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1.
Proc Natl Acad Sci U S A ; 109(42): 17034-9, 2012 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-23035247

RESUMEN

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Apoptosis/efectos de los fármacos , Aurora Quinasa B , Aurora Quinasas , Benzotiazoles , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cartilla de ADN/genética , Diaminas , Citometría de Flujo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Immunoblotting , Compuestos Orgánicos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-myc/metabolismo , Quinolinas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
2.
Bioorg Med Chem ; 19(7): 2145-55, 2011 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21420867

RESUMEN

The site specific functionalization of phosphate groups with amino acid side chains of substrate proteins represents one of the most important regulatory mechanisms of biological systems. Phosphorylation and dephosphorylation are reversibly catalyzed by protein kinases and protein phosphatases, and the aberrant regulation of these enzymes is associated with the onset and progression of various disease states such as cancer, diabetes, neurodegenerative and autoimmune disorders, making these proteins attractive targets for drug discovery. Here we report on strategies currently explored for the identification and development of various inhibitors directed against clinically relevant phosphatases. While over the last years, inhibition of phosphorylation has evolved into a key strategy in targeted therapies, the development of clinically relevant phosphatase inhibitors still faces major bottlenecks and is often plagued by limited selectivity and unfavorable pharmacokinetics. The reader will gain a better understanding of the importance of the field and its current limitations.


Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Animales , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Modelos Moleculares , Terapia Molecular Dirigida/métodos , Fosforilación/efectos de los fármacos , Unión Proteica , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/metabolismo , Ratas
3.
Chemistry ; 14(35): 11132-40, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18979467

RESUMEN

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.


Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , Animales , Productos Biológicos/síntesis química , Bovinos , Muerte Celular/efectos de los fármacos , Línea Celular , Lactonas , Miocardio/ultraestructura , NAD/efectos de los fármacos , NAD/metabolismo , Oxazoles , Relación Estructura-Actividad , Partículas Submitocóndricas/metabolismo
4.
Org Lett ; 10(6): 1239-42, 2008 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-18302399

RESUMEN

A concise synthesis of the core structure of the macrolide neopeltolide was developed featuring a Prins cyclization to fashion the pyran ring. Key steps in the synthesis of aldehyde 16 were a Leighton allylation and a Feringa-Minnaard asymmetric methyl cuprate addition to an unsaturated thioester. For lactonization, a classical Yamaguchi macrolactonization was used. The longest linear sequence consists of 17 steps providing lactone 26 with an overall yield of 23%.

5.
Org Lett ; 9(4): 655-8, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17256947

RESUMEN

The core structure of the macrolactone cruentaren A (1) was prepared via a ring-closing alkyne metathesis reaction. The corresponding ester 33 was constructed from the benzoic acid derivative 14 and the diol 30. As a key step in the synthesis of acid 14, an aldol reaction resulted in the required anti-OH/Me pattern. The anti-configuration in the stereotetrad of diol 30 was established by a Marshall reaction. [reaction: see text].


Asunto(s)
Antifúngicos/síntesis química , Macrólidos/síntesis química , Alquinos/química , Ácido Benzoico/química , Ésteres/química , Indicadores y Reactivos , Litio/química , Conformación Molecular , Estereoisomerismo
7.
Angew Chem Int Ed Engl ; 46(27): 5209-11, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17523207
8.
Curr Opin Chem Biol ; 13(3): 272-83, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19410499

RESUMEN

Protein phosphatases (PPs) constitute a large family of enzymes, which are crucial modulators of cellular phosphorylation events. Malfunction in PP activity has been associated with human diseases, including diabetes, obesity, cancer, and neurodegenerative and autoimmune disorders, and makes this class of enzymes attractive targets for chemical biology and medicinal chemistry research. A number of strategies are currently explored for the identification and development of various classes of PP modulators and have resulted in a plethora of chemically distinct inhibitors. Limited selectivity and adverse pharmacological properties of PP inhibitors are still major bottlenecks for further clinical development and resulted in only a few molecular entities currently in clinical trials.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Animales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/enzimología , Diabetes Mellitus/genética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Fosfoproteínas Fosfatasas/genética , Proteínas Tirosina Fosfatasas/genética
9.
Chemistry ; 14(12): 3709-20, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18306263

RESUMEN

The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.


Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , Animales , Bovinos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Corazón/efectos de los fármacos , Concentración 50 Inhibidora , Macrólidos/química , Ratones , Conformación Molecular , Estereoisomerismo
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