RESUMEN
Neuropeptides belonging to the adipokinetic hormone (AKH) family elicit metabolic effects as their main function in insects, by mobilizing trehalose, diacylgycerol, or proline, which are released from the fat body into the hemolymph as energy sources for muscle contraction required for energy-intensive processes, such as locomotion. One of the AKHs produced in locusts is a decapeptide, Locmi-AKH-I (pELNFTPNWGT-NH2). A head-to-tail cyclic, octapeptide analog of Locmi-AKH-I, cycloAKH (cyclo[LNFTPNWG]) was synthesized to severely restrict the conformational freedom of the AKH structure. In vitro, cycloAKH selectively retains full efficacy on a pest insect (desert locust) AKH receptor, while showing little or no activation of the AKH receptor of a beneficial insect (honeybee). Molecular dynamic analysis incorporating NMR data indicate that cycloAKH preferentially adopts a type II ß-turn under micelle conditions, whereas its linear counterpart and natural AKH adopts a type VI ß-turn under similar conditions. CycloAKH, linear LNFTPNWG-NH2, and Locmi-AKH-I feature the same binding site during docking simulations with the desert locust AKH receptor (Schgr-AKHR), but differ in the details of the ligand/receptor interactions. However, cycloAKH failed to enter the binding pocket of the honeybee receptor 3D model during docking simulations. Since the locust AKH receptor has a greater tolerance than the honeybee receptor for the cyclic conformational constraint in vitro receptor assays, it could suggest a greater tolerance for a shift in the direction of the type II ß turn exhibited by cycloAKH from the type VI ß turn of the linear octapeptide and the native locust decapeptide AKH. Selectivity in biostable mimetic analogs could potentially be enhanced by incorporating conformational constraints that emphasize this shift. Biostable mimetic analogs of AKH offer the potential of selectively disrupting AKH-regulated processes, leading to novel, environmentally benign control strategies for pest insect populations.
Asunto(s)
Abejas , Saltamontes , Hormonas de Insectos/agonistas , Oligopéptidos/agonistas , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptores de Neuropéptido/química , Animales , Abejas/metabolismo , Sitios de Unión , Saltamontes/metabolismo , Control de Insectos , Hormonas de Insectos/síntesis química , Hormonas de Insectos/metabolismo , Proteínas de Insectos/química , Proteínas de Insectos/metabolismo , Imagen por Resonancia Magnética/métodos , Conformación Molecular , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neuropéptidos/agonistas , Neuropéptidos/síntesis química , Neuropéptidos/metabolismo , Oligopéptidos/síntesis química , Oligopéptidos/metabolismo , Ácido Pirrolidona Carboxílico/agonistas , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/metabolismo , Receptores de Neuropéptido/metabolismoRESUMEN
In recent years immunomodulators have gained a strong interest and represent nowadays an active expanding area of research for the control of microbial diseases and for their therapeutic potential in preventing, treating and reducing the morbidity and mortality of different diseases. Pidotimod (3-L-pyroglutamyl-L-thiaziolidine-4carboxylic acid, PDT) is a synthetic dipeptide, which possesses immunomodulatory properties and exerts a well-defined pharmacological activity against infections, but its real mechanism of action is still undefined. Here, we show that PDT is capable of activating tyrosine phosphorylation-based cell signaling in human primary monocytes and triggering rapid adhesion and chemotaxis. PDT-induced monocyte migration requires the activation of the PI3K/Akt signaling pathway and chemokine receptor CXCR3. Indeed, a mAb to CXCR3 and a specific receptor inhibitor suppressed significantly PDT-dependent chemotaxis, and CXCR3-silenced primary monocytes lost responsiveness to PDT chemoattraction. Moreover, our results highlighted that the PDT-induced migratory activity is sustained by the CXCR3A isoform, since CXCR3-transfected L1.2 cells acquired responsiveness to PDT stimulation. Finally, we show that PDT, as CXCR3 ligands, is also able to direct the migration of IL-2 activated T cells, which express the highest levels of CXCR3 among CXCR3-expressing cells. In conclusion, our study defines a chemokine-like activity for PDT through CXCR3A and points on the possible role that this synthetic dipeptide may play in leukocyte trafficking and function. Since recent studies have highlighted diverse therapeutic roles for molecules which activates CXCR3, our findings call for an exploration of using this dipeptide in different pathological processes.
