RESUMEN
The MN ring of Caribbean ciguatoxin C-CTX-1 was synthesized from a meso-syn-2,7-dimethyloxepane derivative corresponding to the M ring via desymmetrization by acetal formation with a camphor derivative, followed by construction of the N ring via the Horner-Wadsworth-Emmons reaction and acetal formation. The meso-syn-2,7-dimethyloxepane derivative was synthesized via photoinduced electrocyclization of a conjugated exo-diene under flow conditions, giving a cyclobutene derivative, followed by ring expansion via oxidative cleavage and diastereoselective reduction of a ß-hydroxy ketone.
RESUMEN
Here we examined the membrane binding and pore formation of amphidinol 3 (AM3) and its truncated synthetic derivatives. Importantly, both of the membrane affinity and pore formation activity were well correlated with the reported antifungal activity. Our data clearly demonstrated that the C1-C30 moiety of AM3 plays essential roles both in sterol recognition and stable pore formation. Based on the current findings, we updated the interacting model between AM3 and sterol, in which the moiety encompassing from C21 to C67 accommodates a sterol molecule with forming hydrogen bonds with the sterol hydroxy group and van der Waals contact between AM3 polyol and sterol skeleton. Although the conformation of the C1-C20 moiety of AM3 is hard to specify due to its flexibility, the region likely contributes to stabilization of pore structure.
Asunto(s)
Anfidinoles , Esteroles , Esteroles/farmacología , Esteroles/química , Alquenos/química , Piranos/químicaRESUMEN
Amphotericin B, an antifungal drug with a long history of use, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol ergosterol. A stable assembly consisting of seven drug molecules was observed to form an ion conductive channel. The structure is somewhat similar to the upper half of the barrel-stave model proposed in the 1970s but substantially different in the number of molecules and in their arrangement. The present structure explains many previous findings, including structure-activity relationships of the drug, which will be useful for improving drug efficacy and reducing adverse effects.
RESUMEN
Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.
Asunto(s)
Alquenos/síntesis química , Piranos/síntesis química , Alquenos/química , Alquenos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Modelos Moleculares , Piranos/química , Piranos/farmacología , Relación Estructura-ActividadRESUMEN
The use of 2- O-alkoxymethyl groups as effective stereodirecting substituents for the construction of 1,2- trans glycosidic linkages is reported. The observed stereoselectivity arises from the intramolecular formation of a five-membered cyclic architecture between the 2- O-alkoxymethyl substituent and the oxocarbenium ion, which provides the expected facial selectivity. Furthermore, the observed stereocontrol and the extremely high reactivity of 2- O-alkoxymethyl-protected donors allowed development of a one-pot sequential glycosylation strategy that should become a powerful tool for the assembly of oligosaccharides.
RESUMEN
Amphidinolâ 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31-C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.
Asunto(s)
Alquenos/síntesis química , Productos Biológicos/síntesis química , Piranos/síntesis química , Alquenos/química , Productos Biológicos/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Piranos/química , EstereoisomerismoRESUMEN
For the complete structure elucidation of an endogenous sperm-activating and -attracting factor isolated from eggs of the ascidian Ascidia sydneiensis ( Assydn-SAAF), its two possible diastereomers with respect to C-25 were synthesized. Starting from ergosterol, the characteristic steroid backbone was constructed by using an intramolecular pinacol coupling reaction and stereoselective reduction of a hydroxy ketone as key steps, and the side chain was introduced by Julia-Kocienski olefination. Comparison of the NMR data of the two diastereomers with those of the natural product led to the elucidation of the absolute configuration as 25 S; thus the complete structure was determined and the first synthesis of Assydn-SAAF was achieved.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Espermatozoides/efectos de los fármacos , Urocordados/química , Animales , Espectroscopía de Resonancia Magnética/métodos , Masculino , Esteroides/química , Esteroides/farmacologíaRESUMEN
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERß (IC50 < µM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
Asunto(s)
Acridinas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Antagonistas de Estrógenos/farmacología , Estrógenos/metabolismo , Acridinas/síntesis química , Acridinas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Unión Competitiva/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Antagonistas de Estrógenos/síntesis química , Antagonistas de Estrógenos/química , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca2+ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 µM, whereas the NOPQR(S) ring system elicited no inhibitory activity.
