RESUMEN
CDK4/6 were attractive chemotherapeutic targets for the treatment of malignant tumors, CDK4/6 selective inhibitors have made outstanding contributions in the treatment of breast cancer. However, these inhibitors share a single skeleton of N-(pyridin-2-yl) pyrimidin-2-amine which cannot overcome the side effects in clinical application. In our previous study, an N'- acetylpyrrolidine-1-carbohydrazide was hit as the initial fragment by analyzing the active site characteristics of CDK6. Two series of N-(pyridin-3-yl) proline were obtained by fragment growth method. The QSAR study was carried out according to the in vitro activities data against CDK4/6, and two compounds 7c and 7p with potent inhibitory activities were found to interact with CDK4 in different binding conformation. They showed potential inhibition of cell proliferation against the breast cancer cell, and 7c exhibited promised anti-breast cancer effect in vivo.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Prolina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Estructura Molecular , Prolina/síntesis química , Prolina/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II, and XII, with each containing a reactive warhead that covalently modifies the catalytic Cys145. Coupling structure-based drug design with the one-pot Ugi four-component reaction, we discovered one of the most potent noncovalent inhibitors, 23R (Jun8-76-3A) that is structurally distinct from the canonical Mpro inhibitor GC376. Significantly, 23R is highly selective compared with covalent inhibitors such as GC376, especially toward host proteases. The cocrystal structure of SARS-CoV-2 Mpro with 23R revealed a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study discovered 23R, one of the most potent and selective noncovalent SARS-CoV-2 Mpro inhibitors reported to date, and a novel binding pocket in Mpro that can be explored for inhibitor design.
Asunto(s)
Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/química , COVID-19/metabolismo , Chlorocebus aethiops , Proteasas 3C de Coronavirus/aislamiento & purificación , Proteasas 3C de Coronavirus/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Prolina/análogos & derivados , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , SARS-CoV-2/enzimología , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacología , Células Vero , Tratamiento Farmacológico de COVID-19RESUMEN
We explored orally effective thyrotropin-releasing hormone (TRH) mimetics, which show high central nervous system effects in structure-activity relationship studies based on in vivo antagonistic activity on reserpine-induced hypothermia (anti-hypothermic effect) in mice starting from TRH. This led us to the TRH mimetic: [(4S,5S)-(5-methyl-2-oxooxazolidine-4-yl)carbonyl]-[3-(thiazol-4-yl)-L-alanyl]-L-prolinamide 1, which shows a higher anti-hypothermic effect compared with that of TRH after oral administration. We next attempted further chemical modification of the N- and C-terminus of 1 to find more orally effective TRH mimetics. As a result, we obtained several N- and C-terminus modified TRH mimetics which showed high anti-hypothermic effects.
Asunto(s)
Hipotermia/tratamiento farmacológico , Prolina/análogos & derivados , Hormona Liberadora de Tirotropina/síntesis química , Hormona Liberadora de Tirotropina/farmacología , Administración Oral , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Masculino , Prolina/administración & dosificación , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Ratas Sprague-Dawley , Hormona Liberadora de Tirotropina/administración & dosificación , Hormona Liberadora de Tirotropina/químicaRESUMEN
A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.
Asunto(s)
Anhidrasa Carbónica II/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Peptidomiméticos/farmacología , Prolina/farmacología , Anhidrasa Carbónica II/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/química , Prolina/síntesis química , Prolina/química , Relación Estructura-ActividadRESUMEN
Azetidinones and ß-amino acids serve as useful building blocks in synthetic organic chemistry and their structural motifs are often found in biologically active compounds. Due to the importance of these compounds, several synthetic strategies have been developed and availability of new synthetic approaches is highly desirable. In this account, we describe the development of an original method that allows the preparation of ß-lactam and ß-homoproline derivatives not easily accessible through traditional processes. The serendipitous discovery made in our lab in 2000 involved the formation of a ß-lactam by heating a mixture of an alkylidenecyclopropane tethered to a formyl group with N-methylhydroxylamine hydrochloride. Investigation of the process resulted in disclosing an alternative synthetic method of azetidinones based on an acid induced fragmentative rearrangement of cycloadducts of nitrones with suitable methylenecyclopropane derivatives. Herein, the scope of this process is reviewed. In addition, both experimental and computational studies of the mechanism for this peculiar fragmentative rearrangement are presented.
