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1.
Bioorg Med Chem ; 26(9): 2452-2465, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29669694

RESUMEN

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Serina C-Palmitoiltransferasa/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacocinética , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Chem Pharm Bull (Tokyo) ; 63(11): 858-65, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26521850

RESUMEN

Different crystal packing of hydrates from anhydrate crystals leads to different physical properties, such as solubility and stability. Investigation of the potential of varied hydrate formation, and understanding the stability in an anhydrous/hydrate system, are crucial to prevent an undesired transition during the manufacturing process and storage. Only one anhydrous form of T-3256336, a novel inhibitor of apoptosis (IAP) protein antagonist, was discovered during synthesis, and no hydrate form has been identified. In this study, we conducted hydrate screening such as dynamic water vapor sorption/desorption (DVS), and the slurry experiment, and characterized the solid-state properties of anhydrous/hydrate forms to determine the most desirable crystalline form for development. New hydrate forms, both mono-hydrate and hemi-hydrate forms, were discovered as a result of this hydrate screening. The characterization of two new hydrate forms was conducted, and the anhydrous form was determined to be the most desirable development form of T-3256336 in terms of solid-state stability. In addition, the stability of the anhydrous form was investigated using the water content and temperature controlled slurry experiment to obtain the desirable crystal form in the crystallization process. The water content regions of the stable phase of the desired form, the anhydrous form, were identified for the cooling crystallization process.


Asunto(s)
Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Oligopéptidos/química , Pirazinas/química , Agua/química , Rastreo Diferencial de Calorimetría , Cristalografía por Rayos X , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Humedad , Modelos Moleculares , Transición de Fase , Solubilidad
3.
Bioorg Med Chem ; 21(18): 5725-37, 2013 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-23928071

RESUMEN

We recently reported the discovery of octahydropyrrolo[1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b', which were obtained by Simmons-Smith cyclopropanation of ethylester 3a and silyl ether 3b'. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner.


Asunto(s)
Diseño de Fármacos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Pirazinas/química , Pirroles/síntesis química , Animales , Benzopiranos/síntesis química , Benzopiranos/farmacocinética , Benzopiranos/uso terapéutico , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Cristalografía por Rayos X , Femenino , Semivida , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Pirazinas/síntesis química , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Pirroles/química , Pirroles/farmacocinética , Pirroles/uso terapéutico , ARN Mensajero/metabolismo , Estereoisomerismo , Trasplante Heterólogo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
4.
Bioorg Med Chem ; 21(24): 7938-54, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24169315

RESUMEN

We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Diseño de Fármacos , Indoles/farmacología , Proteínas Inhibidoras de la Apoptosis/farmacología , Pirazinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/síntesis química , Indoles/química , Proteínas Inhibidoras de la Apoptosis/síntesis química , Proteínas Inhibidoras de la Apoptosis/química , Modelos Moleculares , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-Actividad
5.
Stem Cell Res Ther ; 14(1): 1, 2023 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-36600289

RESUMEN

BACKGROUND: Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs. METHODS: We evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose-response assays, single-cell RNA-sequencing and in vivo efficacy study. RESULTS: We observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used ß-cell inducer but no other tested ALK5 inhibitors induced ß-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced ß-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII. CONCLUSION: Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the ß-cell differentiation mechanism.


Asunto(s)
Células Madre Pluripotentes Inducidas , Humanos , Diferenciación Celular , Técnicas de Cultivo de Célula/métodos , Quinasa 8 Dependiente de Ciclina
6.
Chem Sci ; 13(3): 665-670, 2022 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-35173930

RESUMEN

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon-fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.

