RESUMEN
Several classes of compounds are applied in clinics due to their immunosuppressive properties in transplantology and the treatment of autoimmune diseases. Derivatives of mycophenolic acid, corticosteroids and chemotherapeutics bearing heterocyclic moieties like methotrexate, azathioprine, mizoribine, and ruxolitinib are active substances with investigated mechanisms of action. However, improved synthetic approaches of known drugs and novel derivatives are still being reported to attempt better accessibility and therapeutic properties. In this review article, we present the synthesis of the designed chemical structures based on recent literature reports concerning novel compounds as promising immunosuppressive drugs. Moreover, some of the discussed derivers revealed also other types of activities with prospective medicinal potential.
Asunto(s)
Inmunosupresores , Humanos , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Estructura MolecularRESUMEN
FTY720 is an analog of sphingosine-1-phosphate (S1P) derived from the ascomycete Cordyceps sinensis. As a new immunosuppressant, FTY720 is widely used to treat multiple sclerosis. FTY720 binds to the S1P receptor after phosphorylation, thereby exerting immunosuppressive effects. The nonphosphorylated form of FTY720 can induce cell apoptosis, enhance chemotherapy sensitivity, and inhibit tumor metastasis of multiple tumors by inhibiting SPHK1 (sphingosine kinase 1) and activating PP2A (protein phosphatase 2A) and various cell death pathways. FTY720 can induce neutrophil extracellular traps to neutralize and kill pathogens in vitro, thus exerting anti- infective effects. At present, a series of FTY720 derivatives, which have pharmacological effects such as anti-tumor and alleviating airway hyperresponsiveness, have been developed through structural modification. This article reviews the pharmacological effects of FTY720 and its derivatives.
Asunto(s)
Clorhidrato de Fingolimod , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/química , Humanos , Animales , Inmunosupresores/farmacología , Inmunosupresores/química , Inmunosupresores/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Apoptosis/efectos de los fármacosRESUMEN
Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of the largest dendrimers tested were as active as GA. Detailed profiling of the best hit showed that this dendrimer induces the differentiation of monocytes towards an M2 (anti-inflammatory) state as GA does, however with a distinct immune marker profile. Our peptide dendrimer might serve as starting point to develop a well-defined immunomodulatory analog of GA.
Asunto(s)
Dendrímeros/farmacología , Acetato de Glatiramer/farmacología , Inmunosupresores/farmacología , Monocitos/efectos de los fármacos , Péptidos/farmacología , Receptores de Interleucina-1/antagonistas & inhibidores , Diferenciación Celular/efectos de los fármacos , Dendrímeros/síntesis química , Dendrímeros/química , Acetato de Glatiramer/química , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Péptidos/síntesis química , Péptidos/químicaRESUMEN
Sanglifehrinâ A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrinâ A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo-controlled spirocyclization. The 22-membered macrocyclic core was synthesized by ring-closing metathesis in the presence of 2,6-bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrinâ A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the 2-CF3 analog of sanglifehrin B exhibited higher anti-proliferative activity than the natural products sanglifehrinâ A and B in Jurkat cells. Both natural products induced higher-order homodimerization of cyclophilinâ A (CypA), but only sanglifehrinâ A promoted CypA complexation with inosine-5'-monophosphate dehydrogenaseâ 2 (IMPDH2). The synthesis reported herein will enable further evaluation of the spirolactam and its contribution to sanglifehrin-dependent immunosuppressive activity.
Asunto(s)
Inmunosupresores/farmacología , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Células Jurkat , Lactonas/síntesis química , Lactonas/química , Lactonas/farmacología , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , EstereoisomerismoRESUMEN
Inspired by aspirin and chalcone, herein, we describe a modular biomimetic strategy to achieve a new class of CF3-bearing benzannulated macrolactams. The key to the success of macrolactams was the utilization of a highly chemoselective Rh(iii)-catalyzed native carboxylic acid-directed C-H alkylation. Moreover, the unique CF3-containing benzannulated macrocycles showed decent immunosuppressive effects on B cells in vitro, including proliferation, activation, and antibody production upon specific stimulation implicating TLR and BCR signaling.
