RESUMEN
There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
Asunto(s)
Antimaláricos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Malaria/parasitología , Plasmodium/efectos de los fármacos , Plasmodium/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Descubrimiento de Drogas , Femenino , Estadios del Ciclo de Vida/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/parasitología , Malaria/tratamiento farmacológico , Masculino , Modelos Moleculares , Factor 2 de Elongación Peptídica/antagonistas & inhibidores , Factor 2 de Elongación Peptídica/metabolismo , Plasmodium/genética , Plasmodium/crecimiento & desarrollo , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/metabolismo , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinéticaRESUMEN
The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. While alkyl branching features of the C12-ester influenced potency, the 6,7-epoxide structural motif and position was critical to PKC activation in vitro. A subset of the 6,7-epoxytiglianes were efficacious against established tumors in mice; which generally correlated with in vitro activation of PKC. Importantly, epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diterpenos/química , Diterpenos/farmacología , Proteína Quinasa C/metabolismo , Animales , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
EBC-23, 24, 25, 72, 73, 75 and 76 were isolated from the fruit of Cinnamomum laubatii (family Lauraceae) in the Australian tropical rainforests. EBC-23 (1) was synthesized stereoselectively, in nine linear steps in 8 % overall yield, to confirm the reported relative stereochemistry and determine the absolute stereochemistry. Key to the total synthesis was a series of Tietze-Smith linchpin reactions. The novel spiroacetal structural motif, exemplified by EBC-23 (1), was found to inhibit the growth of the androgen-independent prostate tumor cell line DU145 in the mouse model, indicating potential for the treatment of refractory solid tumors in adults.
Asunto(s)
Acetales/química , Antineoplásicos/química , Piranos/química , Compuestos de Espiro/química , Acetales/aislamiento & purificación , Acetales/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Australia , Línea Celular Tumoral , Cinnamomum/química , Frutas/química , Humanos , Ratones , Ratones Desnudos , Piranos/síntesis química , Piranos/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Estereoisomerismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
EBC-23 (2), a prostate anticancer agent, was isolated from the fruit of Cinnamomum laubatii (family Lauraceae) in the Australian tropical rainforest. Extensive NOE experiments enabled the relative stereochemistry of the proposed EBC-23 (2) structure to be determined. Total synthesis of both enantiopodes over nine linear steps, involving challenging RCM and spiroacetal cyclizations, confirmed the gross structure and relative and absolute stereochemistry.
Asunto(s)
Antineoplásicos/química , Clima , Piranos/química , Lluvia , Compuestos de Espiro/química , Árboles , Antineoplásicos/síntesis química , Australia , Cinnamomum/química , Estructura Molecular , Piranos/síntesis química , Compuestos de Espiro/síntesis química , EstereoisomerismoRESUMEN
An efficient method for the copper-catalyzed N-arylation of hydroxylamines with aryl iodides is described. A variety of N- and O-functionalized hydroxylamines were transformed in good to excellent yield with a broad range of aryl coupling partners. Methods for the selective deprotection of either the N- or O-substituents for further functionalization are also described.
Asunto(s)
Cobre/química , Hidrocarburos Yodados/química , Hidroxilaminas/química , Catálisis , Técnicas Químicas Combinatorias , Estructura MolecularRESUMEN
The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC50 = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED90 values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
Asunto(s)
Antimaláricos/farmacología , Descubrimiento de Drogas , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinolinas/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Modelos Animales de Enfermedad , Ratones , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.
Asunto(s)
Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Pirimidinas/química , Pirimidinas/uso terapéutico , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Humanos , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones SCID , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Pirimidinas/farmacocinética , Pirimidinas/farmacologíaRESUMEN
A simple and effective method for the preparation of benzoxazolones from nitroarenes or aryl halides is described. Partial reduction of a nitro group in the presence of a chloroformate followed by a microwave-assisted rearrangement/ring closure sequence provides a convenient and practical procedure to prepare this important pharmacophore. Rearrangement precursors were also accessed from aryl halides through transition-metal-catalyzed coupling.
Asunto(s)
Benzoxazoles/síntesis química , Hidrocarburos Halogenados/química , Nitrocompuestos/química , Benzoxazoles/química , Catálisis , Técnicas Químicas Combinatorias , Ciclización , Estructura MolecularRESUMEN
Treatment of N-aryl hydroxylamines with trichloroacetonitrile in the presence of imidazole provides a simple and effective method for the preparation of synthetically versatile 2-aminoanilines. Reactions proceed in DMF at 40 degrees C, providing the products in up to 86% isolated yield.
Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Estructura Molecular , EstereoisomerismoRESUMEN
The bis-pyrazole phosphine ligand BippyPhos is effective for the palladium-catalyzed cross-coupling of hydroxylamines with aryl bromides, chlorides, and iodides. Reactions proceed smoothly at 80 degrees C in toluene in the presence of Cs(2)CO(3) to give synthetically versatile N-arylhydroxylamine products in good to excellent yield.