Asunto(s)
Aldehídos/farmacología , Calcio/metabolismo , Glioma/metabolismo , Cetonas/farmacología , Toxinas Marinas/antagonistas & inhibidores , Óxido Nítrico/farmacología , Oxocinas/antagonistas & inhibidores , Piranos/farmacología , Aldehídos/química , Animales , Relación Dosis-Respuesta a Droga , Cetonas/química , Toxinas Marinas/química , Toxinas Marinas/farmacología , Conformación Molecular , Óxido Nítrico/química , Oxocinas/química , Oxocinas/farmacología , Piranos/síntesis química , Piranos/química , Ratas , EstereoisomerismoRESUMEN
Amphotericin B (AmB) is a polyene macrolide antibiotic isolated from Streptomyces nodosus. The antifungal activity of AmB can be attributed to the formation of an ion-channel assembly in the presence of ergosterol (Erg), in which there are two different AmB-Erg orientations, parallel and antiparallel, as reported previously. In this study, to elucidate the structures of those AmB-Erg complexes based on solid-state nuclear magnetic resonance, a (19)F-labeled AmB derivative was newly prepared by a hybrid synthesis that utilized degradation products from the drug. Using the 2-(trimethylsilyl)ethoxymethyl (SEM) group as the protecting group for the carboxylic acid moiety of AmB, the fully deprotected labeled AmB compounds were obtained successfully. Then, these labeled AmBs were subjected to (13)C{(19)F} rotational-echo double-resonance (REDOR) experiments in hydrated lipid bilayers. The results indicated the coexistence of parallel and antiparallel orientations for AmB and Erg pairing, at a ratio of 7:3. A total of six distances between AmB and Erg were successfully obtained. Geometry analysis using the distance constraints derived from the REDOR experiments provided the plausible AmB-Erg complex structure for both the parallel and antiparallel interactions. The flat macrolide of AmB and the tetracyclic core of Erg closely contacted in a face-to-face manner, thus maximizing the van der Waals interaction between the two molecules. This interaction can be attributed to the coexistence of both the parallel and antiparallel orientations.
Asunto(s)
Anfotericina B/química , Antifúngicos/química , Membrana Celular/metabolismo , Ergosterol/química , Membrana Dobles de Lípidos/metabolismo , Provitaminas/química , Anfotericina B/metabolismo , Antifúngicos/metabolismo , Isótopos de Carbono , Dicroismo Circular , Ergosterol/metabolismo , Radioisótopos de Flúor , Canales Iónicos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Provitaminas/metabolismoRESUMEN
2-Naphthylmethoxymethyl (NAPOM) was developed for the protection of various hydroxy (including phenolic hydroxy and carboxy) and mercapto groups. The NAPOM group can be introduced in extremely mild conditions (naphthylmethoxymethyl chloride, 2,6-lutidine, room temperature) without concomitant acyl migration in a 1,2-diol system. Furthermore, selective removal of NAPOM in the presence of naphthylmethyl (NAP) and p-methoxybenzyl (PMB) groups and, conversely, that of PMB in the presence of NAPOM were realized. These results, as well as its easy handling and compatibility with various solvents, show that NAPOM is a novel and useful choice as a protecting group.
RESUMEN
The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Δ7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Δ5, Δ7, and Δ9 positions. Intermolecular distance measurements by (13)C{(19)F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Δ5-sterol (2, 6) and the protruded A-ring of Δ5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the α-face of sterol alicycle interacts with the flat macrolide structure of AmB.
Asunto(s)
Anfotericina B/química , Anfotericina B/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Liposomas/metabolismo , Esteroles/metabolismo , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Hongos/citología , Hongos/efectos de los fármacos , Hongos/metabolismo , Humanos , Liposomas/química , Modelos Moleculares , Conformación Molecular , Micosis/tratamiento farmacológico , Micosis/microbiología , Esteroles/químicaRESUMEN
Stereoselective synthesis of the C1-C29 part of amphidinol 3 (AM3) was achieved. The C1-C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4-C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9-C10 and C14-C15 bonds, respectively. The C21-C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1-C20 and C21-C29 parts was achieved by Julia-Kocienski olefination and regio- and stereoselective dihydroxylation of the C20-C21 double bond in the presence of the C4-C5 and C8-C9 double bonds to afford the C1-C29 part of AM3.
Asunto(s)
Alquenos/síntesis química , Piranos/síntesis química , Alquenos/química , Catálisis , Litio/química , Macrólidos/química , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
Stereoselective synthesis of the C'D'E'F' ring system of maitotoxin was achieved starting from the E' ring through successive formation of the D' and C' rings based on SmI2-mediated reductive cyclization. Construction of the F' ring was accomplished via Suzuki-Miyaura cross-coupling with a side chain fragment and Pd(II)-catalyzed cyclization of an allylic alcohol. The C'D'E'F' ring system inhibited maitotoxin-induced Ca(2+) influx in rat glioma C6 cells with an IC50 value of 59 µM.
Asunto(s)
Toxinas Marinas/antagonistas & inhibidores , Toxinas Marinas/química , Toxinas Marinas/síntesis química , Oxocinas/antagonistas & inhibidores , Oxocinas/química , Oxocinas/síntesis química , Paladio/química , Compuestos Policíclicos/síntesis química , Propanoles/química , Animales , Catálisis , Ciclización , Concentración 50 Inhibidora , Estructura Molecular , Compuestos Policíclicos/química , Ratas , EstereoisomerismoRESUMEN
To implement specific guest responsivity, a hydrophobic cholesterol-based co-ligand, cholest-5-en-3-yl-4-isonicotinate (Cholpy), was incorporated into a two-dimensional Hofmann-type Co(II)Ni(II) coordination polymer. The chemically programmed structure successfully demonstrated the unique guest response with remarkable chromatic changes.