7.
ACS Med Chem Lett ; 11(8): 1645-1652, 2020 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-34345355

RESUMEN

Deoxyhypusine synthase (DHPS) is the primary enzyme responsible for the hypusine modification and, thereby, activation of the eukaryotic translation initiation factor 5A (eIF5A), which is key in regulating the protein translation processes associated with tumor proliferation. Although DHPS inhibitors could be a promising therapeutic option for treating cancer, only a few studies reported druglike compounds with this inhibition property. Thus, in this work, we designed and synthesized a new chemical series possessing fused ring scaffolds designed from high-throughput screening hit compounds, discovering a 5,6-dihydrothieno[2,3-c]pyridine derivative (26d) with potent inhibitory activity; furthermore, the X-ray crystallographic analysis of the DHPS complex with 26d demonstrated a distinct allosteric binding mode compared to a previously reported inhibitor. These findings could be significantly useful in the functional analysis of conformational changes in DHPS as well as the structure-based design of allosteric inhibitors.

8.
J Med Chem ; 63(6): 3215-3226, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32142284

RESUMEN

Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. Therefore, inhibition of DHPS is a promising therapeutic option for the treatment of cancer. To discover novel lead compounds that target DHPS, we conducted synthetic studies with a hit obtained via high-throughput screening. Optimization of the ring structures of the amide compound (2) led to bromobenzothiophene (11g) with potent inhibitory activity against DHPS. X-ray crystallographic analysis of 11g complexed with DHPS revealed a dramatic conformational change in DHPS, which suggests the presence of a novel allosteric site. These findings provide the basis for the development of novel therapy distinct from spermidine mimetic inhibitors.


Asunto(s)
Inhibidores Enzimáticos/química , Indoles/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Tiofenos/química , Sitio Alostérico , Cristalografía por Rayos X , Descubrimiento de Drogas , Pruebas de Enzimas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Guanina/análogos & derivados , Guanina/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Indoles/síntesis química , Indoles/metabolismo , Estructura Molecular , NAD/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/química , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Unión Proteica , Conformación Proteica/efectos de los fármacos , Espermidina/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/metabolismo
9.
J Med Chem ; 62(20): 9175-9187, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31550153

RESUMEN

Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to the lack of therapeutic agents. Herein, we report the design, synthesis, and structure-activity relationships of a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, which was identified from the phenotypic screening of chemicals that increase the level of dysferlin in myocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based phenotypic assay led to the identification of a highly potent compound, 19, with dysferlin elevation effects at double-digit nanomolar concentrations. In addition, the molecular target of our chemical series was identified as tubulin, through a tubulin polymerization assay and a competitive binding assay using a photoaffinity labeling probe.


Asunto(s)
Imidazoles/química , Distrofia Muscular de Cinturas/tratamiento farmacológico , Piridinas/química , Moduladores de Tubulina/uso terapéutico , Sitios de Unión , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Disferlina/metabolismo , Células Hep G2 , Humanos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Simulación del Acoplamiento Molecular , Distrofia Muscular de Cinturas/patología , Proteína MioD/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Estructura Terciaria de Proteína , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología
10.
J Am Chem Soc ; 130(21): 6694-5, 2008 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-18447357

RESUMEN

The first effective method for asymmetric cross-couplings of unactivated alkyl electrophiles has been developed, specifically, a nickel-based catalyst for stereoconvergent Suzuki reactions of homobenzylic bromides with alkylboranes. To the best of our knowledge, there are no previous examples of enantioselective Suzuki couplings of alkyl electrophiles (activated or unactivated). Both of the catalyst components are commercially available.


Asunto(s)
Compuestos de Bencilo/química , Hidrocarburos Halogenados/química , Compuestos de Bencilo/síntesis química , Catálisis , Hidrocarburos Halogenados/síntesis química , Níquel , Paladio , Estereoisomerismo
11.
Chem Commun (Camb) ; (35): 3619-27, 2007 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-17728874

RESUMEN

Chiral metal (M)-salen complexes are one of the most versatile asymmetric catalysts and the catalysis of trans-M(salen) complexes has been well cultivated. On the other hand, non-planar cis-beta M(salen) complexes were recently found to show unique asymmetric catalysis that cannot be attained by trans-M(salen) complexes. Moreover, related non-planar M(salalen) and M(salan) complexes were also found to exert unprecedented asymmetric catalysis. This Feature Article summarizes the seminal studies on asymmetric catalysis of non-planar M(ONNO) complexes, full utilization of which will provide marked improvement in asymmetric synthesis.

