia por Raios X , Fluoresceína-5-Isotiocianato , Concentração Inibidora 50 , Jamaica , Lactonas/química , Lactonas/farmacologia , Toxinas de Lyngbya/química , Toxinas de Lyngbya/isolamento & purificação , Toxinas de Lyngbya/farmacologia , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Panamá , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Control of transepithelial permeability by regulation of tight junctions is exerted by the non-phorbol ester tumor promoters, teleocidin and aplysiatoxin. Similar to the phorbol esters, tetradecanoylphorbol-13-acetate (TPA) and phorbol dibutyrate (PDBU), both teleocidin and aplysiatoxin cause a reversible decrease of transepithelial voltage and transepithelial resistance across LLC-PK1 renal epithelial cell sheets at concentrations as low as 10(-8) M. These compounds are effective from either side of these polar epithelial cells, i.e. apical or basolateral. The decreases in transepithelial gradients and resistance are paralleled by a rise in the transepithelial (paracellular) flux of D-mannitol between the cells (through the tight junctions). These four tumor promoters, TPA, PDBU, teleocidin and aplysiatoxin, are all known protein kinase C activators, and support the case for protein-kinase-C-mediated control of tight junctional permeability.