RESUMEN
Arterial and venous endothelial cells exhibit distinct molecular characteristics at early developmental stages. These lineage-specific molecular programs are instructive to the development of distinct vascular architectures and physiological conditions of arteries and veins, but their roles in angiogenesis remain unexplored. Here, we show that the caudal vein plexus in zebrafish forms by endothelial cell sprouting, migration and anastomosis, providing a venous-specific angiogenesis model. Using this model, we have identified a novel compound, aplexone, which effectively suppresses venous, but not arterial, angiogenesis. Multiple lines of evidence indicate that aplexone differentially regulates arteriovenous angiogenesis by targeting the HMG-CoA reductase (HMGCR) pathway. Treatment with aplexone affects the transcription of enzymes in the HMGCR pathway and reduces cellular cholesterol levels. Injecting mevalonate, a metabolic product of HMGCR, reverses the inhibitory effect of aplexone on venous angiogenesis. In addition, aplexone treatment inhibits protein prenylation and blocking the activity of geranylgeranyl transferase induces a venous angiogenesis phenotype resembling that observed in aplexone-treated embryos. Furthermore, endothelial cells of venous origin have higher levels of proteins requiring geranylgeranylation than arterial endothelial cells and inhibiting the activity of Rac or Rho kinase effectively reduces the migration of venous, but not arterial, endothelial cells. Taken together, our findings indicate that angiogenesis is differentially regulated by the HMGCR pathway via an arteriovenous-dependent requirement for protein prenylation in zebrafish and human endothelial cells.
Asunto(s)
Arterias/efectos de los fármacos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Neovascularización Fisiológica/efectos de los fármacos , Sulfonamidas/farmacología , Venas/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Animales , Animales Modificados Genéticamente , Arterias/fisiología , Células Cultivadas , Sistemas de Liberación de Medicamentos , Evaluación Preclínica de Medicamentos , Embrión no Mamífero , Humanos , Terapia Molecular Dirigida , Neovascularización Fisiológica/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Especificidad por Sustrato/efectos de los fármacos , Venas/fisiología , Pez Cebra/embriología , Pez Cebra/metabolismo , Pez Cebra/fisiologíaRESUMEN
A library of 91 heterocyclic compounds composed of 16 distinct scaffolds has been synthesized through a sequence of phosphine-catalyzed ring-forming reactions, Tebbe reactions, Diels-Alder reactions, and, in some cases, hydrolysis. This effort in diversity-oriented synthesis produced a collection of compounds that exhibited high levels of structural variation both in terms of stereochemistry and the range of scaffolds represented. A simple but powerful sequence of reactions thus led to a high-diversity library of relatively modest size with which to explore biologically relevant regions of chemical space. From this library, several molecules were identified that inhibit the migration and invasion of breast cancer cells and may serve as leads for the development of antimetastatic agents.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Catálisis , Técnicas Químicas Combinatorias , Ciclización , Femenino , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Estructura Molecular , Fosfinas/químicaRESUMEN
A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting alpha-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid.
Asunto(s)
Amidas/química , Oro/química , Iminas/química , Alcaloides de Pirrolicidina/síntesis química , Silanos/química , Catálisis , Ciclización , Cinética , Lactamas/química , Alcaloides de Pirrolicidina/químicaRESUMEN
Protein geranylgeranylation is critical for the function of a number of proteins such as RhoA, Rac, and Rab. Protein geranylgeranyltransferase I (GGTase-I) and Rab geranylgeranyltransferase (RabGGTase) catalyze these modifications. In this work, we first describe the identification and characterization of small molecule inhibitors of GGTase-I (GGTI) with two novel scaffolds from a library consisting of allenoate-derived compounds. These compounds exhibit specific inhibition of GGTase-I and act by competing with a substrate protein. Derivatization of a carboxylic acid emanating from the core ring of one of the GGTI compounds dramatically improves their cellular activity. The improved GGTI compounds inhibit proliferation of a variety of human cancer cell lines and cause G(1) cell cycle arrest and induction of p21(CIP1/WAF1). We also report the identification of novel small molecule inhibitors of RabGGTase. These compounds were identified first by screening our GGTI compounds for those that also exhibited RabGGTase inhibition. This led to the discovery of a common structural feature for RabGGTase inhibitors: the presence of a characteristic six-atom aliphatic tail attached to the penta-substituted pyrrolidine core. Further screening led to the identification of compounds with preferential inhibition of RabGGTase. These compounds inhibit RabGGTase activity by competing with the substrate protein. These novel compounds may provide valuable reagents to study protein geranylgeranylation.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fase G1/efectos de los fármacos , Naftalenos/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transferasas Alquil y Aril/metabolismo , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidores Enzimáticos/química , Humanos , Células K562 , Ratones , Estructura Molecular , Células 3T3 NIH , Naftalenos/química , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rac/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
This article provides an overview of the literature concerning synthetic applications of unsaturated aliphatic amino acids in the period May 2000 to December 2004.
Asunto(s)
Aminoácidos/síntesis química , Química Orgánica/métodos , Aminoácidos de Cadena Ramificada/síntesis química , Indicadores y Reactivos , Estructura Molecular , Unión Proteica , Conformación Proteica , EstereoisomerismoRESUMEN
[reaction: see text] Catalytic Sn(OTf)2-induced cyclization of linear, aryl-containing allylic N,O-acetals produced vinyl-substituted tetrahydroisoquinolines and tetrahydro-1H-beta-carbolines. The usefulness of the vinyl moiety in the resulting products was demonstrated via the synthesis of various key building blocks for alkaloid structures. The alpha-vinyl moiety was utilized in a [2,3] sigmatropic rearrangement, in ring-closing metathesis and a cross-metathesis-based synthesis of vincantril, an antianoxia agent, and a synthetic member of the vincamine type natural products.
Asunto(s)
Alcaloides/síntesis química , Carbolinas/síntesis química , Iminas/química , Isoquinolinas/síntesis química , Sulfonas/química , Compuestos de Vinilo/química , Catálisis , Ciclización , Hipoxia , Estructura Molecular , EstereoisomerismoRESUMEN
A palladium-catalyzed amidation of alkoxyallenes has been developed for the construction of linear allylic N,O-acetals under basic conditions involving (cyclic) amides, sulfonamides, carbamates, and amidophosphates. Application of the methodology provided access to the enantiopure 1-ethylquinolizidine structural motif, which is a key synthon in the synthesis of the naturally occurring poisonous frog quinolizidine 233A and derivatives such as the 1-epi-isomer of quinolizidine 207I.