RESUMEN
Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.
Asunto(s)
Glucurónidos/farmacología , Proteína Quinasa C-epsilon/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Glucurónidos/química , Glucurónidos/metabolismo , Estructura Molecular , Proteína Quinasa C-epsilon/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The discovery of two new components of the migratory pheromone used by sea lamprey to guide adults to spawning grounds was recently reported. These hold promise for use in a pheromone-based control program for this species, an invasive pest in the Great Lakes. Details of the structure determination of these steroidal bis-sulfates [petromyzosterol disulfate (PSDS, 2) and petromyzonamine disulfate (PADS, 3)] are described here. Pattern matching of 1H NMR data was particularly valuable. This involved comparison of spectra of the natural samples of 2 and 3 with those of appropriate steroidal analogues [e.g., petromyzonol sulfate (PS, 1, a previously known sea lamprey bile acid derivative that is a third component of the migratory pheromone), cholesterol sulfate (6), and squalamine (8)] and model compounds containing the unprecedented aminolactam substructure present in 3. The logic underlying the iterative analyses used is presented.
Asunto(s)
Colestanos/química , Petromyzon/metabolismo , Feromonas/química , Pirrolidinonas/química , Animales , Conformación Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
[Structure: see text] Trialkylsilyl triflates effect cyclization of ester-imides such as 2 to produce adducts such as 4a. Trapping of the in situ generated, nucleophilic ketene acetal (cf. 5a) is a key aspect of the transformation. A range of substrates amenable to this operationally simple reaction is reported. In many instances the levels of diastereoselectivity are very high. Mechanistic points are inferred from spectroscopic observations.
Asunto(s)
Ésteres/química , Imidas/química , Ciclización , Estructura Molecular , Alcaloides de Pirrolicidina/químicaRESUMEN
A synthesis of the structurally fascinating fungal metabolite UCS1025A (1) was accomplished. It features a likely biomimetic approach to the octalin subunit via an intramolecular Diels-Alder (IMDA) reaction of a putative triene precursor (2), preceded by an efficient construction of the bisheteratriquinane subunit within that compound. Specifically, an intramolecular silyl triflate-induced cyclization of an in situ-generated silyl ketene acetal onto an imide carbonyl group (e.g., 7 to 8) was developed. The IMDA relative reactivities of a family of valence bond isomers, each differing in the precise nature of the dienophilic subunit, were determined. Under biologically relevant conditions (D2O, pH 7.2 buffer, ca. 25 degrees C), triene 2, via its lactone ring-opened congener, underwent very fast (t1/2 = 10 min) conversion to the ring-opened forms of 1 (i.e., 5a) and the tetraepimeric, alternative endo-adduct, 3 [i.e., (tetraepi)-5a].
Asunto(s)
Alcaloides de Pirrolicidina/síntesis química , Acremonium/química , Materiales Biomiméticos/síntesis química , IsomerismoRESUMEN
The sea lamprey is an ancient, parasitic fish that invaded the Great Lakes a century ago, where it triggered the collapse of many fisheries. Like many fishes, this species relies on chemical cues to mediate key aspects of its life, including migration and reproduction. Here we report the discovery of a multicomponent steroidal pheromone that is released by stream-dwelling larval lamprey and guides adults to spawning streams. We isolated three compounds with pheromonal activity (in submilligram quantities from 8,000 l of larval holding water) and deduced their structures. The most important compound contains an unprecedented 1-(3-aminopropyl)pyrrolidin-2-one subunit and is related to squalamine, an antibiotic produced by sharks. We verified its structure by chemical synthesis; it attracts adult lamprey at very low (subpicomolar) concentrations. The second component is another new sulfated steroid and the third is petromyzonol sulfate, a known lamprey-specific bile acid derivative. This mixture is the first migratory pheromone identified in a vertebrate and is being investigated for use in lamprey control.
Asunto(s)
Migración Animal/efectos de los fármacos , Petromyzon/fisiología , Feromonas/química , Feromonas/farmacología , Esteroides/química , Esteroides/farmacología , Migración Animal/fisiología , Animales , Colestanos/química , Colestanos/farmacología , Ácidos Cólicos/química , Ácidos Cólicos/farmacología , Larva/efectos de los fármacos , Larva/metabolismo , Larva/fisiología , Estructura Molecular , Odorantes , Petromyzon/metabolismo , Feromonas/aislamiento & purificación , Pirrolidinonas/química , Pirrolidinonas/farmacología , Esteroides/aislamiento & purificaciónRESUMEN
Host-[2]rotaxanes, containing a diarginine-derivatized dibenzo-24-crown-8 (DB24C8) ether as the ring and a cyclophane pocket or an aromatic cleft as one blocking group, are cell transport agents. These hosts strongly associate with a variety of amino acids, dipeptides, and fluorophores in water (1 mM phosphate buffer, pH 7.0), DMSO, and a 75/25 (v/v) buffer to DMSO solution. All peptidic guests in all solvent systems have association constants (K(A)'s) in the range of 1 x 10(4) to 5 x 10(4) M(-)(1), whereas the K(A) range for the fluorophores is 1 x 10(4) to 9 x 10(5) M(-)(1). Association constants for the cyclophane itself, cyclophane 3, are smaller. These values are in the 1 x 10(3) to 5 x 10(3) M(-)(1) range, which shows that the rotaxane architecture is advantageous for guest binding. Cyclophane-[2]rotaxane 1 efficiently transports fluorescein and a fluorescein-protein kinase C (PKC) inhibitor into eukaryotic COS-7 cells, including the nucleus. Interestingly, cleft-[2]rotaxane 2 does not transport fluorescein as efficiently, even though the results from the fluorescence assays show that both [2]rotaxanes bind fluorescein with the same ability.
Asunto(s)
Portadores de Fármacos/química , Animales , Arginina/análogos & derivados , Arginina/química , Arginina/farmacocinética , Materiales Biomiméticos/química , Materiales Biomiméticos/metabolismo , Células COS , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Chlorocebus aethiops , Portadores de Fármacos/síntesis química , Portadores de Fármacos/farmacocinética , Éteres Cíclicos/química , Éteres Cíclicos/farmacocinética , Fluoresceína/química , Fluoresceína/farmacocinética , Cinética , Modelos Moleculares , RotaxanosRESUMEN
Small cyclophanes containing aromatic groups and dialkyl ammonium ions were created as model systems of the cation-pi complexes found at some protein binding domains. The hosts had different shapes in order to investigate the effect the arrangement of ammonium ions to aromatic surfaces has on their reactivity. pK(a) values of the hosts were substantially different in DMSO or (95/5) DMSO/D(2)O solutions, which showed that the ions existed in different environments of the hosts. Electrostatic charges, as determined by density functional calculations, revealed that the magnitude of a cationic charge depends on its position relative to an aromatic ring. Association constants of the hosts bound to the sodium salt of N-acetyl phenylalanine in d(6)-DMSO and in (95/5) d(6)-DMSO/D(2)O solutions were inversely proportional to the magnitude of the hosts' acidity constants. These results suggest that the magnitude of the positive charge for cationic groups of cation-pi complexes is reduced by being associated with electron-rich faces of aromatic rings. The aromatic rings, however, lessen the desolvation penalty that must be overcome for ligand binding, giving an overall more favorable association.