RESUMEN
Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C20 lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.
Asunto(s)
Antiácidos/metabolismo , Lípidos/biosíntesis , Lípidos/química , Mycobacterium tuberculosis/metabolismo , Fagosomas/metabolismo , Animales , Regulación Bacteriana de la Expresión Génica , Humanos , Concentración de Iones de Hidrógeno , Lisosomas , Macrófagos/metabolismo , Ratones , Estructura Molecular , Mycobacterium kansasii/genética , PrevalenciaRESUMEN
Phantasmidine, a rigid congener of the well-known nicotinic acetylcholine receptor agonist epibatidine, is found in the same species of poison frog ( Epipedobates anthonyi). Natural phantasmidine was found to be a 4:1 scalemic mixture, enriched in the (2a R,4a S,9a S) enantiomer by chiral-phase LC-MS comparison to the synthetic enantiomers whose absolute configurations were previously established by Mosher's amide analysis. The major enantiomer has the opposite S configuration at the benzylic carbon to natural epibatidine, whose benzylic carbon is R. Pharmacological characterization of the synthetic racemate and separated enantiomers established that phantasmidine is â¼10-fold less potent than epibatidine, but â¼100-fold more potent than nicotine in most receptors tested. Unlike epibatidine, phantasmidine is sharply enantioselective in its activity and the major natural enantiomer whose benzylic carbon has the 4a S configuration is more active. The stereoselective pharmacology of phantasmidine is ascribed to its rigid and asymmetric shape as compared to the nearly symmetric conformations previously suggested for epibatidine enantiomers. While phantasmidine itself is too toxic for direct therapeutic use, we believe it is a useful platform for the development of potent and selective nicotinic agonists, which may have value as pharmacological tools.
Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Venenos de Anfibios/química , Venenos de Anfibios/farmacología , Anuros/metabolismo , Compuestos Heterocíclicos de Anillo en Puente/química , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Nicotina/metabolismo , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Venenos/química , Piridinas/química , Piridinas/farmacología , Receptores Nicotínicos/metabolismo , EstereoisomerismoRESUMEN
The structure of (±)-clavilactone D was revised, and the synthesis was achieved in seven steps from a substituted benzaldehyde. The key step was the base-catalyzed cyclization of an α,ß-carbonyl peroxide, which was obtained by an iron-catalyzed three-component reaction of a benzaldehyde, an alkene, and TBHP. NaBH4-mediated reductive lactonization of the resulting cis-dicarbonyl epoxide led to the α,ß-epoxy-γ-butyrolactone skeleton highly stereoselectively. The synthesis provides a concise, reliable, and practical route to the revised structure of clavilactone D.
RESUMEN
To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guérin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis-specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosinyladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesis. Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis-prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis-prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis. Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis, and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme.
Asunto(s)
Transferasas Alquil y Aril/química , Transferasas Alquil y Aril/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Lípidos/biosíntesis , Modelos Moleculares , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/patogenicidad , Conformación Proteica , Transferasas Alquil y Aril/genética , Proteínas Bacterianas/genética , Cromatografía por Intercambio Iónico , Dimerización , Lípidos/química , Lípidos/genética , Espectrometría de Masas , Estructura Molecular , VirulenciaRESUMEN
Hydrogenation (3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and 17 over 5% Rh/Al2O3 forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9, 15, and 18 in > 95% yield, providing a general route to this little-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyramine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful.
RESUMEN
2,2,6,6-Tetramethylpiperidine (TMP)-catalyzed (1-10%) chlorinations of phenols by SO2Cl2 in aromatic solvents are more ortho selective than with primary and less hindered secondary amine catalysts. Ortho-selective chlorination is successful even with electron deficient phenols such as 2-hydroxybenzaldehyde and 2'-hydroxyacetophenone. Notably, ortho selectivity increases with the reaction temperature. On the other hand, tetraalkylammonium chloride-catalyzed chlorinations are moderately para selective.
