RESUMEN
Hexasubstituted benzenoids are prepared by regioselective bimolecular [2 + 2 + 2] alkyne cyclotrimerizations of diynes with alkynes. These convergent and efficient benzannulations are directed toward and lead to the first total syntheses of the illudalane sequiterpenes fomajorin D and S, in 10 and 7 steps, respectively, from commercially available dimedone. Control experiments suggest that hydrogen bonding may play a role in preorganizing the diyne and alkyne coupling partners for establishing the desired regioselectivity, but other factors are likely involved in the selective formation of other regioisomers.
RESUMEN
Leukocyte antigen-related (LAR) phosphatase is a receptor-type protein tyrosine phosphatase involved in cellular signaling and associated with human disease including cancer and metabolic disorders. Selective inhibition of LAR phosphatase activity by well characterized and well validated small molecules would provide key insights into the roles of LAR phosphatase in health and disease, but identifying selective inhibitors of LAR phosphatase activity has been challenging. Recently, we described potent and selective inhibition of LAR phosphatase activity by the fungal natural product illudalic acid. Here we provide a detailed biochemical characterization of the adduct formed between LAR phosphatase and illudalic acid. A mass spectrometric analysis indicates that two cysteine residues are covalently labeled by illudalic acid and a related analog. Mutational analysis supports the hypothesis that inhibition of LAR phosphatase activity is due primarily to the adduct with the catalytic cysteine residue. A computational study suggests potential interactions between the illudalic acid moiety and the enzyme active site. Taken together, these data offer novel insights into the mechanism of inhibition of LAR phosphatase activity by illudalic acid.
Asunto(s)
Cumarinas , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Humanos , Cumarinas/química , Cumarinas/farmacología , Cisteína/química , Cisteína/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/química , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genéticaRESUMEN
PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog-based inhibition of PHPT1 activity. Four of the seven analogs investigated had IC50 values below 5â µM, with the most potent compound (IA1-8H2) exhibiting an IC50 value of 3.4±0.7â µM. Interestingly, these compounds appear to be non-covalent, non-competitive inhibitors of PHPT1 activity, in contrast to other recently reported PHPT1 inhibitors. Mutating the three cysteine residues to alanine has no effect on inhibition, indicating that cysteine is not critical for interactions between inhibitor and enzyme.
Asunto(s)
Productos Biológicos , Histidina , Productos Biológicos/farmacología , Cisteína , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/metabolismoRESUMEN
Alkyne [2 + 2 + 2] cyclotrimerization is a strategically attractive but tactically challenging approach to the synthesis of highly substituted benzene rings. Here, a bimolecular regioselective cyclotrimerization is applied to the total synthesis of the natural product coprinol and several related alcyopterosins from the illudalane family of sesquiterpenes. The synthesis of coprinol from dimedone was completed in six steps and a 57% overall yield. Alternative functional group manipulations lead to alcyopterosins A, B, and O and two additional congeners, all within six steps.
Asunto(s)
Alquinos , Sesquiterpenos , Estructura Molecular , CiclizaciónRESUMEN
Two divergent and complementary methodologies for preparing neopentylene-tethered (NPT) 1,6-diynes are described. These NPT 1,6-diynes are valuable π-systems for reaction discovery and building blocks for target-oriented synthesis. Ring-opening fragmentation of dimedone (and alkylation) produces alkyne-tethered ß-keto esters 6. One-pot dehydration with optional saponification produces diyne monoester 15 or monoacid 3, which can be further functionalized using traditional alkyne substitution chemistry and/or carboxylate manipulations. For example, copper-catalyzed decarboxylation of acid 3 provides 4,4-dimethyl-1,6-heptadiyne (1), now in ca. 76% yield over four steps from dimedone. A complementary approach using Zard fragmentation chemistry converts alkylated ß-keto esters into the corresponding monoalkylated NPT 1,6-diynes. The utility of substituted NPT 1,6-diynes in target-oriented synthesis is noted herein.
RESUMEN
Chondroitin sulfate proteoglycans (CSPGs) prevent sympathetic nerve regeneration in the heart after myocardial infarction and prevent central nerve regrowth after traumatic brain injury and spinal cord injury. Currently, there are no small-molecule therapeutics to promote nerve regeneration through CSPG-containing scars. CSPGs bind to monomers of receptor protein tyrosine phosphatase sigma (PTPσ) on the surface of neurons, enhancing the ability of PTPσ to bind and dephosphorylate tropomyosin receptor kinases (Trks), inhibiting their activity and preventing axon outgrowth. Targeting PTPσ-Trk interactions is thus a potential therapeutic target. Here, we describe the development and synthesis of small molecules (HJ-01 and HJ-02) that disrupt PTPσ interactions with Trks, enhance Trk signaling, and promote sympathetic nerve regeneration over CSPGs.