Asunto(s)
Linfocitos B/efectos de los fármacos , Inmunosupresores/farmacología , Compuestos Macrocíclicos/farmacología , Rodio/química , Alquilación , Animales , Linfocitos B/metabolismo , Catálisis , Inmunosupresores/síntesis química , Inmunosupresores/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Ratones , Estructura Molecular , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Receptores Toll-Like/metabolismoRESUMEN
Brasilicardinâ A (1) consists of an unusual anti/syn/anti-perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre-clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low-yielding fermentation process using a pathogenic organism and an elaborate, multi-step total synthesis. Our semi-synthetic approach included a) the heterologous expression of the brasilicardinâ A gene cluster in different non-pathogenic bacterial strains producing brasilicardinâ A aglycone (5) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardinâ A (1 a) via a short and straightforward five-steps synthetic route. Additionally, we report the first preclinical data for brasilicardinâ A.
Asunto(s)
Aminoglicósidos/metabolismo , Ingeniería Genética , Inmunosupresores/síntesis química , Transferasas Alquil y Aril/genética , Aminoglicósidos/síntesis química , Aminoglicósidos/química , Aminoglicósidos/farmacología , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Inmunosupresores/química , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Ratones , Plásmidos/genética , Plásmidos/metabolismo , Streptomyces/genética , Streptomyces/metabolismo , Terpenos/químicaRESUMEN
(-)-Isoscopariusinâ A was isolated from the aerial parts of Isodon scoparius. Chemical synthesis and spectroscopic analysis established its structure as an unsymmetrical meroditerpenoid bearing a sterically congested 6/6/4 tricyclic carbon skeleton with seven continuous stereocenters. A gram-scale synthesis was achieved in 12 steps from commercially available (+)-sclareolide. A cobalt catalyzed, hydrogen atom transfer-based olefin isomerization was used to prepare a trisubstituted alkene, which underwent stereoselective [2+2] cycloaddition with a substituted keteniminium ion generated in situ from the corresponding amide. The cyclobutanone product was further elaborated into the fully substituted cyclobutane core through face-selective homologation, and the two side chains were installed by using nickel-catalyzed cross-electrophile coupling and carbodiimide-mediated esterification, respectively. (-)-Isoscopariusinâ A displayed selective inhibition of T-cell proliferation.
Asunto(s)
Inmunosupresores/síntesis química , Isodon/química , Animales , Proliferación Celular/efectos de los fármacos , Inmunosupresores/química , Inmunosupresores/farmacología , Ratones , Conformación Molecular , Componentes Aéreos de las Plantas/química , Linfocitos T/efectos de los fármacosRESUMEN
Celastrol, a friedelane-type triterpenoid isolated from the genus Triperygium, possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (1a-1t, 2a-2l, and 3a-3j) were synthesized and evaluated for their immunosuppressive activities. Compounds 2a-2e showed immunosuppressive effects, with IC50 values ranging from 25 to 83 nM, and weak cytotoxicity (CC50 > 1 µM). Compound 2a, with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that 2a exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.
Asunto(s)
Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Proteína Tirosina Quinasa ZAP-70/efectos de los fármacosRESUMEN
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
Evidence indicates that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in its replication, and cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure-activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Additionally, we discovered the importance of substitution at the 3 position for not only improving anti-HCV activity but also pharmacokinetic profile. Finally, by striking an appropriate balance between potency, solubility, and permeability, we discovered ASP5286 (13) as a potential clinical candidate for anti-HCV therapy.
Asunto(s)
Antivirales/farmacología , Ciclofilinas/antagonistas & inhibidores , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Inmunosupresores/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Inmunosupresores/síntesis química , Inmunosupresores/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Eight new dihydroartemisinin-O-glycosides were synthesized with their relative configurations were determined based on NMR spectrum. In vitro immunosuppressive assay showed that 10α-dihydroartemisinin-ß-O-d-mannoside (19a) demonstrate 88% inhibition towards T cells proliferation and 98% reduction in IFN-γ levels in cell media. These results suggest that dihydroartemisinin-O-glycoside as a potential lead for further in vivo evaluation.
Asunto(s)
Artemisininas/farmacología , Glicósidos/farmacología , Inmunosupresores/farmacología , Interferón gamma/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Artemisininas/síntesis química , Artemisininas/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glicósidos/síntesis química , Glicósidos/química , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The addition of osteoimmunology drugs to bone repair materials is beneficial to bone regeneration by regulating the local immune microenvironment. Fingolimod (FTY720) has been reported to be an osteoimmunology drug that promotes osteogenesis. However, there is no ideal biomaterial for the sustained release of FTY720 in the bone defect areas. In the present work, FTY720 loaded mesoporous bioactive glass (FTY720@MBGs) was successfully prepared based on the mesoporous properties of MBGs and electrostatic attraction. FTY720 achieved a sustained release for 7 days. The in vitro study found that FTY720@MBGs could synergistically promote osteogenesis and inhibit osteoclastogenesis due to their ability to promote macrophages toward the M2 phenotype. The in vivo study confirmed that FTY720@MBGs could significantly improve bone regeneration. This study provides new strategies for designing smart cell-instructive biomaterials that can play a role in all bone healing processes from early inflammation to bone reconstruction.
Asunto(s)
Regeneración Ósea/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Clorhidrato de Fingolimod/farmacología , Inmunosupresores/farmacología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Animales , Células Cultivadas , Clorhidrato de Fingolimod/síntesis química , Clorhidrato de Fingolimod/química , Vidrio/química , Inmunosupresores/síntesis química , Inmunosupresores/química , Macrófagos/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Tamaño de la Partícula , Porosidad , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Propiedades de SuperficieRESUMEN
HCV utilizes cellular protein cyclophilins in the virus replication cycle and cyclophilin inhibitors have become a new class of anti-HCV agents. In our screening of natural products, we identified a unique cyclosporin analogue, FR901459, as a cyclophilin inhibitor with potent anti-HCV activity. In this work, we developed an efficient synthetic methodology to prepare FR901459 derivatives via an N, O-acyl migration reaction. This method allows us to efficiently manipulate the amino acid residues at the 3 position while avoiding lengthy total synthesis for each compound. By using this methodology, we discovered 4, which has superior anti-HCV activity and decreased immunosuppressive activity compared to FR901459.
Asunto(s)
Antivirales/farmacología , Ciclosporina/farmacología , Desarrollo de Medicamentos , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Inmunosupresores/farmacología , Antivirales/síntesis química , Antivirales/química , Ciclofilinas/antagonistas & inhibidores , Ciclofilinas/metabolismo , Ciclosporina/síntesis química , Ciclosporina/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Autoimmune diseases are chronic inflammatory diseases associated with high morbidity and mortality. Treatment options for autoimmune diseases have increased over the past several decades, but they are, in general, limited in their clinical efficacy due to high toxicity and lack of selectivity. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects. To define the structural requirements of subglutinols for immunomodulatory activity and to provide guiding principles on future therapeutic development, we prepared and evaluated several subglutinol analogs for their immunomodulatory activities. Our efforts identified a subglutinol analog with reduced structural complexity as a potential lead compound for future autoimmune drug development. Our study will provide an important framework for the design of potent and nontoxic immunomodulating agents derived from subglutinols.
Asunto(s)
Diterpenos/uso terapéutico , Inmunosupresores/uso terapéutico , Pironas/uso terapéutico , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diterpenos/síntesis química , Diterpenos/toxicidad , Inmunosupresores/síntesis química , Inmunosupresores/toxicidad , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Pironas/síntesis química , Pironas/toxicidad , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacosRESUMEN
INTRODUCTION: Nitric oxide (NO) is an important mediator in the pathogenesis and control of immune system-related disorders and its levels are modulated by inducible NO synthase (iNOS). Oxidative stress is another pathological indication in majority of autoimmune disorders. The present study aims at the development of coupled molecules via selection of pharmacophores for both immunomodulatory and antioxidant activities through iNOS inhibition. METHODS: Variedly substituted coumarin moieties are coupled with naturally occurring phenols through an amide linkage and were predicted for activities using computer-based program PASS. The compounds predicted to have dual activities were synthesized. Docking studies were carried out against iNOS (PDB 1R35) and compounds having good docking score were evaluated for immunomodulatory and antioxidant activities. RESULTS: The synthesized compounds were found to be pure and were obtained in good yields. Compounds with maximum docking score (YR1a, YR2e, YR2c and YR4e) were selected for evaluation by in vitro models. Compounds YR2e and YR2c markedly inhibited the reduction of NBT dye and showed maximum % iNOS inhibition. In DPPH assay, compound YR4e was observed as the most potent antioxidant (EC50 0.33 µM/mL). Based on these studies, compounds YR2e and YR2c were selected for haemagglutination test. Compound YR2e was observed as the most active immunosuppressant with maximal inhibitory ability of iNOS and NBT reduction and lower HAT value of 3.5. CONCLUSION: Compound YR2e can be utilized as a pharmacological agent in the prevention or treatment of immunomodulatory diseases such as tumors, rheumatoid arthritis, ulcerative colitis, organ transplant and other autoimmune disorders.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Inmunosupresores/química , Inmunosupresores/farmacología , Productos Biológicos/síntesis química , Productos Biológicos/metabolismo , Técnicas de Química Sintética , Diseño de Fármacos , Inmunosupresores/síntesis química , Inmunosupresores/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico Sintasa de Tipo II/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Conformación ProteicaAsunto(s)
Inhibidores Enzimáticos/farmacología , Inmunosupresores/farmacología , L-Aminoácido Oxidasa/antagonistas & inhibidores , Fenilalanina/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/química , L-Aminoácido Oxidasa/metabolismo , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Relación Estructura-ActividadRESUMEN
The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.