Asunto(s)
Monocitos/efectos de los fármacos , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptores CXCR3/metabolismo , Tiazolidinas/farmacología , Anticuerpos Monoclonales/inmunología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Dipéptidos/síntesis química , Dipéptidos/farmacología , Humanos , Monocitos/citología , Monocitos/metabolismo , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores CXCR3/antagonistas & inhibidores , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Transducción de Señal/efectos de los fármacos , Linfocitos T/citología , Linfocitos T/metabolismo , Tiazolidinas/síntesis químicaRESUMEN
A general route which provides direct access to pyroglutamates from tetramates, making use of Suzuki coupling on an enol mesylate, followed by reduction, is reported. This work permits direct scaffold hopping from tetramate to substituted pyroglutamates. Some compounds in the library showed modest antibacterial activity against Gram-positive bacteria.
Asunto(s)
Cisteína/química , Ácido Pirrolidona Carboxílico/síntesis química , Serina/química , Treonina/química , Conformación Molecular , Ácido Pirrolidona Carboxílico/química , EstereoisomerismoRESUMEN
A series of l-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of l-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC50 values of 1.44 and 1.21⯵gâ¯mL-1, which were about seven times that of commercial azoxystrobin (7.85⯵gâ¯mL-1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.
Asunto(s)
Antifúngicos/síntesis química , Productos Biológicos/química , Ácido Pirrolidona Carboxílico/análogos & derivados , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Línea Celular , Lipopolisacáridos/farmacología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Óxido Nítrico/metabolismo , Células PC12 , Phytophthora infestans/efectos de los fármacos , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Stimulation of the NTS2 neurotensin receptor causes antipsychotic effects and leads to a promotion of the µ-opioid-independent antinociception, which is important in the modulation of tonic pain sensitivity. We report the synthesis and properties of a small library of peptidic agonists based on the active neurotensin fragment NT(8-13). Two tetrahydrofuran amino acid derivatives were synthesized to replace Tyr11 in NT(8-13). Additionally, Arg8, Arg9, and Ile12 of the lead peptide were exchanged by Lys, Lys, and Gly, respectively. The new compounds showed substantial NTS2 binding affinity and up to 1000-fold selectivity over NTS1. The highest selectivity (Ki(NTS2): 29nM, Ki(NTS1): 35,000nM) was observed for the peptide analog 17Rtrans.
Asunto(s)
Furanos/farmacología , Neurotensina/farmacología , Fragmentos de Péptidos/farmacología , Peptidomiméticos/farmacología , Ácido Pirrolidona Carboxílico/análogos & derivados , Receptores de Neurotensina/agonistas , Animales , Sitios de Unión , Células CHO , Cricetulus , Furanos/síntesis química , Furanos/química , Células HEK293 , Humanos , Conformación Molecular , Simulación de Dinámica Molecular , Imitación Molecular , Neurotensina/síntesis química , Neurotensina/química , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacologíaRESUMEN
Site-specific hydrolysis of peptide bonds at glutamic acid under neutral aqueous conditions is reported. The method relies on the activation of the backbone amide chain at glutamic acid by the formation of a pyroglutamyl (pGlu) imide moiety. This activation increases the susceptibility of a peptide bond toward hydrolysis. The method is highly specific and demonstrates broad substrate scope including cleavage of various bioactive peptides with unnatural amino acid residues, which are unsuitable substrates for enzymatic hydrolysis.