Asunto(s)
Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Traumatismos de la Médula Espinal , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Humanos , Regeneración Nerviosa/fisiología , Monoéster Fosfórico Hidrolasas , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Traumatismos de la Médula Espinal/metabolismoRESUMEN
Macroscopically homogeneous mixtures of p-nitroanisole (pNA) and mesitylene (MES) can be selectively heated using microwave (MW) energy. The pNA solutes agglomerate into distinct phase domains on the attoliter-scale (1 aL = 10-18 L), and these agglomerates can be MW-heated selectively to temperatures that far exceed the boiling point of the surrounding MES solvent. Here, a 1 : 20 mixture of pNA : MES is used as a mixed solvent for aryl Claisen rearrangement of allyl naphthyl ether (ANE). ANE itself does not heat effectively in the MW, but selective MW heating of pNA allows for transfer of thermal energy to ANE to accelerate rearrangement kinetics above what would be expected based on Arrhenius kinetics and the measured bulk solution temperature. This focused study builds on prior work and highlights 1 : 20 pNA : MES as a mixed solvent system to consider for strategically exploiting MW-specific thermal effects.
RESUMEN
Developing an efficient, concise synthesis of the fungal natural product illudalic acid has been a long-standing challenge, made more pressing by the recent discovery that illudalic acid and analogs are selective phosphatase inhibitors. Syntheses of illudalic acid have become progressively more efficient over the decades yet remain strategically grounded in a 17-step synthesis reported in 1977. Here we validate a two-step process-convergent [4 + 2] benzannulation and one-pot coordinated functional group manipulations-for preparing the key trifunctional pharmacophore of illudalic acid. The modular building blocks are readily available in 2-3 steps, for a longest linear sequence (LLS) of 5 steps to illudalic acid from 3,3-dimethylcyclopentanone. A small collection of analogous indanes and tetralins featuring the same pharmacophore were prepared by a similar route. These compounds potently and selectively inhibit the human leukocyte common antigen-related (LAR) subfamily of protein tyrosine phosphatases (PTPs). Evidence supporting a postulated covalent ligation mechanism is provided herein.
Asunto(s)
CumarinasRESUMEN
Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as "neoprofen". The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.
RESUMEN
The development of efficient methods for the synthesis of substituted polycyclic arenes with various topologies is in high demand due to their excellent electrical and optical properties. In this work, a series of gem-dimethylcyclopentane-fused arenes with more than ten topologies were synthesized via a 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD)-mediated dehydro-Diels-Alder reaction with moderate to good yields. The introduction of the near-planar gem-dimethylcyclopentane moiety not only impacts the molecular conjugative system but also regulates the intermolecular π-π interactions and crystal packing, which are critical for the photoelectric performance of arenes. The photophysical properties, molecular geometry, molecular packing of these compounds, and electrochemical properties were investigated by UV-vis absorption, fluorescence emission spectra, DFT calculations, single-crystal X-ray structure analysis, and cyclic voltammetry study.
RESUMEN
Synthetic indole cannabinoids characterized by a 2',2'-dimethylindan-5'-oyl group at the indole C3 position constitute a new class of ligands possessing high affinity for human CB2 receptors at a nanomolar concentration and a good selectivity index. Starting from the neutral antagonist 4, the effects of indole core modification on the pharmacodynamic profile of the ligands were investigated. Several N1 side chains afforded potent and CB2-selective neutral antagonists, notably derivatives 26 (R1 = n-propyl, R2 = H) and 35 (R1 = 4-pentynyl, R2 = H). Addition of a methyl group at C2 improved the selectivity for the CB2 receptor. Moreover, C2 indole substitution may control the CB2 activity as shown by the functionality switch in 35 (antagonist) and 49 (R1 = 4-pentynyl, R2 = CH3, partial agonist).
