RESUMEN

The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in a125I-CXCL12 competition binding assay, exhibiting IC50 in the low-nanomolar range. Furthermore, both candidates displayed high selectivity towards CXCR4 with respect to the cognate receptor CXCR7, ability to block CXCL12-dependent cancer cell migration, and receptor internalization, albeit at a higher concentration compared to 3. Molecular modeling studies on 13 and 17 produced a theoretical model that may serve as a guide for future modifications, aiding in the development of analogs with improved affinity. Finally, the study provides valuable insights into developing therapeutic agents targeting CXCR4-mediated processes, demonstrating the adaptability of our lead peptide 3 to alternative cyclization approaches and offering prospects for comprehensive investigations into the receptor region's interaction with its C-terminal region.

Asunto(s)

Disulfuros , Péptidos , Receptores CXCR4 , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Humanos , Sitios de Unión/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Disulfuros/química , Disulfuros/farmacología , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Lactamas/química , Lactamas/farmacología , Lactamas/síntesis química , Movimiento Celular/efectos de los fármacos , Modelos Moleculares , Línea Celular Tumoral

RESUMEN

Since influenza virus RNA polymerase subunit PAN is a dinuclear Mn2+ dependent endonuclease, metal-binding pharmacophores (MBPs) with Mn2+ coordination has been elucidated as a promising strategy to develop PAN inhibitors for influenza treatment. However, few attentions have been paid to the relationship between the optimal arrangement of the donor atoms in MBPs and anti-influenza A virus (IAV) efficacy. Given that, the privileged hydroxypyridinones fusing a seven-membered lactam ring with diverse side chains, chiral centers or cyclic systems were designed and synthesized. A structure-activity relationship study resulted in a hit compound 16l (IC50 = 2.868 ± 0.063 µM against IAV polymerase), the seven-membered lactam ring of which was fused a pyrrolidine ring. Further optimization of the hydrophobic binding groups on 16l afforded a lead compound (R, S)-16s, which exhibited a 64-fold more potent inhibitory activity (IC50 = 0.045 ± 0.002 µM) toward IAV polymerase. Moreover, (R, S)-16s demonstrated a potent anti-IAV efficacy (EC50 = 0.134 ± 0.093 µM) and weak cytotoxicity (CC50 = 15.35 µM), indicating the high selectivity of (R, S)-16s. Although the lead compound (R, S)-16s exhibited a little weaker activity than baloxavir, these findings illustrated the utility of a metal coordination-based strategy in generating novel MBPs with potent anti-influenza activity.

Asunto(s)

Antivirales , Diseño de Fármacos , Endonucleasas , Virus de la Influenza A , Lactamas , Piridonas , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Lactamas/química , Lactamas/farmacología , Lactamas/síntesis química , Relación Estructura-Actividad , Endonucleasas/antagonistas & inhibidores , Endonucleasas/metabolismo , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Virus de la Influenza A/efectos de los fármacos , Estructura Molecular , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Perros , Células de Riñón Canino Madin Darby , Animales

RESUMEN

An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100-250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).

Asunto(s)

Lactamas , Microondas , Lactamas/química , Lactamas/síntesis química , Lactamas/farmacología , Ciclización , Humanos , Catálisis , Ratones , Animales , Línea Celular Tumoral , Acetamidas/química , Acetamidas/síntesis química , Acetamidas/farmacología , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química

RESUMEN

Lactam cross-links have been employed to stabilize the helical secondary structure and enhance the activity and physiological stability of antimicrobial peptides; however, stabilization of ß-sheets via lactamization has not been observed. In the present study, lactams between the side chains of C- and N-terminal residues have been used to stabilize the ß-sheet conformation in a short ten-residue analogue of chicken angiogenin-4. Designed using a combination of molecular dynamics simulations and Markov state models, the lactam cross-linked peptides are shown to adopt stabilized ß-sheet conformations consistent with simulated structures. Replacement of the peptide side-chain Cys-Cys disulfide by a lactam cross-link enhanced the broad-spectrum antibacterial activity compared to the parent peptide and exhibited greater propensity to induce proinflammatory activity in macrophages. The combination of molecular simulations and conformational and biological analyses of the synthetic peptides provides a useful paradigm for the rational design of therapeutically active peptides with constrained ß-sheet structures.

