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1.
Bioorg Med Chem Lett ; 28(20): 3356-3362, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30227946

RESUMEN

The pyrazolo[1,5-a]pyrimidine LDN-193189 is a potent inhibitor of activin receptor-like kinase 2 (ALK2) but is nonselective for highly homologous ALK3 and shows only modest kinome selectivity. Herein, we describe the discovery of a novel series of potent and selective ALK2 inhibitors by replacing the quinolinyl with a 4-(sulfamoyl)naphthyl, yielding ALK2 inhibitors that exhibit not only excellent discrimination versus ALK3 but also high kinome selectivity. In addition, the optimized compound 23 demonstrates good ADME and in vivo pharmacokinetic properties.


Asunto(s)
Receptores de Activinas Tipo I/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Receptores de Activinas Tipo I/química , Animales , Sitios de Unión , Descubrimiento de Drogas , Humanos , Ratones Endogámicos C57BL , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacocinética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinética
2.
ACS Comb Sci ; 19(12): 748-754, 2017 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-29024590

RESUMEN

A novel three-component, two-step, one-pot nucleophilic aromatic substitution (SNAr)-intramolecular cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.


Asunto(s)
Antimaláricos/química , Naftiridinas/química , Plasmodium falciparum/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Antimaláricos/síntesis química , Antimaláricos/farmacología , Línea Celular , Supervivencia Celular , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología
3.
Bioorg Med Chem Lett ; 26(12): 2907-2911, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27156776

RESUMEN

Novel imidazo[4,5-c]quinolin-2-ones were synthesized and evaluated in asexual blood stage and late stage gametocyte assays of Plasmodium falciparum, a major causative agent of malaria. The design of these compounds is based on a recently identified lead compound from a high throughput screen. A concise synthesis was developed that allowed for generation of analogues with substitution around both the quinoline and imidazolidinone rings. Through structure-activity relationship studies, a number of potent compounds were identified that possessed excellent antimalarial activity against both the asexual and sexual stages with minimal cytotoxicity in mammalian cells. This is the first Letter describing SAR and gametocytocidal activity of imidazo[4,5-c]quinolin-2-ones, a new lead series for malaria treatment and prevention.


Asunto(s)
Antimaláricos/farmacología , Imidazoles/farmacología , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinolonas/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-Actividad
4.
Sci Rep ; 5: 13891, 2015 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-26403635

RESUMEN

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy.


Asunto(s)
Antimaláricos/farmacología , Ensayos Analíticos de Alto Rendimiento , Pruebas de Sensibilidad Parasitaria , Plasmodium/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Calcio/metabolismo , Análisis por Conglomerados , Modelos Animales de Enfermedad , Antagonismo de Drogas , Sinergismo Farmacológico , Quimioterapia Combinada , Homeostasis/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Malaria/tratamiento farmacológico , Malaria/parasitología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fagosomas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Plasmodium/metabolismo
5.
J Am Chem Soc ; 137(16): 5569-75, 2015 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-25892103

RESUMEN

Low oxygen environments are a hallmark of solid tumors, and transcription of many hypoxia-responsive genes needed for survival under these conditions is regulated by the transcription factor HIF-1 (hypoxia-inducible factor 1). Activation of HIF-1 requires binding of its α-subunit (HIF-1α) to the transcriptional coactivator protein p300. Inhibition of the p300/HIF-1α interaction can suppress HIF-1 activity. A screen for inhibitors of the protein binding domains of p300 (CH1) and HIF-1α (C-TAD) identified an extract of the marine ascidian Eudistoma sp. as active. Novel heterocyclic alkaloids eudistidines A (1) and B (2) were isolated from the extract, and their structures assigned by spectroscopic analyses. They contain an unprecedented tetracyclic core composed of two pyrimidine rings fused with an imidazole ring. Eudistidine A (1) was synthesized in a concise four-step sequence featuring a condensation/cyclization reaction cascade between 4-(2-aminophenyl)pyrimidin-2-amine (3) and 4-methoxy-phenylglyoxal (4), while eudistidine B (2) was synthesized in a similar fashion with glyoxylic acid (5) in place of 4. Naturally occurring eudistidine A (1) effectively inhibited CH1/C-TAD binding with an IC50 of 75 µM, and synthetic 1 had similar activity. The eudistidine A (1) scaffold, which can be synthesized in a concise, scalable manner, may provide potential therapeutic lead compounds or molecular probes to study p300/HIF-1α interactions and the role these proteins play in tumor response to low oxygen conditions. The unique structural scaffolds and functional group arrays often found in natural products make these secondary metabolites a rich source of new compounds that can disrupt critical protein-protein binding events.


Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Proteína p300 Asociada a E1A/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Alcaloides/síntesis química , Animales , Proteína p300 Asociada a E1A/química , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Compuestos Policíclicos/síntesis química , Unión Proteica/efectos de los fármacos , Urocordados/química
6.
Chem Sci ; 5(10): 4091-4098, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25346842

RESUMEN

A series of cyclometalated Z-selective ruthenium olefin metathesis catalysts with alterations to the N-heterocyclic carbene (NHC) ligand were prepared. X-Ray crystal structures of several new catalysts were obtained, elucidating the structural features of this class of cyclometalated complexes. The metathesis activity of each stable complex was evaluated, and one catalyst, bearing geminal dimethyl backbone substitution, was found to be comparable to our best Z-selective metathesis catalyst to date.

7.
Proc Natl Acad Sci U S A ; 111(31): 11365-70, 2014 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-25049379

RESUMEN

In the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), NF-κB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IκB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-κB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B-cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.


Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Linfoma de Células B Grandes Difuso/enzimología , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Adenina/análogos & derivados , Animales , Azepinas/farmacología , Azepinas/toxicidad , Proteínas de Ciclo Celular , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular , Sinergismo Farmacológico , Humanos , Quinasa I-kappa B/química , Quinasa I-kappa B/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones SCID , Proteínas Nucleares/metabolismo , Piperidinas , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Pirazoles/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/metabolismo , Triazoles/farmacología , Triazoles/toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Bioorg Med Chem Lett ; 23(15): 4398-403, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23787099

RESUMEN

Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC50 values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-yes/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-yes/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/toxicidad , Relación Estructura-Actividad
9.
Biomacromolecules ; 13(8): 2546-53, 2012 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-22783892

RESUMEN

Described herein is the efficient synthesis and evaluation of bioactive arginine-glycine-aspartic acid (RGD) functionalized polynorbornene-based materials for cell adhesion and spreading. Polynorbornenes containing either linear or cyclic RGD peptides were synthesized by ring-opening metathesis polymerization (ROMP) using the well-defined ruthenium initiator [(H(2)IMes)(pyr)(2)(Cl)(2)Ru═CHPh]. The random copolymerization of three separate norbornene monomers allowed for the incorporation of water-soluble polyethylene glycol (PEG) moieties, RGD cell recognition motifs, and primary amines for postpolymerization cross-linking. Following polymer synthesis, thin-film hydrogels were formed by cross-linking with bis(sulfosuccinimidyl) suberate (BS(3)), and the ability of these materials to support human umbilical vein endothelial cell (HUVEC) adhesion and spreading was evaluated and quantified. When compared to control polymers containing either no peptide or a scrambled RDG peptide, polymers with linear or cyclic RGD at varying concentrations displayed excellent cell adhesive properties in both serum-supplemented and serum-free media. Polymers with cyclic RGD side chains maintained cell adhesion and exhibited comparable integrin binding at a 100-fold lower concentration than those carrying linear RGD peptides. The precise control of monomer incorporation enabled by ROMP allows for quantification of the impact of RGD structure and concentration on cell adhesion and spreading. The results presented here will serve to guide future efforts for the design of RGD functionalized materials with applications in surgery, tissue engineering, and regenerative medicine.


Asunto(s)
Materiales Biocompatibles/síntesis química , Adhesión Celular , Células Endoteliales de la Vena Umbilical Humana/fisiología , Hidrogeles/síntesis química , Oligopéptidos/química , Plásticos/química , Materiales Biocompatibles/química , Supervivencia Celular , Células Cultivadas , Humanos , Hidrogeles/química , Polietilenglicoles/química , Polimerizacion , Unión Proteica , Ingeniería de Tejidos
10.
J Am Chem Soc ; 134(1): 693-9, 2012 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-22097946

RESUMEN

Several new C-H-activated ruthenium catalysts for Z-selective olefin metathesis have been synthesized. Both the carboxylate ligand and the aryl group of the N-heterocyclic carbene have been altered and the resulting catalysts evaluated using a range of metathesis reactions. Substitution of bidentate with monodentate X-type ligands led to a severe attenuation of metathesis activity and selectivity, while minor differences were observed between bidentate ligands within the same family (e.g., carboxylates). The use of nitrato-type ligands in place of carboxylates afforded a significant improvement in metathesis activity and selectivity. With these catalysts, turnover numbers approaching 1000 were possible for a variety of cross-metathesis reactions, including the synthesis of industrially relevant products.