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Receptor Cannabinoide CB2/antagonistas & inhibidores , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Relación Estructura-ActividadRESUMEN
Agglomerates of polar molecules in nonpolar solvents are selectively heated by microwave radiation. The magnitude of the selective heating was directly measured by using the temperature dependence of the intensities of the Stokes and anti-Stokes bands in the Raman spectra of p-nitroanisole (pNA) and mesitylene. Under dynamic heating conditions, a large apparent temperature difference (ΔT) of over 100 °C was observed between the polar pNA solute and the nonpolar mesitylene solvent. This represents the first direct measurement of the selective microwave heating process. The magnitude of the selective microwave heating was affected by the properties of the agglomerated pNA. As the concentration of the pNA increases, the magnitude of the selective heating of the pNA was observed to decrease. This is explained by the tendency of the pNA dipoles to orient in an antiparallel fashion in the aggregates as measured by the Kirkwood g value, which decreased with increasing concentration. This effect reduces the net dipole moment of the agglomerates, which decreases the microwave absorption. After the radiation was terminated, the effective temperature of the dipolar molecules returned slowly to that of the medium. The slow heat transfer was modeled successfully by treating the solutions as a biphasic solvent/solute system. Based on modeling and the fact that the agglomerate can be heated above the boiling temperature of the solvent, an insulating layer of solvent vapor is suggested to form around the heated agglomerate, slowing convective heat transfer out of the agglomerate. This is an effect unique to microwave heating.
RESUMEN
A four-step synthesis of 4,4-dimethyl-1,6-heptadiyne and an associated five-step synthesis of alcyopterosin O, an illudalane sesquiterpene natural product, are described starting from commercially available dimedone. The process features C-C bond-cleaving fragmentation and elimination methods for making alkynes, and it proceeds by way of nonsymmetrical diynes that are themselves valuable synthetic building blocks, as exemplified by the synthesis of alcyopterosin O.
RESUMEN
A high-temperature retro-Diels-Alder reaction is accelerated by microwave (MW) heating to rates higher than expected based on Arrhenius kinetics and the measured temperature of the reaction mixture. Observations are consistent with selective MW heating of the polar reactant relative to other, less polar components of the reaction mixture.
RESUMEN
The fungal metabolite illudinine is prepared in seven steps and ca. 55% overall yield from dimedone using an "open and shut" (ring-opening and ring-closing) strategy. Tandem ring-opening fragmentation and olefination of dimedone establishes alkyne and vinylarene functionality linked by a neopentylene tether. Oxidative cycloisomerization then provides the illudinine framework. The key innovation in this second-generation synthesis of illudinine is the use of the nitrile functional group, rather than an ester, as the functional precursor to the carboxylic acid of illudinine. The small, linear nitrile (C≡N) is associated with improved selectivity, π-conjugation, and reactivity at multiple points in the synthetic sequence relative to the carboxylic acid ester. Preliminary assays indicate that illudinine and several related synthetic analogues are monoamine oxidase inhibitors, which is the first reported indication of biological activity associated with this natural product. Illudinine was found to inhibit monoamine oxidase B (MAO-B) with an IC50 of 18 ± 7.1 µM in preliminary assays.
Asunto(s)
Inhibidores de la Monoaminooxidasa , Monoaminooxidasa , Ciclohexanonas , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/farmacología , Sesquiterpenos , Relación Estructura-ActividadRESUMEN
The protein tyrosine phosphatase (PTP) family of enzymes includes many attractive therapeutic targets, such as those in the leukocyte common antigen-related (LAR) subfamily of receptor PTPs. Synthesis and PTP inhibitory activity of illudalic acid and its methyl ether are described, with a focus on selective inhibition of LAR PTP relative to a small collection of other representative PTPs. The synthesis comprises 16 steps and provides illudalic acid in up to 12% overall yield from neopentylene-fused benzoate 1 (20 steps from commercial materials). Illudalic acid dose-dependently (measured IC50 = 2.1 ± 0.2 µM) and time-dependently inhibits LAR consistent with previous reports of covalent binding. The kinetics of LAR inhibition by illudalic acid are consistent with a two-step mechanism in which the inhibitor and enzyme first interact noncovalently (KI = 130 ± 50 µM), followed by covalent ligation at a rate kinact = 1.3 ± 0.4 min-1. The kinact/KI ratio of 104 corresponds to a t∞1/2 of 0.5 min, as discussed herein. The phenol methyl ether of illudalic acid was found to be less potent in our dose-response assays (measured IC50 = 55 ± 6 µM) but more selective for LAR, with a weaker initial noncovalent interaction and faster covalent ligation of LAR as compared to illudalic acid itself. A truncated analogue of illudalic acid that lacks the neopentylene ring fusion was found to be devoid of significant activity under our assay conditions, in contrast to previous reports. These observations collectively help inform further development of illudalic acid analogues as potent and selective inhibitors of the LAR subfamily of tyrosine phosphatases.