Asunto(s)
Aminoácidos/química , Oxazoles/química , Prolina/análogos & derivados , beta-Lactamas/síntesis química , Prolina/síntesis química , Prolina/química , beta-Lactamas/químicaRESUMEN
In this study, the novel bifunctional homochiral thiourea-L-prolinamides 1-4, tertiary amino-L-prolinamide 5, and bis-L-prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene 8 and (11S,12S)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene ent-8. Highly enantioselective and diastereoselective aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn) between aliphatic ketones (20 equiv) and a range of aromatic aldehydes (1 equiv) were successfully carried out in the presence of water (10 equiv) and monochloroacetic acid (10 mol%), solvent-free conditions, at room temperature over 24 h using organocatalysts 1-7 (5 mol%). Stereoselective induction using density functional theory-based methods was consistent with the experimental data.
Asunto(s)
Aldehídos/química , Prolina/análogos & derivados , Acetona/química , Catálisis , Técnicas de Química Sintética , Teoría Funcional de la Densidad , Cetonas/química , Estructura Molecular , Prolina/síntesis química , Prolina/química , Solventes , Estereoisomerismo , Tiourea/químicaRESUMEN
On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.
Asunto(s)
Antivirales/farmacología , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Isoindoles/farmacología , Lactamas Macrocíclicas/farmacología , Prolina/análogos & derivados , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Ciclopropanos/síntesis química , Ciclopropanos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Genotipo , Hepacivirus/genética , Humanos , Isoindoles/síntesis química , Isoindoles/química , Lactamas Macrocíclicas/síntesis química , Lactamas Macrocíclicas/química , Pruebas de Sensibilidad Microbiana , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Serina Proteasas/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismoAsunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , N-Acetilgalactosaminiltransferasas/antagonistas & inhibidores , Adenocarcinoma/metabolismo , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Colorrectales/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , N-Acetilgalactosaminiltransferasas/metabolismo , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Sarcosina/síntesis química , Sarcosina/química , Sarcosina/farmacologíaRESUMEN
The synthesis of new analogues of cyclolinopeptide A (CLA) and their linear precursors modified with (R)- and (S)-4-methylpseudoproline in the Pro3-Pro4 fragment are presented. The peptides were tested in comparison with cyclosporine A (CsA) in concanavalin A (Con A) and pokeweed mitogen (PWM)-induced mouse splenocyte proliferation and in secondary humoral immune response in vitro to sheep erythrocytes (SRBC). Their effects on expression of selected signaling molecules in the Jurkat T cell line were also determined. In addition, the structural features of the peptides, applying nuclear magnetic resonance and circular dichroism, were analyzed. The results showed that only peptides 7 and 8 modified with (R)-4-methylpseudoproline residue (c(Leu1-Val2-(R)-(αMe)Ser(ΨPro)3-Pro4-Phe5-Phe6-Leu7-Ile8-Ile9) and c(Leu1-Val2-Pro3-(R)-(αMe)Ser(ΨPro)4-Phe5-Phe6-Leu7-Ile8-Ile9), respectively) strongly suppressed mitogen-induced splenocyte proliferation and the humoral immune response, with peptide 8 being more potent. Likewise, peptide 8 more strongly elevated expression of Fas, a proapoptotic signaling molecule in Jurkat cells. We postulate that the increased biological activity of peptide 8, compared to the parent molecule and other studied peptides, resulted from its more flexible structure, found on the basis of both CD and NMR studies. CD and NMR spectra showed that replacement of Pro3 by (R)-(αMe)Ser(¬Pro) caused much greater conformational changes than the same replacement of the Pro4 residue. Such a modification could lead to increased conformational freedom of peptide 8, resulting in a greater ability to adopt a more compact structure, better suited to its putative receptor. In conclusion, peptide 8 is a potent immune suppressor which may find application in controlling immune disorders.
Asunto(s)
Enfermedades del Sistema Inmune/tratamiento farmacológico , Inmunosupresores/química , Inmunosupresores/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Prolina/análogos & derivados , Tiazoles/química , Tiazoles/farmacología , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dicroismo Circular/métodos , Femenino , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/metabolismo , Inmunosupresores/síntesis química , Linfocitos/citología , Linfocitos/efectos de los fármacos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Ratones , Ratones Endogámicos CBA , Péptidos Cíclicos/síntesis química , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Ovinos , Bazo/citología , Bazo/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/síntesis químicaRESUMEN
Stachydrine is a natural product with multiple protective biological activities, including those involved in preventing cancer, ischemia, and cardiovascular disease. However, its use has been limited by low bioavailability and unsatisfactory efficacy. To address this problem, a series of stachydrine derivatives (A1/A2/A3/A4/B1/B2/B3/B4) were designed and synthesized, and biological studies were carried out in vitro and in vivo. When compared with stachydrine, Compound B1 exhibited better neuroprotective effects in vitro, and significantly reduced infarction size in the model of the middle cerebral artery occlusion rat model. Therefore, Compound B1 was selected for further research on ischemic stroke. Graphical abstract.