Asunto(s)
Alquenos/química , Rutenio/química , Catálisis , Cinética , Estereoisomerismo , Especificidad por Sustrato
11.
Org Lett ; 12(15): 3540-3, 2010 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-20614867

RESUMEN

The first intramolecular cycloaddition reactions of cyclopropenone ketals with tethered electron-deficient, electron-rich, and neutral 1-substituted dienes are reported, constituting inverse electron demand, normal, and neutral Diels-Alder reactions, that provide exclusively the exo [4 + 2] cycloaddition products without the intervention of [1 + 2], [3 + 2], or [3 + 4] cycloadducts in reactions whose courses do not depend on the reaction conditions, the diene activating substituent, or the nature of the tethering.


Asunto(s)
Ciclopropanos/química , Polienos/química , Ciclización , Éteres Cíclicos/química , Estructura Molecular , Estereoisomerismo
12.
J Am Chem Soc ; 132(25): 8527-9, 2010 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-20527885

RESUMEN

The first intramolecular thermal reactions of cyclopropenone ketals are reported and the work examined substrates tethered to an electron-deficient olefin bearing a single electron-withdrawing substituent. Whereas the intermolecular variants of the reactions provide only the products of an endo-selective [1 + 2] cycloaddition or a carbonyl addition reaction of a thermally generated pi-delocalized singlet vinylcarbene, the intramolecular variants provide either [1 + 2] or [3 + 2] cycloadducts in reactions that depend on the reaction conditions, the alkene-activating substituent, and the nature of the tethering. In addition to providing key mechanistic insights into the thermal [3 + 2] cycloaddition reaction for such substrates, they were also found to proceed under conditions that reflect the ease and regioselectivity of the cyclopropenone ketal cleavage for pi-delocalized singlet vinylcarbene generation. The most effective combination of structural features that impact the reactivity was observed with substrates bearing an aldehyde- or ketone-substituted electron-deficient olefin and incorporating an aryl cyclopropenone ketal substituent built into the linking tether. Simply warming a solution of such substrates in toluene at 80-100 degrees C directly provided the [3 + 2] cycloadducts in excellent yields (60-88%) under mild thermal reaction conditions.


Asunto(s)
Ciclopropanos/química , Estereoisomerismo , Temperatura
13.
J Am Chem Soc ; 124(33): 9751-5, 2002 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-12175233

RESUMEN

The influence of natural and unnatural i, i + 4 aromatic side chain-side chain interactions on alpha-helix stability was determined in Ala-Lys host peptides by circular dichroism (CD). All interactions investigated provided some stability to the helix; however, phenylalanine-phenylalanine (F-F) and phenylalanine-pentafluorophenylalanine (F-f5F) interactions resulted in the greatest enhancement in helicity, doubling the helical content over i, i + 5 control peptides at internal positions. Quantification of these interactions using AGADIR multistate helix-coil algorithm revealed that the F-F and F-f5F interaction energies are equivalent at internal positions in the sequence (deltaGF-F = deltaGF-f5F = -0.27 kcal/mol), despite the differences in their expected geometries. As the strength of a face-to-face stacked phenyl-pentafluorophenyl interaction should surpass an edge-to-face or offset-stacked phenyl-phenyl interaction, we believe this result reflects the inability of the side chains in F-f5F to attain a fully stacked geometry within the context of an alpha-helix. Positioning the interactions at the C-terminus led to much stronger interactions (deltaGF-F = -0.8 kcal/mol; deltaGF-f5F = -0.55 kcal/mol) likely because of favorable chi(1) rotameric preferences for aromatic residues at C-capping regions of alpha-helices, suggesting that aromatic side chain-side chain interactions are an effective alpha-helix C-capping method.


Asunto(s)
Aminoácidos/química , Péptidos/química , Estructura Secundaria de Proteína , Alanina/química , Secuencia de Aminoácidos , Dicroismo Circular , Lisina/química , Datos de Secuencia Molecular , Fenilalanina/química , Termodinámica
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