Asunto(s)

Antibacterianos , Simulación de Dinámica Molecular , Animales , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Péptidos Antimicrobianos/química , Péptidos Antimicrobianos/farmacología , Péptidos Antimicrobianos/síntesis química , Estructura Secundaria de Proteína , Pruebas de Sensibilidad Microbiana , Ratones , Lactamas/química , Lactamas/farmacología , Lactamas/síntesis química , Pollos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/síntesis química , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Reactivos de Enlaces Cruzados/química

RESUMEN

Asp-based lactam cyclic peptides are considered promising drug candidates. However, using Fmoc solid-phase peptide synthesis (Fmoc-SPPS) for these peptides also causes aspartimide formation, resulting in low yields or even failure to obtain the target peptides. Here, we developed a diaminodiacid containing an amide bond as a ß-carboxyl-protecting group for Asp to avoid aspartimide formation. The practicality of this diaminodiacid has been illustrated by the synthesis of lactam cyclic peptide cyclo[Lys9,Asp13] KIIIA7-14 and 1Y.

Asunto(s)

Amidas , Ácido Aspártico , Lactamas , Péptidos Cíclicos , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Lactamas/química , Lactamas/síntesis química , Amidas/química , Amidas/síntesis química , Ácido Aspártico/química , Ácido Aspártico/síntesis química , Ácido Aspártico/análogos & derivados , Técnicas de Síntesis en Fase Sólida , Estructura Molecular

RESUMEN

The most relevant lipase-catalyzed strategies for the synthesis of pharmaceutically important cyclic and acyclic α-, ß- and γ-amino carboxylic acid enantiomers through hydrolysis of the corresponding amino carboxylic esters and lactams, over the last decade are overviewed. A brief Introduction part deals with the importance and synthesis of enantiomeric amino acids, and formulates the objectives of the actual work. The strategies are presented in the Main Text, in chronological order, classified as kinetic, dynamic kinetic and sequential kinetic resolution. Mechanistic information of the enzymatic transformations is also available at the end of this overview. The pharmacological importance of the enantiomeric amino acids is given next to their synthesis, in the Main Text, and it is also illustrated in the Conclusions and Outlook sections.

Asunto(s)

Aminoácidos , Ácidos Carboxílicos , Ésteres , Lactamas , Aminas , Aminoácidos/síntesis química , Aminoácidos/química , Aminoácidos/farmacocinética , Aminoácidos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacología , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacocinética , Ésteres/farmacología , Hidrólisis , Cinética , Lactamas/síntesis química , Lactamas/química , Lactamas/farmacocinética , Lactamas/farmacología , Lipasa/metabolismo , Estereoisomerismo , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química

RESUMEN

A study on the reactivity of 3-amino α,ß-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,ß-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.

Asunto(s)

Antineoplásicos , Lactamas , beta-Lactamas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Reacción de Cicloadición , Iminas , Lactamas/síntesis química , Lactamas/química , Estereoisomerismo , beta-Lactamas/química

RESUMEN

The challenging synthesis of a fused C3-symmetric trilactam (1) was executed in racemic and enantiomerically pure form. The rigidity, symmetry and high density of hydrogen bonding motifs make 1 an attractive candidate for self-assembly study, which revealed different hydrogen bond patterns in the crystals of rac-1-d3 and (+)-(SSS)-1.

Asunto(s)

Lactamas , Enlace de Hidrógeno , Lactamas/síntesis química , Estereoisomerismo

RESUMEN

Nature forms S-S bonds by oxidizing two sulfhydryl groups, and no enzyme installing an intact hydropersulfide (-SSH) group into a natural product has been identified to date. The leinamycin (LNM) family of natural products features intact S-S bonds, and previously we reported an SH domain (LnmJ-SH) within the LNM hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line as a cysteine lyase that plays a role in sulfur incorporation. Here we report the characterization of an S-adenosyl methionine (SAM)-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin (GNM) biosynthesis, discovery of hydropersulfides as the nascent products of the GNM and LNM hybrid NRPS-PKS assembly lines, and revelation of three SH domains (GnmT-SH, LnmJ-SH, and WsmR-SH) within the GNM, LNM, and weishanmycin (WSM) hybrid NRPS-PKS assembly lines as thiocysteine lyases. Based on these findings, we propose a biosynthetic model for the LNM family of natural products, featuring thiocysteine lyases as PKS domains that directly install a -SSH group into the GNM, LNM, or WSM polyketide scaffold. Genome mining reveals that SH domains are widespread in Nature, extending beyond the LNM family of natural products. The SH domains could also be leveraged as biocatalysts to install an -SSH group into other biologically relevant scaffolds.