Asunto(s)
Cumarinas/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Cumarinas/química , Relación Dosis-Respuesta a Droga , Humanos , Éteres Metílicos/química , Proteínas Tirosina Fosfatasas/metabolismo , Análisis Espectral/métodosRESUMEN
Microwave (MW) heating is more effective than conventional (CONV) heating for promoting a high-temperature oxidative cycloisomerization reaction that was previously reported as a key step in a total synthesis of the natural product illudinine. The thermal reaction pathway as envisioned is an inverse electron-demand dehydro-Diels-Alder reaction with in situ oxidation to generate a substituted isoquinoline, which itself is unstable to the reaction conditions. Observed reaction yields were higher at a measured bulk temperature of 200 °C than at 180 °C or 220 °C; at 24â hours than at earlier or later time points; and when the reaction solution was heated using MW energy as opposed to CONV heating with a metal heat block. Selective MW heating of polar solute aggregates is postulated to explain these observations.
RESUMEN
Multiple myeloma (MM) cells demonstrate high basal endoplasmic reticulum (ER) stress and are typically exquisitely sensitive to agents such as proteasome inhibitors that activate the unfolded protein response. The flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum oxidoreductin enzyme (Ero1L) catalyzes de-novo disulfide bridge formation of ER resident proteins and contributes to proper protein folding. Here we show that increased Ero1L expression is prognostic of poor outcomes for MM patients relapsing on therapy. We propose that targeting protein folding via inhibition of Ero1L may represent a novel therapeutic strategy for the treatment of MM. In this report we show that treatment of MM cells with EN-460, a known inhibitor of ERO1L, was sufficient to inhibit cell proliferation and induce apoptosis. Furthermore, we show that cell death correlated in part with induction of ER stress. We also show that EN460 inhibited the enzyme activity of Ero1L, with an IC50 of 22.13⯵M, consistent with previous reports. However, EN-460 was also found to inhibit other FAD-containing enzymes including MAO-A (IC50â¯=â¯7.91⯵M), MAO-B (IC50â¯=â¯30.59⯵M) and LSD1 (IC50â¯=â¯4.16⯵M), suggesting overlap in inhibitor activity and the potential need to develop more specific inhibitors to enable pharmacological validation of ERO1L as a target for the treatment of MM. We additionally prepared and characterized azide-tagged derivatives of EN-460 as possible functional probe compounds (e.g., for photo-affinity labeling) for future target-engagement studies and further development of structure-activity relationships.
Asunto(s)
Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Imidazoles/farmacología , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiple/patología , Oxidorreductasas/metabolismo , Pirazolonas/química , Sitios de Unión , Línea Celular Tumoral , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/metabolismo , Humanos , Imidazoles/química , Imidazoles/uso terapéutico , Estimación de Kaplan-Meier , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/genética , Pronóstico , Dominios y Motivos de Interacción de Proteínas , Pirazolonas/farmacología , Relación Estructura-ActividadRESUMEN
This Personal Account describes collaborative investigations into apocryphal microwave effects in organic chemistry. Focused research on microwave-assisted organic synthesis has been fraught with confusion, controversy, and misinformation. Microwave heating is an undoubtedly useful tactic for organic synthesis, but whether or not it can offer strategic advantages remains an open question in the minds of many people. (Ironically, those who do not consider it an open question are split as to whether it has been resolved affirmatively or negatively.) Our research in this area is guided by the hypothesis that microwave heating can alter reaction kinetics in ways distinct from what is observable under conventional heating. Here we provide a succinct record of the origins of our interests, our initial queries and associated controversies, and recent efforts to identify, quantify, and begin to leverage selective microwave heating for strategic advantage in organic synthesis.
RESUMEN
A rhodium-catalyzed cycloisomerization and oxidation of tethered dienynes for the synthesis of indanes is described. An auxiliary fragmentation/olefination method (also described herein) provides novel access to tethered alkyne-dienoate substrates. The reported method circumvents current limitations in and expands the scope of inverse-demand Diels-Alder-type cycloadditions. Traditional discovery substrates involving malonate-, ether-, and sulfonamide-based tethers are problematic in the current methodology, underscoring the unique virtue of neopentylene-tethered substrates for reaction discovery.