RESUMEN
The IL-36 cytokines are known to play various roles in mediating the immune response to infection in a tissue- and pathogen-dependent manner. The present study seeks to investigate the role of IL-36R signaling in C57BL/6 mouse corneas in response to Pseudomonas aeruginosa infection. IL-36α-/-, IL-36γ-/-, and IL-36R-/- mice had significantly more severe keratitis than wild-type mice. At six hours postinfection, IL-36α pretreatment augmented P. aeruginosa-induced expression of IL-1Ra, IL-36γ, LCN2, and S100A8/A9. At one day postinfection, exogenous IL-36α suppressed, whereas IL-36α deficiency promoted, the expression of IL-1ß. At three days postinfection, exogenous IL-36α suppressed Th1 but promoted Th2 immune response. IL-36α stimulated the infiltration of IL-22-expressing immune cells, and IL-22 neutralization resulted in more severe keratitis. IL-36α alone stimulated dendritic cell infiltration in B6 mouse corneas. Taken together, our study suggests that IL-36R signaling plays a protective role in the pathogenesis of P. aeruginosa keratitis by promoting the innate immune defense, Th2, and/or Th22/IL-22 immune responses. Exogenous IL-36α might be a potential therapy for improving the outcome of P. aeruginosa keratitis.
Asunto(s)
Córnea/inmunología , Interleucina-1/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Animales , Interleucina-1/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.
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Aciltransferasas/antagonistas & inhibidores , Antibacterianos/farmacología , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Pirazoles/farmacología , Aciltransferasas/metabolismo , Antibacterianos/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Imidazoles/metabolismo , Pruebas de Sensibilidad Microbiana , Unión Proteica , Pirazoles/metabolismoRESUMEN
Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Pseudomonas aeruginosa Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these fell into two categories: those with alterations in the target MexB (F628L and ΔV177) and those with an alteration in a putative sensor kinase of unknown function, PA1438 (L172P). The alterations in MexB were consistent with reported structural studies of the D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and a >50-fold upregulation of PA1438 and the neighboring response regulator gene, PA1437. We propose that these be renamed mmnR and mmnS for MexMN regulator and MexMN sensor, respectively. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several ß-lactams, monobactams, and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem and biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds, was downregulated, suggesting that this channel is also part of the MmnSR regulon. Transcriptome sequencing (RNA-seq) of cells encoding MmnSL172P revealed, among other things, an interrelationship between the regulation of mexMN and genes involved in heavy metal resistance.
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Piperidinas/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , beta-Lactamas/farmacología , Imipenem/farmacología , Pruebas de Sensibilidad Microbiana , Monobactamas/farmacología , Pseudomonas aeruginosa/genética , Tazobactam/farmacología , Tienamicinas/farmacología , Transcriptoma/genéticaRESUMEN
Upregulated expression of efflux pumps, lpxC target mutations, LpxC protein overexpression, and mutations in fabG were previously shown to mediate single-step resistance to the LpxC inhibitor CHIR-090 in P. aeruginosa Single-step selection experiments using three recently described LpxC inhibitors (compounds 2, 3, and 4) and mutant characterization showed that these mechanisms affect susceptibility to additional novel LpxC inhibitors. Serial passaging of P. aeruginosa wild-type and efflux pump-defective strains using the LpxC inhibitor CHIR-090 or compound 1 generated substantial shifts in susceptibility and underscored the interplay of efflux and nonefflux mechanisms. Whole-genome sequencing of CHIR-090 passage mutants identified efflux pump overexpression, fabG mutations, and novel mutations in fabF1 and in PA4465 as determinants of reduced susceptibility. Two new lpxC mutations, encoding A214V and G208S, that reduce susceptibility to certain LpxC inhibitors were identified in these studies, and we show that these and other target mutations differentially affect different LpxC inhibitor scaffolds. Lastly, the combination of target alteration (LpxCA214V) and upregulated expression of LpxC was shown to be tolerated in P. aeruginosa and could mediate significant decreases in susceptibility.
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Pseudomonas aeruginosa/efectos de los fármacos , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Pruebas de Sensibilidad Microbiana , Mutación/genética , Pseudomonas aeruginosa/genética , Secuenciación Completa del GenomaRESUMEN
A series of structure based drug design hypotheses and focused screening efforts drove improvements in the potency and lipophilic efficiency of tetrahydro-pyrazolopyridine based ERK2 inhibitors. Elaboration of a fragment chemical lead established a new lipophilic aryl-Tyr interaction resulting in a substantial potency improvement. Subsequent cleavage of the lipophilic moiety led to reconfiguration of the ligand bound binding cleft. The reconfiguration established a polar contact between a newly liberated N-H and a vicinal Asp, resulting in further improvements in lipophilic efficiency and in vitro clearance.