Asunto(s)
Ácido Glutámico/química , Péptidos/química , Secuencia de Aminoácidos , Aminoácidos/química , Hidrólisis , Estructura Molecular , Péptidos/farmacología , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/químicaRESUMEN
N-aralkylpyroglutamides of substituted bispidine were prepared and evaluated for their ability to inhibit collagen induced platelet aggregation, both in vivo and in vitro. Some compounds showed high anti-platelet efficacy (in vitro) of which six inhibited both collagen as well as U46619 induced platelet aggregation with concentration dependent anti-platelet efficacy through dual mechanism. In particular, the compound 4j offered significant protection against collagen epinephrine induced pulmonary thromboembolism as well as ferric chloride induced arterial thrombosis, without affecting bleeding tendency in mice. Therefore, the present study suggests that the compound 4j displays a remarkable antithrombotic efficacy much better than aspirin and clopidogrel.
Asunto(s)
Plaquetas/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Embolia Pulmonar/prevención & control , Ácido Pirrolidona Carboxílico/uso terapéutico , Trombosis/prevención & control , Animales , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/patología , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Hemorragia/inducido químicamente , Humanos , Ratones , Adhesividad Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Embolia Pulmonar/sangre , Embolia Pulmonar/patología , Ácido Pirrolidona Carboxílico/efectos adversos , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , Trombosis/sangre , Trombosis/patologíaRESUMEN
pENW, a three mer peptide derived from Agkistrodon acutus Guenther venom, has been found to be an antagonist of the GPIIb/IIIa receptor and shows antiplatelet aggregation activity. Based on pENW and a GPIIb/IIIa inhibitor Tirofiban, a series of tryptophan derivatives were designed, synthesized and evaluated for their antiplatelet aggregation activity induced by ADP. The most potent compound 87 was also tested for the bleeding time and antithrombotic activity in vivo in comparison with Tirofiban. The results indicated that 87 shows similar antiplatelet aggregation activity as Tirofiban to the aggregation of platelet induced by all of the four agonists, but has lower bleeding risk than Tirofiban, representing a promising lead compound for further study.
Asunto(s)
Diseño de Fármacos , Oligopéptidos/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Ácido Pirrolidona Carboxílico/análogos & derivados , Animales , Plaquetas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estructura Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacología , Conejos , Relación Estructura-ActividadRESUMEN
Glutamine is one of the most abundant metabolites in blood and is a precursor as well as end product central to numerous important metabolic pathways. A number of surprising and unexpected roles for glutamine, including cancer cell glutamine addiction discovered recently, stress the importance of accurate analysis of glutamine concentrations for understanding its role in health and numerous diseases. Utilizing a recently developed NMR approach that offers access to an unprecedented number of quantifiable blood metabolites, we have identified a surprising glutamine cyclization to pyroglutamic acid that occurs during protein removal. Intact, ultrafiltered and protein precipitated samples from the same pool of human serum were comprehensively investigated using (1)H NMR spectroscopy at 800 MHz to detect and quantitatively evaluate the phenomenon. Interestingly, although glutamine cyclization occurs in both ultrafiltered and protein precipitated serum, the cyclization was not detected in intact serum. Strikingly, due to cyclization, the apparent serum glutamine level drops by up to 75% and, concomitantly, the pyroglutamic acid level increases proportionately. Further, virtually under identical conditions, the magnitude of cyclization is vastly different for different portions of samples from the same pool of human serum. However, the sum of glutamine and pyroglutamic acid concentrations in each sample remains the same for all portions. These unexpected findings indicate the importance of considering the sum of apparent glutamine and pyroglutamic acid levels, obtained from the contemporary analytical methods, as the actual blood glutamine level for biomarker discovery and biological interpretations.
Asunto(s)
Glutamina/química , Ácido Pirrolidona Carboxílico/sangre , Ácido Pirrolidona Carboxílico/síntesis química , Ciclización , Glutamina/sangre , Humanos , Espectroscopía de Resonancia Magnética , Ácido Pirrolidona Carboxílico/químicaRESUMEN
The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [(11)C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/µmol with a total synthesis time of â¼40-min from EOB.
Asunto(s)
Tomografía de Emisión de Positrones , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/farmacología , Radiofármacos/farmacología , Receptores Purinérgicos P2X7/metabolismo , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Humanos , Imagen Molecular , Estructura Molecular , Ácido Pirrolidona Carboxílico/química , Radiofármacos/síntesis química , Radiofármacos/química , Extracción en Fase Sólida , Relación Estructura-ActividadRESUMEN
L-Pyroglutamic acid succinimidyl ester (L-PGA-OSu) and its isotopic variant (L-PGA[d5]-OSu) were newly synthesized and evaluated as the chiral labeling reagents for the enantioseparation of amino acids, in terms of separation efficiency by reversed-phase chromatography and detection sensitivity by ESI-MS/MS. The enantiomers of amino acids were easily labeled with the reagents at 60°C within 10 min in an alkaline medium containing triethylamine. Although all the diastereomers derived from 18 proteolytic amino acids could not be satisfactorily separated, the pairs of 9 amino acids were completely separated by reversed-phase chromatography using the small particle (1.7 µm) ODS column (Rs=1.95-8.05). The characteristic daughter ions, i.e., m/z 84.04 and m/z 89.04, were detected from all the derivatives by the collision induced dissociation of the protonated molecular ions. A highly sensitive detection at a low-fmol level (0.5-3.2 fmol) was also obtained from the selected reaction monitoring (SRM) chromatograms. An isotope labeling strategy using light and heavy L-PGA-OSu for the differential analysis of the DL-amino acids in different sample groups is also presented in this paper. The differential analysis of biological sample (i.e., human serum) and food product (i.e., yogurt) were tried to demonstrate the efficiency of the proposed method. The ratios of the DL-amino acids in human serum samples, spiked with the different concentrations of D-amino acids, were determined by the procedures using L-PGA-OSu and L-PGA[d5]-OSu. The D/L ratios in the two sample groups at different concentrations of amino acids were similar to the theoretical values. Furthermore, the ratios of D/L-alanine values in different yogurt products were comparable to the ratios obtained from the d/l values using only light reagent (i.e., L-PGA-OSu). Consequently, the proposed strategy is useful for the differential analysis not only in biological samples but also in food products.
Asunto(s)
Aminoácidos/análisis , Cromatografía Líquida de Alta Presión , Metabolómica , Ácido Pirrolidona Carboxílico/química , Espectrometría de Masa por Ionización de Electrospray , Succinatos/química , Aminoácidos/sangre , Aminoácidos/química , Bebidas/análisis , Deuterio/química , Humanos , Marcaje Isotópico , Ácido Pirrolidona Carboxílico/síntesis química , Estereoisomerismo , Succinatos/síntesis químicaRESUMEN
BACKGROUND: A detailed comprehension of central mechanisms underlying feeding behavior holds considerable promise for the treatment of alimentary disorders. METHODS: In order to elucidate the tight interrelationships occurring at the hypothalamic neuronal endings between aminergic neurotransmitters and co-localized appetite modulators, we initially studied the effects of two anorexigenic peptides structurally related to thyrotropin-releasing hormone (TRH, 1), namely cyclo(His-Pro) (CHP, 2) and pGlu-His-Gly-OH (3), on [(3)H]-norepinephrine and [(3)H]-dopamine release from perfused rat hypothalamic synaptosomes. Furthermore, a number of TRH and CHP analogues were synthesized and tested for their ability to influence neurotransmitter release in the selected neuronal model. RESULTS: Peptide 3 showed only a slight inhibitory activity on norepinephrine release, whereas no effect was observed for compound 2. TRH analogue 8, metabolically stabilized by the replacement of pyroglutamate with the pyrohomocysteic acid (pHcs), was found to be inactive. Conversely, a significant inhibitory effect on dopamine and norepinephrine release was observed for the CHP-related diketopiperazines cyclo(Leu-Pro) (11) and cyclo(His-Gly) (14). CONCLUSIONS: These results suggest a potential role for cyclo-dipeptides 11 and 14 in the hypothalamic modulation of appetite suppressant circuitry.