Asunto(s)
Isquemia Encefálica/prevención & control , Accidente Cerebrovascular Isquémico/prevención & control , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/uso terapéutico , Prolina/análogos & derivados , Animales , Animales Recién Nacidos , Isquemia Encefálica/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Accidente Cerebrovascular Isquémico/metabolismo , Prolina/síntesis química , Prolina/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N-H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- to excellent yields. This synthetic route can tolerate a variety of functional groups including those with acidic protons on the aryl bromide coupling partner. This methodology is also applicable for cross-coupling with heteroaryl bromides to yield pyrrole-thiophene, pyrrole-pyridine, and 2,3'-bi-pyrrole based bi-heteroaryls.
Asunto(s)
Técnicas de Química Sintética , Acoplamiento Oxidativo , Prolina/análogos & derivados , Catálisis , Ciclización , Estructura Molecular , Prolina/síntesis química , Prolina/química , Pirroles/químicaRESUMEN
A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.
Asunto(s)
Anticoagulantes/farmacología , Diseño de Fármacos , Factor XIa/antagonistas & inhibidores , Prolina/farmacología , Anticoagulantes/síntesis química , Anticoagulantes/química , Relación Dosis-Respuesta a Droga , Factor XIa/metabolismo , Humanos , Estructura Molecular , Prolina/síntesis química , Prolina/química , Relación Estructura-ActividadRESUMEN
Magnetic proline-based surface-active ionic liquid ([ProC10][FeCl3Br]) have been synthesized and investigated for their application in hydrophobic drug delivery. Hydrophobic drugs lead to poor absorptivity, drug aggregation, and high local toxicity. Herein, the vesicular structures formed from [ProC10][FeCl3Br] have been used as drug delivery reactors. The self-assembly behavior of [ProC10][FeCl3Br] in aqueous medium has been investigated using tensiometry, fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The physicochemical interactions of [ProC10][FeCl3Br] with animal DNA have been studied using circular dichroism (CD), fluorescence, zeta potential, and gel electrophoresis to confirm its bio-friendly nature. The engendered vesicles prepared from [ProC10][FeCl3Br] have been investigated for the in vitro drug delivery of guest molecule pyrene as a hydrophobic model drug and ciprofloxacin as a hydrophobic antibiotic drug. The drug loading capacity and spontaneous kinetic release of the drug have been studied using various theoretical mathematical drug release models.
Asunto(s)
Antibacterianos/química , Ciprofloxacina/química , Líquidos Iónicos/química , Nanopartículas/química , Prolina/química , Tensoactivos/química , Animales , ADN/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Interacciones Hidrofóbicas e Hidrofílicas , Líquidos Iónicos/síntesis química , Cinética , Fenómenos Magnéticos , Estructura Molecular , Tamaño de la Partícula , Prolina/síntesis química , Propiedades de Superficie , Tensoactivos/síntesis químicaRESUMEN
Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the inâ vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.
Asunto(s)
Antineoplásicos/farmacología , Carbamatos/farmacología , Profármacos/farmacología , Prolina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Carbamatos/síntesis química , Carbamatos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclización , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Prolina/síntesis química , Prolina/químicaRESUMEN
A general and robust method for the incorporation of aspartates with a thioacid side chain into peptides has been developed. Pseudoproline tripeptides served as building blocks for the efficient fluorenylmethyloxycarbonyl (Fmoc) solid-phase synthesis of thioacid-containing peptides. These peptides were readily converted to complex N-glycopeptides by using a fast and chemoselective one-pot deprotection/ligation procedure. Furthermore, a novel side reaction that can lead to site-selective peptide cleavage using thioacids (CUT) was discovered and studied in detail.