RESUMEN
A short and efficient synthesis of model spiroiminals that have the same stereochemistry as marineosins A and B, but different conformations, was carried out in six or seven steps from 6-methyltetrahydropyran-2-one. These spiroiminals were also prepared biomimetically by reduction of an enol ether. A more highly substituted spiroiminal with the same stereochemistry and conformation as marineosin A was prepared in 11 steps from parasorbic acid. A macrocyclic pyrrole lactone was prepared stereospecifically in 10 steps. A five-step sequence converted the lactone to a late hemi-iminal intermediate that has resisted the methylation and spiroiminal formation that would lead to marineosin A.
Asunto(s)
Compuestos de Espiro/síntesis química , Estructura Molecular , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
Reaction of a substituted indole-3-acetyl chloride with N-5-azidopentyl-N'-hydroxyguanidine generated a substituted 3-(5-azidopentylamino)-5-((indol-3-yl)methyl)-1,2,4-oxadiazole. Reduction of the azide with zinc and ammonium formate afforded the amine, which was elaborated to the guanidine, completing short and efficient syntheses of the cytotoxic natural products phidianidines A and B in 19% overall yield by a convergent route that will make analogues readily available for biological evaluation. Initial screening in the NCI 60 cell line at 10(-5) M indicated that the bromine on the indole is necessary for activity and that the amine precursor to phidianidine A is more potent than phidianidine A.
Asunto(s)
Alcaloides Indólicos/química , Alcaloides Indólicos/síntesis química , Oxadiazoles/química , Oxadiazoles/síntesis química , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (±)-7,8-dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)(3) and to an amino phenol with KHMDS and oxygen.
Asunto(s)
Alcaloides/síntesis química , Quinolizinas/síntesis química , Alcaloides/química , Estructura Molecular , Quinolizinas/química , EstereoisomerismoRESUMEN
The Diels-Alder reaction of maldoxin with an isopropenylallene at 60-75 °C afforded an adduct closely related to chloropestolide A (24%) and a second adduct (0-11%) that underwent an ene reaction to generate the chloropupukeanolide D (11-22%) skeleton. The Diels-Alder reaction occurred with good selectively (>5:1) from a single face of maldoxin under much milder conditions than previously reported for the analogous dimethoxycyclohexadienone. Furthermore, the ene reaction took place under mild conditions whereas the analogous Diels-Alder adduct from the dimethoxycyclohexadienone did not undergo an ene reaction.
RESUMEN
Many bacterial pathogens, including Staphylococcus aureus, require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of S. aureus IMPDH (SaIMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 µM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. Five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant S. aureus strains readily emerged in vitro. Resistance resulted from substitutions in the cofactor/inhibitor binding site of SaIMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive SaIMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of SaIMPDH as a target for the treatment of S. aureus infections, suggesting other functions of this protein may be responsible for its role in infection.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , IMP Deshidrogenasa/genética , Inosina , Ratones , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureusRESUMEN
A convergent, practical route to unstable hexacyclic parnafungin A and C models has been developed. Two iodoxanthones were prepared in four or five steps (33-50% overall yield). Suzuki-Miyaura coupling of the iodoxanthones with excess readily available 3-carbomethoxy-2-nitrophenyl pinacol boronate afforded the hindered highly functionalized 2-arylxanthones (53-58%) in the first key step. In the second key step, zinc reduction gave benzisoxazolinones that were treated with MsCl and then base to generate the unstable hexacyclic parnafungin A (13% overall yield for 8 steps) and C (8% overall yield for 9 steps) models. Analogously to the parnafungins, hexacyclic parnafungin C model decomposes to a phenanthridine with a half-life of 2 d in CDCl(3).
Asunto(s)
Oxazolidinonas/síntesis química , Fenantridinas/síntesis química , Compuestos Policíclicos/síntesis química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/química , Fenantridinas/química , Compuestos Policíclicos/químicaRESUMEN
Dinemasone C was prepared in three steps (8% overall yield) from cis-tetrahydro-4-hydroxy-6-methyl-2-pyrone by aldol reaction with 2,4-hexadienal, epoxidation followed by cyclization, and epimerization of the ring fusion. Dinemasone C, epi-dinemasone C, anhydrodinemasone BC, and nor-dinemasone B are active against bacteria, including Legionella pneumophila Corby, algae, and fungi.