Asunto(s)
Catecolaminas/metabolismo , Oligopéptidos/farmacología , Péptidos Cíclicos/farmacología , Péptidos/síntesis química , Péptidos/farmacología , Piperazinas/farmacología , Ácido Pirrolidona Carboxílico/análogos & derivados , Hormona Liberadora de Tirotropina/análogos & derivados , Hormona Liberadora de Tirotropina/farmacología , Animales , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Oligopéptidos/síntesis química , Péptidos Cíclicos/síntesis química , Piperazinas/síntesis química , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/farmacología , Ratas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Alkylation of α-amino acid derived iminoesters with Baylis-Hillman (BH) reaction template based allyl bromides/allyl acetates followed by acidic hydrolysis furnished α-methylene-ß-substituted-pyroglutamates and α-alkylidene pyroglutamates respectively. Application of these methodologies has been demonstrated in the synthesis of fused [3.2.0]-γ-lactam-ß-lactones. Further, substrate controlled stereoselective alkylation of L-threonine derived oxazoles with BH reaction based allyl bromides and acetates yielded optically pure α-methylene-ß-substituted pyroglutamates, and α-alkylidene pyroglutamates. These methodologies have been applied in the preparation of chiral [3.2.0] heterobicyclic pyroglutamates containing hydroxyethyl side chain. All the synthesized pyroglutamates have been evaluated for their anti-cancer and enzyme proteasome inhibition activity.
Asunto(s)
Aminoácidos/química , Productos Biológicos/síntesis química , Ácido Pirrolidona Carboxílico/análogos & derivados , Ácido Pirrolidona Carboxílico/síntesis química , Acetatos/química , Alquilación , Compuestos Alílicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Hidrólisis , Lactonas/química , Oxazoles/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Ácido Pirrolidona Carboxílico/farmacología , EstereoisomerismoRESUMEN
Lamprey gonadotropin-releasing hormone type III (lGnRH-III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH-III have been published, raising questions on the structure-activity relationship. We synthesized 21 lGnRH-III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp6 for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl-group to the side chain of Lys8 or side chain cyclization of amino acids 1-8 increased the antiproliferative activity of lGnRH-III demonstrating that the proposed salt bridge between Asp6 and Lys8 is not crucial. Conformational studies of lGnRH-III were performed through NMR spectroscopy, and the solution structure of GnRH-I was solved. In solution, lGnRH-III adopts an extended backbone conformation in contrast to the well-defined ß-turn conformation of GnRH-I.
Asunto(s)
Antineoplásicos/síntesis química , Hormona Liberadora de Gonadotropina/síntesis química , Ácido Pirrolidona Carboxílico/análogos & derivados , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Hormona Liberadora de Gonadotropina/química , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Conformación Proteica , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacología , Relación Estructura-ActividadRESUMEN
Here we report on the synthesis and biochemical characterization (enzymatic stability, cellular uptake, in vitro antitumor activity, membrane interaction and GnRH-receptor binding affinity) of novel short-chain fatty acid (SCFA) acylated daunorubicin-GnRH-III bioconjugates, which may serve as drug delivery systems for targeted cancer chemotherapy. Ser in position 4 of GnRH-III was replaced by Lys, followed by the acylation of its ε-amino group with various fatty acids. SCFAs are potentially chemoprotective agents by suppressing the growth of cancer cells and therefore may enhance the antitumor activity of the bioconjugates. We found that all synthesized bioconjugates had high cytostatic effect in vitro, were stable in cell culture medium for 6 h and degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked daunorubicin-Lys as the smallest active metabolite. In the presence of α-chymotrypsin, all compounds were digested, the degradation rate strongly depending on the type of fatty acid. The bioconjugate containing Lys(nBu) in position 4 was taken up most efficiently by the cancer cells and exerted higher in vitro cytostatic effect than the previously developed GnRH-III((4)Lys(Ac), (8)Lys(Dau = Aoa)) or the parent GnRH-III(Dau = Aoa) bioconjugate. Our results could be explained by the increased binding affinity of the newly developed compound containing Lys(nBu) to the GnRH receptors.
