RESUMEN
Increasing the structural options in medicinal chemistry is a promising approach to develop new drug candidates. In this research, we designed and synthesized a series of B-hydroxyphenyl phosphine borane derivatives and investigated their structure-property and structure-activity relationships. The synthesized B-phenylphosphine borane derivatives exhibited sufficient stability in aqueous media, weaker hydrophobicity than the corresponding alkanes and silanes, and sufficient affinity for lipid membranes to enable permeability. Several B-hydroxyphenyl phosphine borane derivatives exhibited significant estrogen receptor (ER) agonistic activity with superior ligand-lipophilicity efficiency (LLE). The phosphine borane framework appears to be a promising option for structural development in drug discovery studies.
RESUMEN
Liver X receptor (LXR) α and LXRß are nuclear receptors playing key roles in lipid metabolism, and LXR ligands are attractive drug candidates for metabolic disorders. Here we report the structural development of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenylsilane derivatives as LXR agonists bearing silyl functionalities as the hydrophobic pharmacophore, based on the structure of the known sulfonamide LXR agonist T0901317. Most of the synthesized compounds exhibit agonistic activity toward LXRs, but the LXR subtype-selectivity differs depending upon the substituents on the silicon atom. Among them, tri(n-propyl) derivative 12 shows potent LXR-agonistic activity with moderate α subtype-selectivity, while dimethylphenylsilyl derivative 19 shows modest ß-selectivity. These results indicate that silanes can serve as an alternative to the sulfonamide moiety of LXR agonists, and are promising structural options for the development of novel subtype-selective LXR agonists.
Asunto(s)
Hidrocarburos Fluorados , Receptores Citoplasmáticos y Nucleares , Hidrocarburos Fluorados/farmacología , Hígado/metabolismo , Receptores X del Hígado/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/farmacologíaRESUMEN
Niemann-Pick disease type C is a rare, fatal neurodegenerative disorder characterized by massive intracellular accumulation of cholesterol. In most cases, loss-of-function mutations in the NPC1 gene that encodes lysosomal cholesterol transporter NPC1 are responsible for the disease, and more than half of the mutations are considered to interfere with the biogenesis or folding of the protein. We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones. A photo-crosslinking study confirmed direct binding of itraconazole to a representative folding-defective mutant protein, NPC1-I1061T. Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the oxysterol-derived chaperones or an HDAC inhibitor, LBH-589, our findings should offer new starting points for medicinal chemistry efforts to develop better pharmacological chaperones for NPC1.
Asunto(s)
Descubrimiento de Drogas/métodos , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Pliegue de Proteína/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/análisis , Mutación/efectos de los fármacos , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/genética , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Selective estrogen receptor (ER) down-regulators (SERDs) are pure ER antagonists that also induce ER degradation upon binding to the receptor. Although SERDs have been developed for the treatment of ER-positive breast cancers for nearly a decade, their precise mechanism(s) of action and structure-activity relationship are still unclear. Generally, Western blotting is used to examine the effects of SERDs on ER protein levels, but the methodology is low-throughput and not quantitative. Here, we describe a quantitative, high-throughput, luciferase-based assay for the evaluation of SERDs activity. For this purpose, we established stable recombinant HEK-293 cell lines expressing ERα fused with emerald luciferase. We also designed and synthesized new diphenylmethane derivatives as candidate SERDs, and evaluated their SERDs activity using the developed system in order to examine their structure-activity relationship, taking EC50 as a measure of potency, and Emax as a measure of efficacy.
Asunto(s)
Compuestos de Bencidrilo/química , Regulación hacia Abajo/efectos de los fármacos , Receptor alfa de Estrógeno/antagonistas & inhibidores , Compuestos de Bencidrilo/farmacología , Sitios de Unión , Ciclofenil/química , Ciclofenil/metabolismo , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Fenoles/química , Fenoles/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERα-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4-heterocycle-4-phenylheptane skeleton.
Asunto(s)
Antagonistas del Receptor de Estrógeno/farmacología , Heptanos/farmacología , Indoles/farmacología , Pirroles/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Tiofenos/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Antagonistas del Receptor de Estrógeno/síntesis química , Antagonistas del Receptor de Estrógeno/química , Heptanos/síntesis química , Heptanos/química , Humanos , Indoles/síntesis química , Indoles/química , Ligandos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Receptores de Estrógenos/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Células Tumorales CultivadasRESUMEN
Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Glicoproteínas de Membrana/antagonistas & inhibidores , Fenantridinas/farmacología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Péptidos y Proteínas de Señalización Intracelular , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Estructura Molecular , Mutación , Proteína Niemann-Pick C1 , Fenantridinas/síntesis química , Fenantridinas/química , Relación Estructura-ActividadRESUMEN
Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment. Based on the idea that polypharmacological agents with multiple targets would have a more robust action, we set out to develop dual BRD4/HDAC inhibitors. Here, we describe the design and synthesis of N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) as a BRD4/HDAC dual inhibitor. This compound showed HL-60 cell growth-inhibitory and apoptosis-inducing activity, as well as all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation-enhancing activity, and c-MYC production-inhibitory activity. Interestingly, it also showed growth-inhibitory activity towards BRD4 inhibitor-resistant cells.
