RESUMEN
As ENT inhibitors including dilazep have shown efficacy improving oHSV1 targeted oncolytic cancer therapy, a series of dilazep analogues was synthesized and biologically evaluated to examine both ENT1 and ENT2 inhibition. The central diamine core, alkyl chains, ester linkage and substituents on the phenyl ring were all varied. Compounds were screened against ENT1 and ENT2 using a radio-ligand cell-based assay. Dilazep and analogues with minor structural changes are potent and selective ENT1 inhibitors. No selective ENT2 inhibitors were found, although some analogues were more potent against ENT2 than the parent dilazep.
Asunto(s)
Dilazep/análogos & derivados , Tranportador Equilibrativo 1 de Nucleósido/antagonistas & inhibidores , Transportador Equilibrativo 2 de Nucleósido/antagonistas & inhibidores , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Dilazep/síntesis química , Dilazep/farmacología , Tranportador Equilibrativo 1 de Nucleósido/genética , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Transportador Equilibrativo 2 de Nucleósido/genética , Transportador Equilibrativo 2 de Nucleósido/metabolismo , Humanos , Unión Proteica , Ratas , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , PorcinosRESUMEN
A diversity-oriented synthesis (DOS) strategy was developed for the synthesis of stereochemically diverse fused-ring systems containing a pyran moiety. Each scaffold contains an amine and methyl ester for further diversification via amine capping and amide coupling. Scaffold diversity was evaluated in comparison to previously prepared scaffolds by a shape-based principal moments of inertia (PMI) analysis.
Asunto(s)
Glicósidos/síntesis química , Glicósidos/química , Conformación Molecular , Piranos/química , EstereoisomerismoRESUMEN
The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.
Asunto(s)
Azetidinas/farmacocinética , Sistema Nervioso Central/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Animales , Azetidinas/sangre , Azetidinas/síntesis química , Células CACO-2 , Permeabilidad de la Membrana Celular/efectos de los fármacos , Sistema Nervioso Central/citología , Células Endoteliales/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Solubilidad , Compuestos de Espiro/sangre , EstereoisomerismoRESUMEN
An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.
Asunto(s)
Aldehídos/química , Descubrimiento de Drogas/métodos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Animales , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/química , Compuestos Macrocíclicos/química , Ratones , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Especificidad por SustratoRESUMEN
Three new Vitamin D analogs 3-5 incorporating a -CHF(2) group as an -OH surrogate have been prepared. Two of these new analogs (3 and 5) are strongly antiproliferative toward murine keratinocytes and are approximately 50 times less calciuric in vivo than the natural hormone calcitriol. The transcriptional activity of the 25-CHF(2) analog 3 is higher than that of the 1-CHF(2) analog 4.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Diseño de Fármacos , Flúor/química , Hormonas/química , Vitamina D/análogos & derivados , Animales , Productos Biológicos/síntesis química , Calcio/orina , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Hormonas/síntesis química , Hormonas/farmacología , Metilación , Ratones , Estructura Molecular , Ratas , Vitamina D/síntesis química , Vitamina D/química , Vitamina D/farmacologíaRESUMEN
The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , TransfecciónRESUMEN
Replacing the 1alpha-OH group of the natural hormone 1alpha,25-dihydroxyvitamin D(3) (calcitriol) by a 1alpha-CHF(2) group and incorporating a potentiating side chain produced two new hybrid analogs 6 and 7. Both of these two hybrid analogs are as transcriptionally active as calcitriol and are strongly antiproliferative in vitro but are low-calcemic in vivo.
Asunto(s)
Antineoplásicos/síntesis química , Calcitriol/análogos & derivados , Calcitriol/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Calcitriol/química , Calcitriol/farmacología , Calcio/orina , Línea Celular , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Ratones , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Calcitriol/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Transcripción GenéticaRESUMEN
The new 24-phenylsulfone 4a, a low-calcemic analog of the natural hormone 1alpha,25-dihydroxyvitamin D(3), is a potent (IC(50) = 28nM) and highly selective inhibitor of the human 24-hydroxylase enzyme CYP24.
Asunto(s)
Calcitriol/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacología , Esteroide Hidroxilasas/antagonistas & inhibidores , Sulfonas/química , Animales , Calcitriol/análogos & derivados , Línea Celular , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Inhibidores Enzimáticos/química , Humanos , Análisis Espectral , Transcripción Genética/efectos de los fármacos , Vitamina D3 24-HidroxilasaRESUMEN
While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach, we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation.
Asunto(s)
Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Lactamas/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/enzimología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/química , Humanos , Lactamas/química , Neuroblastoma/genética , Neuroblastoma/patología , Tretinoina/metabolismoRESUMEN
A build/couple/pair (B/C/P) strategy was employed to generate a library of 7936 stereochemically diverse 12-membered macrolactams. All 8 stereoisomers of a common linear amine precursor were elaborated to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds were further diversified via capping of two amine functionalities on SynPhase Lanterns. Reagents used for solid-phase diversification were selected using a sparse matrix design strategy with the aim of maximizing coverage of chemical space while adhering to a preset range of physicochemical properties.
Asunto(s)
Lactamas Macrocíclicas/síntesis química , Ciclización , Lactamas Macrocíclicas/química , Técnicas de Síntesis en Fase Sólida/métodos , EstereoisomerismoRESUMEN
The synthesis of a stereochemically diverse library of medium-sized rings accessible via a 'build/couple/pair' strategy is described. Key aspects of the synthesis include S(N)Ar cycloetherification of a linear amine template to afford eight stereoisomeric 8-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD-0476 (probe ML187), which had an approximately three-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening, and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.
RESUMEN
A series 2a-4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a.
Asunto(s)
Queratinocitos/efectos de los fármacos , Cetonas/química , Vitamina D/análogos & derivados , Animales , Calcio/orina , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conformación Molecular , Ratas , Relación Estructura-Actividad , Vitamina D/síntesis química , Vitamina D/farmacologíaRESUMEN
A new series of catechol hydrazines was synthesized and their structure-activity relationship (SAR) was analyzed for developing an effective phosphodiesterase 4 (PDE4) inhibitor as an anti-asthmatic drug candidate. Among the (E)-Analogues tested using in vitro assays, 5CC showed a strong PDE4 inhibitory activity and a significantly improved rolipram binding profile compared with rolipram, a prototype PDE4 inhibitor. Moreover, from in-vivo asthma model, we observed that (E)-Analogue 5CC had a good efficacy against guinea-pig respiratory tract inflammation and bronchoconstriction, along with a remarkably reduced emetic side effect, compared with rolipram. Conclusively, (E)-Analogue 5CC seems to be a promising candidate for the development of anti-asthmatic PDE4 inhibitors.