Asunto(s)
Antineoplásicos/farmacología , Daunorrubicina/farmacología , Ácidos Grasos/química , Hormona Liberadora de Gonadotropina/farmacología , Ácido Pirrolidona Carboxílico/análogos & derivados , Acilación , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Daunorrubicina/síntesis química , Daunorrubicina/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Hormona Liberadora de Gonadotropina/síntesis química , Hormona Liberadora de Gonadotropina/química , Células HT29 , Humanos , Células MCF-7 , Estructura Molecular , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacología , Receptores LHRH/química , Receptores LHRH/metabolismo , Relación Estructura-ActividadRESUMEN
The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected α-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step-economic transformations were accomplished by cooperative activation by using a robust planar chiral bis-Pd catalyst, a Brønsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Brønsted base (NaOAc). In particular the second- and third-generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic α-amino acids, α-alkyl proline, and α-alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary α-amino acids.
Asunto(s)
Aminoácidos/química , Aminoácidos/síntesis química , Paladio/química , Prolina/química , Prolina/síntesis química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Biomimetic intramolecular aldol reactions on oxazolidine templates derived from serine may be used to generate densely functionalised pyroglutamates, which are simpler mimics of the right hand side of oxazolomycin. Some of the compounds from this sequence exhibit in vivo activity against S. aureus and E. coli, suggesting that pyroglutamate scaffolds may be useful templates for the development of novel antibacterials, and cheminformatic analysis has been used to provide some structure-activity data.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Biomimética/métodos , Oxazoles/química , Ácido Pirrolidona Carboxílico/química , Ácido Pirrolidona Carboxílico/farmacología , Compuestos de Espiro/química , Antibacterianos/síntesis química , Escherichia coli/efectos de los fármacos , Modelos Moleculares , Conformación Molecular , Pirrolidinonas , Ácido Pirrolidona Carboxílico/síntesis química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A direct and facile access to enantioenriched pyroglutamate derivatives bearing a unique quaternary stereogenic center has been developed via Cu(I)/BINAP-catalyzed tandem Michael addition-elimination of α-substituted aldimino esters with Morita-Baylis-Hillman (MBH) carbonates followed by a deprotection/lactamization protocol, which performs well over a broad scope of substrates and provides biologically active pyroglutamate derivatives in good yields and excellent enantioselectivities.
Asunto(s)
Cobre/química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Ácido Pirrolidona Carboxílico/análogos & derivados , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/química , EstereoisomerismoRESUMEN
Highly stereoselective Friedel-Crafts reactions have been performed using a chiral anthracene template to control the selectivity of the reaction. In the case of additions to fully substituted N-acyliminium ions, competitive elimination and condensation reactions were observed. Retro-Diels-Alder reaction of one of the reaction products led to a precursor that could be used for the construction of pyroglutamic acids bearing quaternary stereogenic centres.
Asunto(s)
Ácido Pirrolidona Carboxílico/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Ácido Pirrolidona Carboxílico/química , EstereoisomerismoRESUMEN
Alkylation of amino-acid derived iminoesters with Baylis-Hillman (BH) template based allyl bromides furnished α-methylene-ß-substituted-pyroglutamates, while the corresponding alkylation with BH derived allylic acetates provided α-alkylidene-pyroglutamates. These methodologies have been applied in the synthesis of fused [3.2.0]-γ-lactam-ß-lactones.