Asunto(s)

Productos Biológicos/metabolismo , Liasas de Carbono-Azufre/metabolismo , Cisteína/análogos & derivados , Metiltransferasas/metabolismo , Sintasas Poliquetidas/metabolismo , Sulfuros/metabolismo , Animales , Productos Biológicos/química , Cisteína/metabolismo , Cistina/química , Cistina/metabolismo , Humanos , Lactamas/síntesis química , Lactamas/química , Lactamas/metabolismo , Macrólidos/síntesis química , Macrólidos/química , Macrólidos/metabolismo , Modelos Químicos , Estructura Molecular , Péptido Sintasas/metabolismo , Streptomyces/genética , Streptomyces/metabolismo , Especificidad por Sustrato , Sulfuros/química , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/metabolismo , Tionas/síntesis química , Tionas/química , Tionas/metabolismo , Dominios Homologos src

RESUMEN

As new environmentally friendly and effective antifungal agents are deeply needed, efficient ecofriendly strategies were designed to access two series of compounds inspired from natural γ-lactams. Designed compounds were fully characterized and evaluated as antifungal candidates against Zymoseptoria tritici, the main pathogen on wheat crops. The targeted derivatives were prepared from natural resources using green solvents, simple procedures, and limited purification steps. These bio-inspired compounds revealed as good candidates for further development of efficient crop protection products. Indeed, the HIT compounds exhibited IC50 around 1 µg/mL and were more active than the references tebuconazole and bixafen towards some multidrug-resistant strains. Two dozen of derivatives have been obtained for each series and allowed to establish early structure-activity relationships useful for the development of next generation of γ-lactam derivatives with improved efficacy.

Asunto(s)

Antifúngicos/farmacología , Ascomicetos/efectos de los fármacos , Lactamas/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Lactamas/síntesis química , Lactamas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular

RESUMEN

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 µg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and ß-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone.

Asunto(s)

Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacos , Lactamas/farmacología , Sideróforos/farmacología , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Lactamas/síntesis química , Lactamas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pseudomonas aeruginosa/efectos de los fármacos , Sideróforos/síntesis química , Sideróforos/química , Relación Estructura-Actividad

RESUMEN

Piperidine and δ-Lactam chemicals have wide application, which are currently produced from fossil resource in industry. Production of this kind of chemicals from lignocellulosic biomass is of great importance, but is challenging and the reported routes give low yield. Herein, we demonstrate the strategy to synthesize 2-methyl piperidine (MP) and 6-methylpiperidin-2-one (MPO) from biomass-derived triacetic acid lactone (TAL) that is produced microbially from glucose. In this route, TAL was firstly converted into 4-hydroxy-6-methylpyridin-2(1H)-one (HMPO) through facile aminolysis, subsequently HMPO was selectively transformed into MP or MPO over Ru catalysts supported on beta zeolite (Ru/BEA-X, X is the molar ratio of Si to Al) via the tandem reaction. It was found that the yield of MP could reach 76.5 % over Ru/BEA-60 in t-BuOH, and the yield of MPO could be 78.5 % in dioxane. Systematic studies reveal that the excellent catalytic performance of Ru/BEA-60 was closely correlated with the cooperative effects between active metal and acidic zeolite with large pore geometries. The related reaction pathway was studied on the basis of control experiments.

Asunto(s)

Lactamas/síntesis química , Piperidinas/síntesis química , Pironas/química , Biomasa , Lactamas/química , Estructura Molecular , Piperidinas/química

RESUMEN

(-)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17R) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17R) desTHPdactylolide that was anticipated to be metabolically more stable than (17R) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide.

Asunto(s)

Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Lactamas/farmacología , Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/síntesis química , Lactonas/química

RESUMEN

α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

Asunto(s)

Cisteamina/química , Lactamas/farmacología , Sesquiterpenos de Guayano/farmacología , Células A549 , Animales , Chlorocebus aethiops , Células HEK293 , Humanos , Lactamas/síntesis química , Lactamas/toxicidad , FN-kappa B/metabolismo , Prueba de Estudio Conceptual , Sesquiterpenos de Guayano/síntesis química , Sesquiterpenos de Guayano/toxicidad , Transducción de Señal/efectos de los fármacos , Células Vero

RESUMEN

In this study, the melanoma targeting property of 67Ga-NODAGA-GGNle-CycMSHhex {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH2} was determined on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NODAGA as a radiometal chelator for facile room temperature radiolabeling of NODAGA-GGNle-CycMSHhex. The IC50 value of NODAGA-GGNle-CycMSHhex was 0.87 ± 0.12 nM on B16/F10 melanoma cells. 67Ga-NODAGA-GGNle-CycMSHhex was readily prepared at room temperature with greater than 98% radiolabeling yield and displayed MC1R-specific binding on B16/F10 melanoma cells. The B16/F10 melanoma uptake of 67Ga-NODAGA-GGNle-CycMSHhex was 10.31 ± 0.78, 14.96 ± 1.34, 13.7 ± 3.33 and 10.4 ± 2.2% ID/g at 0.5, 2, 4 and 24 h post-injection, respectively. Approximately 85% of the injected dose was cleared out the body via urinary system at 2 h post-injection. 67Ga-NODAGA-GGNle-CycMSHhex showed high tumor/blood, tumor/muscle and tumor/skin uptake ratios after 2 h post-injection. Overall, 67Ga-NODAGA-GGNle-CycMSHhex could be easily prepared at room temperature and exhibited favorable melanoma targeting property, suggesting the potential use of NODAGA as a radiometal chelator for facile room temperature radiolabeling of α-MSH peptides.