Asunto(s)
Colesterol/química , Cobalto/química , Complejos de Coordinación/química , Níquel/química , Ligandos , Modelos Moleculares , Polímeros/químicaRESUMEN
Stereoselective synthesis of the C43-C67 part of amphidinol 3 (AM3) and its C51-epimer was achieved starting from a common intermediate corresponding to the tetrahydropyran moiety of AM3, via asymmetric oxidations and Julia-Kocienski olefination. By comparing NMR data of the synthetic specimens with those of AM3, the absolute configuration at C51 of AM3 was revised from R to S.
Asunto(s)
Alquenos/química , Piranos/química , Piranos/síntesis química , Alquenos/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
A novel SAAF was isolated from the title ascidian. The structure was elucidated using the entire sample of 4 nmol, suggesting that the position of the OH group confers genus-specificity to sperm chemotaxis in ascidians. This study not only provides insight into the chemical tactics in sperm chemotaxis but demonstrates that the innovative techniques allow structure determination of natural products in trace amounts.
Asunto(s)
Colestanoles/aislamiento & purificación , Espermatozoides/fisiología , Ésteres del Ácido Sulfúrico/aislamiento & purificación , Urocordados/química , Animales , Colestanoles/química , Colestanoles/metabolismo , Masculino , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-Actividad , Ésteres del Ácido Sulfúrico/química , Ésteres del Ácido Sulfúrico/metabolismo , Urocordados/genéticaRESUMEN
Amphidinol 3 (AM3), a membrane-active agent isolated from the dinoflagellate Amphidinium klebsii, consists of a long carbon chain containing 25 stereogenic centers. Although the absolute configuration of AM3 was determined by extensive NMR analysis and degradation of the natural product, the partial structure corresponding to the tetrahydropyran ring system was found to be antipodal to that of karlotoxin 2, a structurally related compound recently isolated from the dinoflagellate Karlodinium veneficum. By extensive degradation of the natural product and conversion of the resulting alcohol to an MTPA ester, the absolute configuration at C45 of AM3 was confirmed to be R, supporting the originally proposed structure.
Asunto(s)
Alquenos/química , Piranos/química , Dinoflagelados/química , Ésteres , Estructura Molecular , Policétidos , EstereoisomerismoRESUMEN
Lipid rafts have attracted much attention because of their significant functional roles in membrane-associated processes. It is thought that sphingomyelin and cholesterol are essential for forming lipid rafts; however, their motion characteristics are not fully understood despite numerous studies. Here we show accurate local motions encompassing an entire sphingomyelin molecule, which were captured by measuring quadrupole splittings for 19 kinds of site-specifically deuterated sphingomyelins (that is, molecular motion capture of sphingomyelin). The quadrupole splitting profiles, which are distinct from those reported from perdeuterated sphingomyelins or simulation studies, reveal that cholesterol enhances the order in the middle parts of the alkyl chains more efficaciously than at the shallow positions. Comparison with dimyristoylphosphocholine bilayers suggests that cholesterol is deeper in sphingomyelin bilayers, which likely explains the so-called umbrella effect. The experiments also demonstrate that (i) the C2'-C3' bond predominantly takes the gauche conformation, (ii) the net ordering effect of cholesterol in sphingomyelin bilayers is not larger than that in phosphatidylcholine bilayers, (iii) cholesterol has no specific preference for the acyl or sphingosine chain, (iv) the acyl and sphingosine chains seem mismatched by about two methylene lengths, and (v) the motion of the upper regions of sphingomyelin chains is less temperature dependent than that of lower regions probably due to intermolecular hydrogen bond formation among SM molecules. These insights into the atomic-level dynamics of sphingomyelin provide critical clues to understanding the mechanism of raft formation.
Asunto(s)
Microdominios de Membrana/química , Esfingomielinas/química , Colesterol/química , Deuterio , Membrana Dobles de Lípidos/química , Conformación Molecular , Movimiento (Física) , Resonancia Magnética Nuclear Biomolecular , Fosfatidilcolinas/químicaRESUMEN
We experimentally examined the propagation of temporally square modulated optical pulses through a coupled ring resonator. Sharp transient spikes appeared as the square pulses entered the system. The main signal gradually grew up through coupled-resonator-induced transparency (CRIT), with the time constant determined by a second resonator. Transient spikes were attributed to the higher and lower spectral components of the incident pulse, to which the resonators cannot respond; hence, they were interpreted as optical precursors. The experiments, therefore, demonstrated that precursors and the main signal can be observed separately, with amplitudes comparable to that of the incident step in CRIT.