Asunto(s)
Glicopéptidos/síntesis química , Oligopéptidos/química , Prolina/análogos & derivados , Técnicas de Síntesis en Fase Sólida/métodos , Tiazoles/química , Ácidos/química , Secuencia de Aminoácidos , Fluorenos/síntesis química , Fluorenos/química , Glicopéptidos/química , Oligopéptidos/síntesis química , Prolina/síntesis química , Prolina/química , Compuestos de Sulfhidrilo/química , Tiazoles/síntesis químicaRESUMEN
Due to its unique structure, proline plays important structural and functional roles in proteins. However, this special amino acid lacks an adequate vibrational mode that can be exploited to probe its local electrostatic and hydration status via infrared spectroscopy. Herein, we show that the CâO stretching vibration of a proline derivative, 4-oxoproline, is sensitive to local environment and hence can be used as a site-specific infrared probe. We further validate this notion by applying this unnatural amino acid to assess the thermodynamics of proline cis-trans isomerization in a peptide environment and examine the amino acid dimer formation in concentrated proline and glycine solutions.
Asunto(s)
Dimerización , Prolina/análogos & derivados , Prolina/química , Isomerismo , Estructura Molecular , Prolina/análisis , Prolina/síntesis química , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática , Termodinámica , Agua/químicaRESUMEN
Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2 S,3 R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor ( Ki = 0.61 µM) over GluN1/GluN2B-D ( Ki = 2.7-62 µM).
Asunto(s)
Proteínas de Transporte de Glutamato en la Membrana Plasmática/metabolismo , Prolina/análogos & derivados , Prolina/farmacología , Receptores Ionotrópicos de Glutamato/metabolismo , Animales , Diseño de Fármacos , Humanos , Ligandos , Modelos Moleculares , Prolina/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
We report here the preparation, physico-chemical characterization, and biological evaluation of a new liposome formulation as a tool for tumor angiogenesis inhibition. Liposomes are loaded with sunitinib, a tyrosine kinase inhibitor, and decorated with cyclo-aminoprolineRGD units (cAmpRGD), efficient and selective ligands for integrin αVß3. The RGD units play multiple roles since they target the nanovehicles at the integrin αVß3-overexpressing cells (e.g. activated endothelial cells), favor their active cell internalization, providing drug accumulation in the cytoplasm, and likely take part in the angiogenesis inhibition by interfering in the αVß3-VEGFR2 cross-talk. Both in vitro and in vivo studies show a better efficacy of this integrated antiangiogenic tool with respect to the free sunitinib and untargeted sunitinib-loaded liposomes. This system could allow a lower administration of the drug and, by increasing the vector specificity, reduce side-effects in a prolonged antiangiogenic therapy.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Integrina alfaVbeta3/metabolismo , Oligopéptidos/química , Prolina/análogos & derivados , Sunitinib/farmacología , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Adhesión Celular/efectos de los fármacos , Células Progenitoras Endoteliales/citología , Células Progenitoras Endoteliales/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Humanos , Recién Nacido , Lípidos/química , Liposomas , Ratones , Nanopartículas/química , Neovascularización Patológica/tratamiento farmacológico , Oligopéptidos/síntesis química , Fosfolípidos/síntesis química , Fosfolípidos/química , Fosforilación/efectos de los fármacos , Prolina/síntesis química , Prolina/química , Sunitinib/química , Sunitinib/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Vitronectina/metabolismoRESUMEN
Six different types of O-benzyl protected proline derivatives have been synthesized from D-glycals and 2C-formyl-glycals. One of the di-O-benzyl protected proline derivatives has been utilized for the synthesis of polysubstituted pyrrolizidines via [3 + 2] cycloaddition in a stereoselective manner. Further, we also report on the stereoselective synthesis of biologically active 1C-aryl/alkyl pyrrolidines i.e. 4-epi-radicamine B, 4-epi-radicamine A, 1C-butyl and 1C-methyl pyrrolidines through double reductive amination of a variety of D-glucal derived diketones with p-methoxybenzylamine.
Asunto(s)
Desoxiglucosa/análogos & derivados , Prolina/síntesis química , Pirroles/síntesis química , Desoxiglucosa/química , Estructura Molecular , Prolina/química , Pirroles/químicaRESUMEN
( R)-Boc-2-methylproline (3a) was synthesized in good yield with excellent stereochemical control from alanine benzyl ester hydrochloride 11. The process, which is based on a modification of one described by Kawabata, proceeds in four steps and requires no chromatography. The product ( R)-Boc-2-methylproline (3a) was then carried forward in three steps to produce veliparib 1, a poly(ADP-ribose) polymerase inhibitor.