Asunto(s)
Antibacterianos/farmacología , Antifúngicos/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antifúngicos/síntesis química , Antifúngicos/química , Bacillus megaterium/efectos de los fármacos , Basidiomycota/efectos de los fármacos , Chlorella/efectos de los fármacos , Ciclización , Escherichia coli/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Legionella pneumophila/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , EstereoisomerismoRESUMEN
A Kiyooka aldol condensation of an aldehyde with a trimethylsilyl ketene acetal and the oxazaborolidinone prepared from N-Ts-(S)-valine gives two of the four possible aldol adducts, which were oxidized and deprotected to complete the synthesis of (-)-berkelic acid and (-)-22-epi-berkelic acid. This synthesis establishes the absolute stereochemistry and assigns the stereochemistry at C-22. A biosynthetic pathway is proposed that is consistent with the known absolute stereochemistry at the quaternary carbon of spiciferone A, spicifernin, and berkelic acid and provides a simple explanation for the differing stereochemistry at C-18 and C-19 of spicifernin and berkelic acid.
Asunto(s)
Compuestos de Espiro/química , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Compuestos de Espiro/síntesis química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacología , EstereoisomerismoRESUMEN
The mechanistic details of Mn(OAc)(3)-based oxidative free-radical additions and cyclizations are reviewed. The mechanisms of electron transfer to generate radicals, electron transfer to convert the radicals to oxidized products, and further oxidation of the products are covered.
RESUMEN
An extremophilic challenge: Stereospecific condensation of a fully functionalized ketal aldehyde and a 2,6-dihydroxybenzoic acid is the key step in the synthesis of (-)-berkelic acid confirming Fürstner's reassignment of the stereochemistry at C18 and C19, establishing the absolute stereochemistry, and tentatively assigning the stereochemistry at C22.
Asunto(s)
Aldehídos/síntesis química , Hidroxibenzoatos/síntesis química , Compuestos de Espiro/síntesis química , Aldehídos/química , EstereoisomerismoRESUMEN
Reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. Reduction of the ketone, hydrolysis, iodolactonization, ozonolysis, and intramolecular aldol reaction provided a spiro lactone cyclopentenal. Retro-iodolactonization with activated Zn, formation of the beta-lactone, and reduction of the aldehyde completed an efficient first synthesis of (+/-)-vibralactone. No protecting groups were used except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid.
Asunto(s)
Lactonas/síntesis química , Alquilación , Basidiomycota/química , Lactonas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Mander reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis of the enol ether afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. This was converted in five steps (reduction of the ketone, saponification, iodolactonization, ozonolysis, and intramolecular aldol reaction) to a spiro lactone cyclopentenal. An efficient first synthesis of (+/-)-vibralactone was completed by retro-iodolactonization with activated Zn, formation of the beta-lactone (vibralactone C), and reduction of the aldehyde. Except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid, no protecting groups were used. A similar sequence starting with asymmetric reductive alkylation of the (2S)-2-methoxymethoxymethylpyrrolidine amide of 2-methoxybenzoic acid with prenyl bromide afforded (-)-vibralactone confirming the absolute stereochemical assignment that was based on computational methods.
Asunto(s)
Lactonas/síntesis química , Alquilación , Éteres de Hidroxibenzoatos , Lactonas/química , Salicilatos/química , EstereoisomerismoRESUMEN
Addition of guanidine to a 6-methylhexahydroindenone in MeOH at 85 degrees C afforded 7-epineoptilocaulin. A similar reaction with a 6-propylhexahydroindenone afforded netamine E. MnO2 oxidation of 7-epineoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isoptilocaulin.
Asunto(s)
Alcaloides/biosíntesis , Ácido Oleanólico/análogos & derivados , Quinazolinas/síntesis química , Quinazolinas/metabolismo , Saponinas/síntesis química , Ácido Oleanólico/síntesis química , Quinazolinas/química , EstereoisomerismoRESUMEN
Acid-catalyzed condensation of 2,6-dihydroxybenzoic acid 3 with ketal aldehyde 14 in methanol at 25 degrees C, followed by CH2N2 esterification, gave a 4:1:4:1 mixture of diastereomers 15b-18b in 60% yield. Equilibration of this mixture with TFA in CDCl3 provided tetracycle 15b (83% yield) with the complete skeleton of berkelic acid. A similar condensation at 0 degrees C afforded 15b-18b and a reduction product 19b, which was probably formed by a 1,5-hydride shift.