Asunto(s)
Inhibidores de Histona Desacetilasas/síntesis química , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Acetilación , Adenina/síntesis química , Adenina/química , Adenina/toxicidad , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/toxicidad , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-myc/metabolismo , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Tretinoina/farmacologíaRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a"). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.
Asunto(s)
PPAR alfa/agonistas , PPAR delta/agonistas , Acetamidas/síntesis química , Acetamidas/química , Acetamidas/metabolismo , Sitios de Unión , Genes Reporteros , Células HEK293 , Humanos , Ligandos , PPAR alfa/metabolismo , PPAR delta/metabolismo , Unión Proteica , Estereoisomerismo , Tiazolidinedionas/químicaRESUMEN
The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPARα/δ dual agonists. The SAR studies revealed that the acetamide functionality and adjacent methyl group contribute greatly to the agonistic activity. Compound (S)-10 was the most potent PPARα/δ dual agonist among the compounds synthesized (PPARα EC50=17nM, PPARδ EC50=23nM).
Asunto(s)
Acetamidas/farmacología , PPAR alfa/agonistas , PPAR delta/agonistas , Acetamidas/síntesis química , Acetamidas/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors. Among the compounds examined, 20, 28 and 29 enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation and inhibited tumor necrosis factor (TNF)-α production by THP-1 cells.
Asunto(s)
Antineoplásicos/farmacología , Azepinas/farmacología , Benzodiazepinas/farmacología , Diferenciación Celular/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Triazoles/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Azepinas/química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Proteínas de Ciclo Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Células Tumorales CultivadasRESUMEN
Acetyl-CoA carboxylases (ACCs) catalyze a critical step in de novo lipogenesis, and are considered as promising targets for treatment of obesity, dyslipidemia and type 2 diabetes mellitus. On the other hand, peroxisome proliferator-activated receptors (PPARs) are well-established therapeutic targets for these metabolic syndrome-related diseases. Therefore, we considered that dual modulators of ACC and PPARs would be promising candidates as therapeutic agents. Here, we designed a series of acetamides based on the molecular similarity between ACC inhibitors and PPAR agonists. Screening of the synthesized compounds identified N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel ACC2 inhibitors with PPARα/PPARδ dual agonistic activity. Structure-activity relationship studies and further structural elaboration afforded compounds with distinct activity profiles. Our findings should be helpful for the discovery of candidate agents with an appropriate balance of ACC-inhibitory and PPAR-activating activities for therapeutic lipid control.
Asunto(s)
Acetamidas/farmacología , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , PPAR alfa/agonistas , PPAR delta/agonistas , Acetamidas/síntesis química , Acetamidas/química , Acetil-CoA Carboxilasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
Acetylation of histone is a key epigenetic modification, and contributes to many DNA-dependent cellular processes. The bromodomain structure, which consists of approximately 110 amino acid residues, serves as a 'reader' that recognizes acetylated lysine in histones, leading to recruitment of positive transcriptional elongation factor b (P-TEFb), and thereby promoting transcriptional activity and chromatin remodeling. Among bromodomain-containing proteins, members of the bromodomain and extra-terminal domain (BET) family contain tandem N-terminal bromodomains. BET proteins, especially BRD4, have attracted interest as candidate therapeutic targets due to their putative involvement in the pathogenesis of various diseases, including cancer and inflammatory diseases. Several BET inhibitors are under clinical trial for treatment of various cancers. Furthermore, polypharmacological agents such as dual kinase/BET inhibitors and dual histone deacetylase (HDAC)/BET inhibitors have recently been developed, in addition to agents that degrade BET family proteins, such as proteolysis-targeting chimeras (PROTACs). This paper reviews recent progress in epigenetic therapy targeting the BET bromodomain.
Asunto(s)
Antineoplásicos/farmacología , Epigénesis Genética/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Dominios Proteicos/efectos de los fármacos , Acetilación , Proteínas de Ciclo Celular , Histonas/metabolismo , Humanos , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/química , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/químicaRESUMEN
Vitamin D receptor (VDR) is a family of nuclear receptors (NR) that regulates physiological effects such as the immune system, calcium homeostasis, and cell proliferation. We synthesized non-secosteroidal VDR ligands bearing a long alkyl chain based on the diphenylpentane skeleton. The VDR-mediated transcriptional activities of the synthesized compounds were evaluated using a reporter gene assay and HL-60 cell differentiation-inducing assay. We herein described the structure-activity relationship and effects of alkyl-chain length on VDR-mediated transcriptional activity.
