RESUMO
A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Cianetos/química , Cianetos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Aminas/química , Aminas/farmacologia , Anti-Inflamatórios/química , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/química , Quinolinas/farmacologia , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Bioassay-guided fractionation of the Caribbean sponge Svenzea flava collected near Mona Island, off the west coast of Puerto Rico, led to the isolation of two isocyanide amphilectane-type diterpenes named monamphilectines B and C (2 and 3). Attached to the backbone of each of these compounds is the first α-substituted monocyclic ß-lactam ring to be isolated from a marine organism. The molecular structures of 2 and 3 were established by spectroscopic methods and then confirmed unequivocally by chemical correlation and comparison of physical and chemical data with the natural products. The new ß-lactams were successfully synthesized in one step, starting from the known diisocyanide 4, via parallel Ugi four-center three-component reactions (U-4C-3CR) that also established their absolute stereostructures. Interestingly, compounds 2 and 3 exhibited activities in the low nanomolar range against the human malaria parasite Plasmodium falciparum.
RESUMO
Two new natural products, 3 and 4, and their predecessor 7-isocyanoisoneoamphilecta-1(14),15-diene (2), of the rare isoneoamphilectane class of marine diterpenes, along with the known amphilectane diterpenes 6-8, were isolated from the n-hexane extract of the marine sponge Svenzea flava collected at Great Inagua Island, Bahamas. The molecular structures of compounds 3 and 4 were established by spectroscopic (1D/2D NMR, IR, UV, HRMS) methods and confirmed by a series of chemical correlation studies. In a first ever case study of the assignment of the absolute configuration of a molecule based on the isoneoamphilectane carbon skeleton, the absolute configuration of compound 5 was established as 3S,4R,7S,8S,11R,12S,13R by application of vibrational circular dichroism (VCD). In vitro anti-TB screenings revealed that metabolites 2-4 and, in particular, semisynthetic analogue 5, are strong growth inhibitors of Mycobacterium tuberculosis H37Rv.
Assuntos
Antituberculosos/farmacologia , Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Poríferos/química , Animais , Antituberculosos/química , Antituberculosos/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Dicroísmo Circular , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , VibraçãoRESUMO
A new investigation of the active sponge extracts of Prosuberites laughlini collected off the West coast of Puerto Rico has yielded three new cyclic heptapeptides, namely euryjanicins E (1)-G (3), containing multiple phenylalanine and proline residues. In CDCl3 solution, each euryjanicin F (2) and G (3) exists as an inseparable complex mixture of conformational isomers. The molecular structures of 1-3 were elucidated by a combination of chemical degradation, extensive ESI-MS/MS n analyses, and 2D NMR methods. The elucidation of the absolute configuration was achieved by HPLC following analysis of the acid hydrolysates after derivatization with Marfey's reagent. When assayed against the National Cancer Institute 60 tumor cell line panel, the new cyclic peptides did not display significant in vitro cytotoxicity.
RESUMO
The effects of five Hymeniacidon sp. amphilectane metabolites (1-5) and two semi-synthetic analogs (6 and 7) on thromboxane B(2) (TXB(2)) and superoxide anion (O(2)(-)) generation from Escherichia coli LPS-activated rat brain microglia were investigated. All Hymeniacidon sp. metabolites and analogs potently inhibited TXB(2) (IC(50)=0.20-4.69µM) with low lactate dehydrogenase release and minimal mitochondrial dehydrogenase inhibition. While a lack of O(2)(-) inhibition would suggest that Hymeniacidon sp. metabolites and derivatives inhibit TXB(2) synthesis by a cyclooxygenase-dependent mechanism, their pharmacologic potency and limited in vitro cytotoxicity warrants further investigation to develop them as lead compounds to modulate enhanced TBX(2) release by activated microglia in neuroinflammatory disorders.
Assuntos
Encéfalo/metabolismo , Diterpenos/farmacologia , Microglia/efeitos dos fármacos , Poríferos/química , Tromboxano B2/metabolismo , Animais , Diterpenos/metabolismo , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Superóxidos/metabolismoRESUMO
The novel bromotriterpene polyethers aplysqualenol A (1) and aplysqualenol B (2) have been isolated from the Caribbean sea slug Aplysia dactylomela collected in Puerto Rico, and their structures and relative configurational assignments established from spectroscopic data aided by quantum mechanical calculations of NMR chemical shifts. Although both these compounds may be conceived as polyoxycyclic derivatives of the C30 squalene skeleton, remarkably 1 and 2 possess an unprecedented C15 to C24 flexible chain of 14S* spatial disposition that contains a unique ether bridge between C16 and C19. Biological activity screening tests revealed that, although aplysqualenol A (1) does not have significant anti-infective properties, it possesses potent antitumoral and antiviral activities.
RESUMO
Monamphilectine A (1), a new diterpenoid ß-lactam alkaloid showing potent antimalarial activity, was isolated in milligram quantities following bioassay-directed extraction of a Puerto Rican marine sponge Hymeniacidon sp. Its structure, established by interpretation of spectral data, was confirmed unequivocally by chemical interconversion and comparison of physical, chemical, and bioactivity data with the natural product. The one-step semisynthesis of monamphilectine A was based on a multicomponent Ugi reaction that also established its absolute stereostructure.