RESUMO
Extracts of laboratory cultures of the fungus Penicilium purpurogenum obtained from rotting fruit of the tree Averrhoa bilimbi growing in Sri Lanka have yielded 10 new meroterpenoids, dhilirolides E-N (5-14). The structures of the new dhilirolides have been elucidated by analysis of spectroscopic data and a single-crystal X-ray diffraction analysis of dhilirolide L (12). Dhilirolides A-N (1-14) represent the four unprecedented and rearranged dhilirane, isodhilirane, 14,15-dinordhilirane, and 23,24-dinorisodhilirane meroterpenoid carbon skeletons. Stable isotope feeding studies have confirmed the meroterpenoid biogenetic origin of the dhilirolides and provided support for a proposed genesis of the new carbon skeletons. Dhilirolide L (12) showed significant feeding inhibition and sublethal developmental disruption in the cabbage looper Trichoplusia ni, an important agricultural pest, at low concentrations.
Assuntos
Inseticidas/química , Isótopos/química , Penicillium/química , Terpenos/química , Animais , Estrutura Molecular , Sri Lanka , Difração de Raios XRESUMO
Four butenolides, ramariolides A-D (1-4), have been isolated from the fruiting bodies of the coral mushroom Ramaria cystidiophora. Their structures were elucidated by analysis of 1D and 2D NMR data and a single-crystal X-ray diffraction analysis of 1, and their absolute configurations were established using Mosher's method. The major metabolite, ramariolide A (1), which contains an unusual spiro oxiranebutenolide moiety, showed in vitro antimicrobial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis.
Assuntos
4-Butirolactona/análogos & derivados , Agaricales/química , Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Acinetobacter/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antituberculosos/química , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ressonância Magnética Nuclear Biomolecular , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacosRESUMO
The marine natural product latonduine A (1) shows F508del-cystic fibrosis transmembrane regulator (CFTR) corrector activity in cell-based assays. Pull-down experiments, enzyme inhibition assays, and siRNA knockdown experiments suggest that the F508del-CFTR corrector activities of latonduine A and a synthetic analogue MCG315 (4) result from simultaneous inhibition of PARP3 and PARP16. A library of synthetic latonduine A analogs has been prepared in an attempt to separate the PARP3 and PARP16 inhibitory properties of latonduine A with the goal of discovering selective small-molecule PARP3 and PARP16 inhibitory cell biology tools that could confirm the proposed dual-target F508del-CFTR corrector mechanism of action. The structure activity relationship (SAR) study reported herein has resulted in the discovery of the modestly potent (IC50 3.1 µM) PARP3 selective inhibitor (±)-5-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (5) that shows 96-fold greater potency for inhibition of PARP3 compared with its inhibition of PARP16 in vitro and the potent (IC50 0.362 µM) PARP16 selective inhibitor (±)-7,8-dichloro-5-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (6) that shows 205-fold selectivity for PARP16 compared with PARP3 in vitro. At 1 or 10 µM, neither 5 or 6 alone showed F508del-CFTR corrector activity, but when added together at 1 or 10 µM each, the combination exhibited F508del-CFTR corrector activity identical to 1 or 10 µM latonduine A (1), respectively, supporting its novel dual PARP target mechanism of action. Latonduine A (1) showed additive in vitro corrector activity in combination with the clinically approved corrector VX809, making it a potential new partner for cystic fibrosis combination drug therapies.
RESUMO
Two new IDO inhibitory meroterpenoids, xestolactone A (1) and xestosaprol O (2), have been isolated from the sponge Xestospongia vansoesti. Xestolactone A (1) has an unprecedented degraded meroterpenoid carbon skeleton. A short synthesis of the xestosaprol O (2) analogues 3 and 4 features the application of a rarely used photochemical coupling reaction. Synthetic analogue 3 is â¼40 times more potent than the inspirational natural product 2.
Assuntos
Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Indolamina-Pirrol 2,3,-Dioxigenase/química , Lactonas/síntese química , Poríferos/química , Xestospongia/química , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, deconvolution identified the latonduines as F508del-CFTR trafficking correctors that give functional correction in vivo. Using a biotinylated azido derivative of latonduine, we identified the poly(ADP-ribose) polymerase (PARP) family as latonduine target proteins. We show that latonduine binds to PARPs 1, 2, 3, 4, 5a, and 5b and inhibits PARP activity, especially PARP-3. Thus, latonduine corrects F508del-CFTR trafficking by modulating PARP activity. Latonduines represent pharmacologic agents for F508del-CFTR correction, and PARP-3 is a pathway for the development of CF treatments.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Transporte Proteico/efeitos dos fármacos , Alcaloides/química , Alcaloides/farmacologia , Animais , Linhagem Celular , Cricetinae , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Retículo Endoplasmático/metabolismo , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Camundongos , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Poríferos/química , Ligação Proteica , Dobramento de Proteína/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismoRESUMO
Dhilirolides A (1) to D (4), a family of secondary metabolites with a putative meroterpenoid biogenetic origin and the unprecedented dhilirane and isodhilirane carbon skeletons, have been isolated from laboratory cultures of the fruit-infecting fungus Penicillium purpurogenum collected in Sri Lanka. The structures of 1 to 4 were elucidated by interpretation of NMR data and a single crystal X-ray diffraction analysis of 1.