Asunto(s)
Pentanos/química , Receptores de Calcitriol/agonistas , Alquilación , Bioensayo , Diferenciación Celular/efectos de los fármacos , Células HL-60 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Pentanos/síntesis química , Pentanos/farmacología , Receptores de Calcitriol/química , Receptores de Calcitriol/genética , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetylated lysines in histones. Among them, BRD4 is a candidate target molecule of therapeutic agents for diverse diseases, including cancer and inflammatory disease. As a part of our continuing structural development studies of thalidomide to obtain a broad spectrum of biological modifiers based on the 'multi-template' approach, in this work we focused on BRD4-inhibitory activity, and discovered that N6-benzoyladenine derivatives exhibit this activity. Structure-activity relationship studies led to N6-(2,4,5-trimethoxybenzoyl)adenine (29), which exhibits potent BRD4 bromodomain1 inhibitory activity with an IC50 value of 0.427µM. N6-Benzoyladenine appears to be a new chemical scaffold for development of BRD4 inhibitors.
Asunto(s)
Adenina/análogos & derivados , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Adenina/química , Adenina/farmacología , Proteínas de Ciclo Celular , Descubrimiento de Drogas , Relación Estructura-ActividadRESUMEN
Niemann-Pick disease type C is a fatal neurodegenerative disease, and its major cause is mutations in NPC1 gene. This gene encodes NPC1 protein, a late endosomal polytopic membrane protein required for intracellular cholesterol trafficking. One prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization of the protein, leading to loss-of-function phenotype. We have previously demonstrated that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to NPC1(I1061T) mutant protein corrects the localization/maturation defect of the mutant protein. Here, we disclose detailed structure-activity relationships of oxysterol derivatives as pharmacological chaperones for NPC1(I1061T) mutant.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Glicoproteínas de Membrana/antagonistas & inhibidores , Esteroles/farmacología , Proteínas Portadoras/genética , Relación Dosis-Respuesta a Droga , Humanos , Péptidos y Proteínas de Señalización Intracelular , Glicoproteínas de Membrana/genética , Estructura Molecular , Mutación , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/genética , Esteroles/síntesis química , Esteroles/química , Relación Estructura-ActividadRESUMEN
Polo-like kinase (Plk) 1 is a serine-threonine protein kinase that plays a role in cell division, and its overexpression is highly correlated with aggressiveness and prognosis of many cancers. We have designed, synthesized and evaluated a series of terphenyl compounds as inhibitors of the kinase activity of Plk1. Some of them act as non-ATP-competitive Plk1 inhibitors.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Compuestos de Terfenilo/farmacología , Proteínas de Ciclo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Compuestos de Terfenilo/síntesis química , Compuestos de Terfenilo/química , Quinasa Tipo Polo 1RESUMEN
Suppression of vitamin D receptor (VDR)-mediated transcription is expected to be of therapeutic value in Paget's disease of bone. It is known that interaction between VDR and coactivators is necessary for VDR transactivation, and the interaction occurs when VDR recognizes an LXXLL peptide motif of coactivators. We previously reported that benzodiazepine derivatives designed as LXXLL peptide mimetics inhibited the interaction of VDR and coactivators, and reduced VDR transcription. Here, we investigated the structure-activity relationship of 7- and 8-substituted benzodiazepine derivatives, and established that the amino group at the 8-position is critical for the inhibitory activity.
Asunto(s)
Benzodiazepinas/química , Materiales Biomiméticos/química , Péptidos/química , Receptores de Calcitriol/antagonistas & inhibidores , Secuencia de Aminoácidos , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Sitios de Unión , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/farmacología , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Relación Estructura-Actividad , Activación Transcripcional/efectos de los fármacosRESUMEN
A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2-yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5-dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2-furamide (17) possessed the most potent inhibitory activity against Ca(2+)-induced mitochondrial swelling. The structural development, synthesis and structure-activity relationship of these compounds are described.
Asunto(s)
Calcio/química , Dantroleno/farmacología , Proteínas de Transporte de Membrana Mitocondrial/antagonistas & inhibidores , Relajación Muscular/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Calcio/metabolismo , Cristalografía por Rayos X , Ciclosporina/síntesis química , Ciclosporina/química , Ciclosporina/farmacología , Ciclosporinas/síntesis química , Ciclosporinas/química , Ciclosporinas/farmacología , Dantroleno/análogos & derivados , Dantroleno/química , Relación Dosis-Respuesta a Droga , Células HL-60 , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Modelos Moleculares , Estructura Molecular , Peso Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 µM but showed no transactivational activity even at 30 µM. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.
Asunto(s)
Dibenzoxazepinas/química , Dibenzoxazepinas/farmacología , Receptores Nucleares Huérfanos/química , Cristalografía por Rayos X , Dibenzoxazepinas/síntesis química , Diseño de Fármacos , Ligandos , Receptores X del Hígado , Espectroscopía de Resonancia Magnética , Transcripción Genética/efectos de los fármacosRESUMEN
We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC(50): 0.13 µM) than clinically used anti-androgen bicalutamide (IC(50): 0.67 µM) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds.