RESUMO
Lyngbyabellin M is a non-ribosomal peptide synthetase/polyketide synthase derived metabolite isolated from the cyanobacterium M. bouillonii displaying thiazole rings and a distinct chlorinated octanoic acid chain. Its absolute configuration was proposed based on the comparison of its spectroscopic data with those of other representatives of this family of marine natural products, as well as degradation and derivatization studies. Here the first total synthesis of (+)-lyngbyabellin M is described based on the coupling of three key intermediates: two chiral thiazole moieties and an anti hydroxycarboxylic acid prepared stereoselectively via a boron enolate mediated aldol reaction directed by Masamune's chiral auxiliary.
Assuntos
Cianobactérias/química , Toxinas de Lyngbya/síntese química , Tiazóis/síntese química , Toxinas de Lyngbya/química , Toxinas de Lyngbya/isolamento & purificação , Análise Espectral , Estereoisomerismo , Tiazóis/química , Tiazóis/isolamento & purificaçãoRESUMO
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
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.