13.
J Med Chem ; 56(3): 1228-46, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23298277

RESUMEN

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Oligopéptidos/química , Oligopéptidos/farmacología , Peptidomiméticos , Prolina/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Oligopéptidos/síntesis química
18.
Chem Asian J ; 3(2): 351-8, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18175304

RESUMEN

Asymmetric oxidation catalysis with an aluminum-based complex was achieved by a combination of newly synthesized chiral aluminum(salalen) complexes (salalen = half-reduced salen = salan/salen-hybridized [ONNO]-type tetradentate ligand; salan = reduced salen, salen = N,N'-ethylenebis(salicylideneiminato)) derived from binol (1,1'-bi-2,2'-naphthol) with aqueous hydrogen peroxide as the oxidant. The combination was found to be efficient for asymmetric sulfur oxidation. Various sulfides were smoothly converted into the corresponding sulfoxides with high to excellent enantioselectivity. Thioacetals are also good substrates for the oxidation.

19.
J Am Chem Soc ; 129(7): 1978-86, 2007 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-17260986

RESUMEN

Optically active aluminum(salalen) complex 2 was newly synthesized in a modular synthetic manner, and it was found to serve as an efficient catalyst for hydrophosphonylation of aldehydes and aldimines, giving the corresponding alpha-hydroxy and alpha-amino phosphonates with high enantioselectivity, respectively. The scope of the hydrophosphonylation was wide, and both aliphatic and aromatic aldehydes and aldimines were successfully used as substrates for the reaction. The potent catalysis of the complex is attributed to its unique structure: it adopts a distorted trigonal bipyramidal configuration which allows the salalen ligand to take a cis-beta-like structure wherein the chiral amino group is located close to the metal center.


Asunto(s)
Aldehídos/química , Aluminio/química , Iminas/química , Compuestos Organometálicos/síntesis química , Organofosfonatos/química , Catálisis , Etilenodiaminas/química , Compuestos Organometálicos/química , Estereoisomerismo
20.
Plant Cell Physiol ; 47(3): 355-62, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16415067

RESUMEN

The Arabidopsis FAD7 gene encodes a plastid omega-3 fatty acid desaturase that catalyzes the desaturation of dienoic fatty acids to trienoic fatty acids in chloroplast membrane lipids. The expression of FAD7 was rapidly and locally induced by ozone exposure, which causes oxidative responses equivalent to pathogen-induced hypersensitive responses and subsequently activates various defense-related genes. This induction was reduced in salicylic acid (SA)-deficient NahG plants expressing SA hydroxylase, but was unaffected in etr1 and jar1 mutants, which are insensitive to ethylene and jasmonic acid (JA), respectively. The SA dependence of the FAD7 induction was confirmed by the exogenous application of SA. SA-induced expression of FAD7 in the npr1 mutant which is defective in an SA signaling pathway occurred to the same extent as in the wild type. Furthermore, in the sid2 mutant which lacks an enzyme required for SA biosynthesis, the expression of FAD7 was induced by ozone exposure. These results suggest that the ozone-induced expression of FAD7 gene requires SA, but not ethylene, JA, NPR1 and SID2.


Asunto(s)
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/efectos de los fármacos , Ácido Graso Desaturasas/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Transferasas Intramoleculares/metabolismo , Ozono/farmacología , Ácido Salicílico/farmacología , Arabidopsis/genética , Arabidopsis/metabolismo , Ciclopentanos/metabolismo , Etilenos/metabolismo , Ácido Graso Desaturasas/metabolismo , Oxigenasas de Función Mixta/genética , Mutación/genética , Nucleotidiltransferasas/genética , Oxilipinas , Hojas de la Planta/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , Ácido Salicílico/metabolismo , Transducción de Señal , Factores de Tiempo
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