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Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Piridinas/química , Relación Estructura-Actividad , Adenosina Trifosfato/metabolismo , Animales , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ligandos , Proteína Quinasa 1 Activada por Mitógenos/química , Modelos Moleculares , Conformación Proteica , RatasRESUMEN
A series of structure based drug design hypotheses and focused screening efforts led to the identification of tetrahydropyrrolo-diazepenones with striking potency against ERK2 kinase. The role of fluorination in mitigating microsomal clearance was systematically explored. Ultimately, it was found that fluorination of a cyclopentanol substructure provided significant improvement in both potency and human metabolic stability.
Asunto(s)
Azepinas/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Azepinas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 2 Anillos/química , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Relación Estructura-ActividadRESUMEN
PURPOSE: This case report aims to describe a new method for increasing intraocular pressure (IOP) in patients with acute hypotony resulting from uveitis flare-ups and preexisting glaucoma drainage devices. The temporary glaucoma tube plug method described is effective and safe. METHODS: This case report presents a 47-year-old female patient with a history of chronic panuveitis and secondary glaucoma, who had 2 previously implanted Ahmed glaucoma valves. The patient developed panuveitis flare-up and persistent hypotony. A novel method of ab interno plugging of the glaucoma tubes using 2-0 prolene suture plugs was performed. Following treatment, the IOP increased successfully and remained within the normal range. CONCLUSION: The temporary ab interno glaucoma tube plug method effectively increased IOP in a patient with 2 preimplanted Ahmed glaucoma valves with persistent low IOP due to uveitis.
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Implantes de Drenaje de Glaucoma , Presión Intraocular , Hipotensión Ocular , Humanos , Femenino , Persona de Mediana Edad , Presión Intraocular/fisiología , Hipotensión Ocular/fisiopatología , Hipotensión Ocular/etiología , Hipotensión Ocular/diagnóstico , Hipotensión Ocular/cirugía , Glaucoma/cirugía , Glaucoma/fisiopatología , Glaucoma/complicaciones , Implantación de Prótesis , Tonometría Ocular , Agudeza Visual/fisiología , Técnicas de SuturaRESUMEN
A 67-year-old woman with history of mild suture hyper-sensitivity presented with localized scleritis after strabismus surgery. After infection was ruled out, the patient was prescribed topical and systemic non-steroidal anti-inflammatory drugs and systemic steroids, which led to full clinical resolution. [J Pediatr Ophthalmol Strabismus. 2024;61(1):e4-e6.].
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Escleritis , Estrabismo , Femenino , Humanos , Anciano , Escleritis/diagnóstico , Escleritis/tratamiento farmacológico , Escleritis/etiología , Complicaciones Posoperatorias , Estrabismo/cirugía , Músculos Oculomotores/cirugía , Suturas/efectos adversosRESUMEN
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, with several underlying pathophysiological mechanisms, some of which are still uncertain. The cornea is an avascular tissue and sensitive to hyperglycemia, resulting in several diabetic corneal complications including delayed epithelial wound healing, recurrent erosions, neuropathy, loss of sensitivity, and tear film changes. The manifestation of DPN in the cornea is referred to as diabetic neurotrophic keratopathy (DNK). Recent studies have revealed that disturbed epithelial-neural-immune cell interactions are a major cause of DNK. The epithelium is supplied by a dense network of sensory nerve endings and dendritic cell processes, and it secretes growth/neurotrophic factors and cytokines to nourish these neighboring cells. In turn, sensory nerve endings release neuropeptides to suppress inflammation and promote epithelial wound healing, while resident immune cells provide neurotrophic and growth factors to support neuronal and epithelial cells, respectively. Diabetes greatly perturbs these interdependencies, resulting in suppressed epithelial proliferation, sensory neuropathy, and a decreased density of dendritic cells. Clinically, this results in a markedly delayed wound healing and impaired sensory nerve regeneration in response to insult and injury. Current treatments for DPN and DNK largely focus on managing the severe complications of the disease. Cell-based therapies hold promise for providing more effective treatment for diabetic keratopathy and corneal ulcers.
Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus Experimental , Epitelio Corneal , Animales , Humanos , Córnea/metabolismo , Complicaciones de la Diabetes/complicaciones , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Inflamación , Cicatrización de Heridas/fisiologíaRESUMEN
Objective Abrupt changes in ophthalmology education caused by the COVID-19 pandemic have resulted in novel online curriculum development. The aims of this study were to identify (1) the scope of online curricula implemented both prior to and during the COVID-19 pandemic; (2) perception of educators on these online modalities; and (3) early lessons from online implementation that may guide future curricular planning. Methods Implementation of online curricula was evaluated by using a national online survey of Ophthalmology Directors of Medical Student Education (DMSE) via Qualtrics software. Participants Medical Student Educators of the Association of University Professors of Ophthalmology (AUPO) were surveyed. Results Fifty responses were collected, representing a 64.9% response rate. Prior to the COVID-19 pandemic, 44% of institutions had no online components in their courses, but 78.3% of institutions reported increasing online components in response to the pandemic. Required courses were significantly associated both with having implemented online components before the pandemic and implementing online-only versions of these courses in response to the pandemic. The three most popular modalities used for online teaching were lectures, interactive cases, and problem-based learning, with a median satisfaction of 4.0, 4.32, and 4.35, (out of five) respectively. The least popular modalities used were online teaching of physical exam skills and telemedicine, both with a median satisfaction of 2.5. Median overall educator satisfaction with online teaching was four (out of five). The most common weakness related to online teaching was the lack of effective physical exam skills training. Conclusion Our data demonstrate that most institutions successfully shifted their ophthalmology curriculum to a virtual and online version in response to the COVID-19 pandemic. DMSEs adapted quickly, transitioning in-person clinical courses, and extracurricular activities to online formats. Overall, educator satisfaction with online curricula was high. Integration of online curricula provides the opportunity to enrich institutional curriculums and overcome limitations imposed by decreasing curriculum time. This study reveals an early window into the utilization, strengths, and weaknesses of online ophthalmology education, which can serve as a guiding point to enhance ophthalmology curriculum development.
RESUMEN
Diabetic keratopathy, a sight-threatening corneal disease, comprises several symptomatic conditions including delayed epithelial wound healing, recurrent erosions, and sensory nerve (SN) neuropathy. We investigated the role of neuropeptides in mediating corneal wound healing, including epithelial wound closure and SN regeneration. Denervation by resiniferatoxin severely impaired corneal wound healing and markedly upregulated proinflammatory gene expression. Exogenous neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) partially reversed resiniferatoxin's effects, with VIP specifically inducing interleukin-10 expression. Hence, we focused on VIP and observed that wounding induced VIP and VIP type 1 receptor (VIPR1) expression in normal (NL) corneas, but not corneas from mice with diabetes mellitus (DM). Targeting VIPR1 in NL corneas attenuated corneal wound healing, dampened wound-induced expression of neurotrophic factors, and exacerbated inflammatory responses, while exogenous VIP had the opposite effects in DM corneas. Remarkably, wounding and diabetes also affected the expression of Sonic Hedgehog (Shh) in a VIP-dependent manner. Downregulating Shh expression in NL corneas decreased while exogenous Shh in DM corneas increased the rates of corneal wound healing. Furthermore, inhibition of Shh signaling dampened VIP-promoted corneal wound healing. We conclude that VIP regulates epithelial wound healing, inflammatory response, and nerve regeneration in the corneas in an Shh-dependent manner, suggesting a therapeutic potential for these molecules in treating diabetic keratopathy.
Asunto(s)
Enfermedades de la Córnea/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Epitelio Corneal/fisiopatología , Proteínas Hedgehog/fisiología , Regeneración Nerviosa/fisiología , Péptido Intestinal Vasoactivo/fisiología , Cicatrización de Heridas/fisiología , Animales , Citocinas/análisis , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Femenino , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/fisiología , Transducción de Señal/fisiologíaRESUMEN
Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only a few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with either of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome- and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications.
Asunto(s)
Complejos de Coordinación/química , Proteínas Nucleares/metabolismo , Proteolisis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complejos de Coordinación/metabolismo , Cisteína/química , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Dominios Proteicos , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-Actividad , Ubiquitinación , Zinc/químicaAsunto(s)
Neuralgia , Nocicepción , Ratones , Animales , Ratones Endogámicos C57BL , Hiperalgesia , CaraRESUMEN
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.
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Amidohidrolasas/antagonistas & inhibidores , Isoxazoles/química , Isoxazoles/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación MolecularRESUMEN
Selectivity is a central aspect of lead optimization in the drug discovery process. Medicinal chemists often try to decrease molecular flexibility to improve selectivity, given the common belief that the two are interdependent. To investigate the relationship between polypharmacology and conformational flexibility, we mined the Protein Data Bank and constructed a dataset of pharmaceutically relevant ligands that crystallized in more than one protein target while binding to each co-crystallized receptor with similar in vitro affinities. After analyzing the molecular conformations of these 100 ligands, we found that 59 ligands bound to different protein targets without significantly changing conformation, suggesting that there is no distinct correlation between conformational flexibility and polypharmacology within our dataset. Ligands crystallized in similar proteins and highly ligand-efficient compounds with five or fewer rotatable bonds were less likely to adjust conformation when binding.