Asunto(s)
Glicoproteínas de Membrana/agonistas , ARN Nuclear Pequeño/inmunología , Receptor Toll-Like 7/agonistas , Adulto , Alarminas/química , Animales , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Secuencia de Bases , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Glicoproteínas de Membrana/deficiencia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Persona de Mediana Edad , ARN/inmunología , ARN/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/química , Ribonucleoproteínas Nucleares Pequeñas/inmunología , Análisis de Secuencia de ARN , Receptor Toll-Like 7/deficiencia , Adulto JovenRESUMEN
FR252921, FR252922, and FR256523 are a family of potent macrocyclic polyene immunosuppressive agents with a novel mode of action. However, the lack of an efficient and flexible synthesis has hindered further biological studies, mostly due to the fact that the natural products appear to be kinetic isomers regarding the triene moiety. Herein, we report the development and application of an unprecedented, unique domino Suzuki-Miyaura/4π-electrocyclic ring-opening macrocyclization, resulting in a concise, unified, and stereoselective synthetic route to these complex targets in only 10 steps. This in turn enables ready access to a range of unnatural analogues, among which several compounds showed inhibition of T-lymphocyte proliferation at levels equal or superior to those of the natural products themselves.
Asunto(s)
Inmunosupresores/síntesis química , Lactamas/síntesis química , Lactonas/síntesis química , Compuestos Macrocíclicos/síntesis química , Inmunosupresores/química , Lactamas/química , Lactonas/química , Compuestos Macrocíclicos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Background: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has been revealed to possess strong in vitro and in vivo immunosuppressive effects. Purpose: The aim of present study was to prepare and characterize BBP-encapsulated polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-b-PEG) nanoparticles and to evaluate its in vivo efficacy against innate and adaptive immune responses. Methods: Male BALB/c mice were orally administered with BBP alone and BBP- encapsulated nanoparticles equivalent to 5, 10 and 20 mg/kg of BBP in distilled water for a period of 14 days. The immunomodulatory potential was appraised by determining its effects on non-specific and specific immune parameters. Results: The results showed that BBP was successfully encapsulated in PLGA-b-PEG polymer with 154.3 nm size and high encapsulation efficiency (79%) while providing a sustained release for 48 hours. BBP nanoparticles showed significant enhanced dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity, reactive oxygen species (ROS) production, serum levels of ceruloplasmin and lysozyme, immunoglobulins and myloperoxidase (MPO) plasma levels when compared to unencapsulated BBP. Enhanced dose-dependent inhibition was also observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines, and reduction in rat paw oedema in BBP nanoparticles treated mice. At higher doses the suppressive effects of the BBP nanoparticles on various cellular and humoral parameters of immune responses were comparable to that of cyclosporine-A at 20 mg/kg. Conclusion: These findings suggest that the immunosuppressive effects of BBP were enhanced as PLGA-b-PEG nanoparticles.
Asunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Curcumina/análogos & derivados , Inmunidad Innata/efectos de los fármacos , Inmunosupresores/farmacología , Nanopartículas/química , Piperidinas/farmacología , Polietilenglicoles/química , Poliglactina 910/química , Inmunidad Adaptativa/inmunología , Animales , Curcumina/síntesis química , Curcumina/química , Curcumina/farmacología , Relación Dosis-Respuesta a Droga , Inmunidad Innata/inmunología , Inmunosupresores/síntesis química , Inmunosupresores/química , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Ovinos , Relación Estructura-ActividadRESUMEN
The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.