Asunto(s)

Acetatos/química , Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo/química , Lactamas/química , Melanoma Experimental/diagnóstico , Péptidos Cíclicos/química , alfa-MSH/química , Acetatos/síntesis química , Acetatos/farmacocinética , Animales , Técnicas de Química Sintética , Radioisótopos de Galio/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Lactamas/síntesis química , Lactamas/farmacocinética , Ratones , Ratones Endogámicos C57BL , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacocinética , Distribución Tisular , alfa-MSH/síntesis química , alfa-MSH/farmacocinética

RESUMEN

A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H1, serotonin receptors 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, serotonin transporter (SERT) and dopamine receptor D2 was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H1 receptor in sub-micromolar concentrations.

Asunto(s)

Antidepresivos Tricíclicos/farmacología , Lactamas/farmacología , Receptores Dopaminérgicos/metabolismo , Receptores Histamínicos/metabolismo , Receptores de Serotonina/metabolismo , Antidepresivos Tricíclicos/síntesis química , Antidepresivos Tricíclicos/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/síntesis química , Lactamas/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

We report here a Ru-catalyzed enantioselective synthesis of biaryl-bridged NH lactams through asymmetric reductive amination and a spontaneous ring-closing cascade from keto esters and NH4OAc with H2 as reductant. The reaction features broad substrate generality and high enantioselectivities (up to >99% ee). To showcase the practical utility, a highly enantioselective synthesis of 5-ethylindolobenzazepinone C, a promising antimitotic agent, has been rapidly completed. Furthermore, the amide group in the products enables versatile elaborations through directed C-H functionalization.

Asunto(s)

Amidas/química , Lactamas/síntesis química , Aminación , Catálisis , Lactamas/química , Estructura Molecular

RESUMEN

N-Methyl-d-aspartate receptors (NMDARs) are crucial for the normal function of the central nervous system (CNS), and fundamental in memory and learning-related processes. The overactivation of these receptors is associated with numerous neurodegenerative and psychiatric disorders. Therefore, NMDAR is considered a relevant therapeutic target for many CNS disorders. Herein, we report the synthesis and pharmacological evaluation of a new scaffold with antagonistic activity for NMDAR. Specifically, a chemical library of eighteen 1-aminoindan-2-ol tetracyclic lactams was synthesized and screened as NMDAR antagonists. The compounds were obtained by chiral pool synthesis using enantiomerically pure 1-aminoindan-2-ols as chiral inductors, and their stereochemistry was proven by X-ray crystallographic analysis of two target compounds. Most compounds reveal NMDAR antagonism, and eleven compounds display IC50 values in a Ca2+ entry-sensitive fluo-4 assay in the same order of magnitude of memantine, a clinically approved NMDAR antagonist. Docking studies suggest that the novel compounds can act as NMDAR channel blockers since there is a compatible conformation with MK-801 co-crystallized with NMDAR channel. In addition, we show that the tetracyclic 1-aminoindan-2-ol derivatives are brain permeable and non-toxic, and we identify promising hits for further optimization as modulators of the NMDAR function.

Asunto(s)

Lactamas/farmacología , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Barrera Hematoencefálica/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células HEK293 , Células Hep G2 , Humanos , Lactamas/síntesis química , Lactamas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Enfermedades del Sistema Nervioso/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-Actividad

RESUMEN

Amide functional groups are prominent in a broad range of organic compounds with diverse beneficial applications. In this work, we report the synthesis of these functional groups via an iron(iii) chloride-catalyzed direct amidation of esters. The reactions are conducted under solvent-free conditions and found to be compatible with a range of amine and ester substrates generating the desired amides in short reaction times and good to excellent yields at a catalyst loading of 15 mol%.

Asunto(s)

Amidas/química , Cloruros/química , Ésteres/química , Compuestos Férricos/química , Solventes/química , Antituberculosos/química , Antituberculosos/farmacología , Catálisis , Lactamas/síntesis química , Lactamas/química , Pirimidinas/química , Pirimidinas/farmacología

RESUMEN

We report a RhIII -catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ-lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cpt ligand on the RhIII catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C-H activation depends on the choice of Cp ligand on the RhIII catalyst. The irreversible C-H activation is observed and becomes turnover-limiting with [Cpt RhCl2 ]2 as catalyst.

Asunto(s)

Acrilamidas/química , Alquenos/química , Lactamas/síntesis química , Compuestos Organometálicos/química , Rodio/química , Catálisis , Lactamas/química , Estructura Molecular