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Proteínas/metabolismo , Benzamidas/química , Benzamidas/metabolismo , Bases de Datos de Proteínas , Diseño de Fármacos , Proteasa del VIH/química , Proteasa del VIH/metabolismo , Mesilato de Imatinib , Indinavir/química , Indinavir/metabolismo , Indoles/química , Indoles/metabolismo , Cinética , Ligandos , Piperazinas/química , Piperazinas/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas/química , Proteínas Proto-Oncogénicas c-kit/química , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Ácidos Sulfónicos/química , Ácidos Sulfónicos/metabolismoRESUMEN
The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.
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Adenosina Trifosfato/farmacología , Neoplasias/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridazinas/farmacología , Triazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Catálisis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cinética , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridazinas/química , Triazoles/química , Carga Tumoral/efectos de los fármacosRESUMEN
Recent reports of inward torquoselectivities in thermal electrocyclic ring-opening reactions of 3-silylcyclobutenes have revealed that saturated silyl substituents, just like the extensively studied pi-acceptors, can exert contrasteric effects. The origins of torquoselectivity for substituents lacking pi orbitals have been explained using B3LYP density functional calculations. Orbital interactions involving the substituent vacant orbitals and the occupied orbitals associated with the breaking bonds are found to control these contrasteric torquoselectivities, with minor contributions from electrostatic effects. Reaction energetics and transition states for electrocyclic ring-opening reactions of 3-silyl, fluorosilyl, difluorosilyl, trifluorosilyl, methylsilyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ammonio, phosphonio, formyl, and borohydrido cyclobutenes are reported to complement previous extensive studies of unsaturated substituents. Inward stereoselectivities are predicted for various silyl and phosphonium substituents, along with potent pi-acceptors studied earlier. Cope and Diels-Alder reactions involving silyl substituents are also computed.
RESUMEN
Theoretical studies of stereoselectivity have been carried out with B3LYP and MP2 calculations. The high endo selectivity of hetero-Diels-Alder reactions of ortho-xylylenes with acetaldehydes is shown to result from attractive CH-pi interactions between alkyl groups of the aldehyde and the aromatic ring in the transition states of the reaction. For the hetero-Diels-Alder reactions of ortho-xylylenes with benzaldehyde, the stereoselectivity is shown to be mainly governed by the attractive pi-pi interactions between the phenyl rings of the benzaldehyde and the ortho-xylylene. MP2 calculations are necessary to reproduce the stabilizing dispersion interactions.
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Aldehídos/química , Xilenos/química , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
Density functional theory has been applied at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level to examine the energetics of alpha,beta- versus beta,gamma-unsaturation for some common organic functional groups. Specifically, the relative stabilities of allyl-X (H2C=CHCH2X) and 1-propenyl-X (H3CCH=CHX) isomers have been computed for X = methyl, vinyl, phenyl, formyl, acetyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, sulfamoyl, and methoxysulfonyl, and the results are compared to available experimental data. The intrinsic preference of 3 kcal/mol for the 1-propenyl isomer when X = CH3 is exceeded by 2-4 kcal/mol for first-row conjugating groups, but it is not met for the sulfur-containing groups. In particular, alpha,beta-unsaturation is favored by less than 1 kcal/mol for the sulfone and sulfonamide analogues, while it is preferred by 8 kcal/mol for the vinyl-substituted case. Detailed structural results and torsional energy profiles are also reported.
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Alquenos/química , Modelos Moleculares , Termodinámica , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
The allowed conrotatory cyclobutene ring-opening has a distinctly nonplanar carbon skeleton. Classic experiments by Brauman and Archie, and by Freedman et al., placed the allowed/forbidden gap at greater than 15 kcal/mol. Wolfgang Roth proposed that a system forced to planarity might have a smaller preference for the conrotatory mode than unconstrained systems. Such systems have now been studied theoretically and experimentally, and results that confirm Roth's postulate are presented here. The experiments were performed in Bochum, and the calculations were carried out in Osaka and Los Angeles. As the cyclobutene ring-opening transition structure approaches planarity, the energy gap between allowed conrotatory and the forbidden disrotatory pathways decreases. For the ring-opening of a cyclobutene fused to norbornene, the energy gap between the forbidden and the allowed transition state is only 4.1 kcal/mol by CASSCF and 8.0 kcal/mol by CAS-MP2 as compared to 13.4 and 19.2 kcal/mol, respectively, for the parent cyclobutene. Experimental studies of 3,4-dimethylcyclobutenes fused to various ring systems are reported, and a trend is found toward a reduced allowed/forbidden gap as the planarity of the cyclobutene is enforced.