RESUMEN
The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most potent compounds against a variety of human breast and prostate cancer (BC/PC) cell lines were compounds 16 (VNHM-1-66), 20 (VNHM-1-81), and 22 (VNHM-1-73). In these cell lines, the compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In PC cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. More importantly, VNHM-1-81 has strong in vivo antibreast and antiprostate cancer activities, while VNHM-1-73 exhibited strong in vivo antibreast cancer activity, with no apparent host toxicity. Clearly, these lead compounds are strong candidates for development for the treatments of human breast and prostate cancers.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Tretinoina/análogos & derivados , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Células MCF-7 , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Estructura Molecular , Neoplasias de la Próstata/patología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Adrenérgicos/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Tretinoina/síntesis química , Tretinoina/química , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
Resistance to aromatase inhibitors is a major concern in the treatment of breast cancer. Long-term letrozole cultured (LTLC) cells represent a model of resistance to aromatase inhibitors. The LTLC cells were earlier generated by culturing MCF-7Ca, the MCF-7 human breast cancer cell line stably transfected with human placental aromatase gene for a prolonged period in the presence of letrozole. In the present study the effect of RAMBA, VN/14-1 on the sensitivity of LTLC cells upon multiple passaging and the mechanisms of action of VN/14-1 in such high passage LTLC (HP-LTLC) cells was investigated. We report that multiple passaging of LTLC cells (HP-LTLC cell clones) led to profound decrease in their sensitivity to VN/14-1. Additionally, microarray studies and protein analysis revealed that VN/14-1 induced marked endoplasmic reticulum (ER) stress and autophagy in HP-LTLC cells. We further report that VN/14-1 in combination with thapsigargin exhibited synergistic anti-cancer effect in HP-LTLC cells. Preliminary pharmacokinetics in rats revealed that VN/14-1 reached a peak plasma concentration (Cmax) within 0.17h after oral dosing. Its absolute oral bioavailability was >100%. Overall these results indicate potential of VN/14-1 for further clinical development as a potential oral agent for the treatment of breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Autofagia/efectos de los fármacos , Neoplasias de la Mama/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Imidazoles/farmacología , Imidazoles/farmacocinética , Tretinoina/análogos & derivados , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Disponibilidad Biológica , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Imidazoles/administración & dosificación , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Ratas , Ratas Sprague-Dawley , Tapsigargina/farmacología , Tretinoina/administración & dosificación , Tretinoina/farmacocinética , Tretinoina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Metal ions have well-established catalytic and structural roles in proteins. Much of the knowledge acquired about metalloenzymes has been derived using spectroscopic techniques and X-ray crystallography, but these methodologies are less effective for studying metal ions that are not tightly bound to biomacromolecules. In order to prevent deleterious chemistry, cells tightly regulate the uptake, distribution, and intracellular concentrations of metal ions. Investigation into these homeostasis mechanisms has necessitated the development of alternative ways to study metal ions. Photochemical tools such as small molecule and protein-based fluorescent sensors as well as photocaged complexes have provided insight into the homeostasis and signaling mechanisms of Ca(2+), Zn(2+), and Cu(+), but a comprehensive picture of metal ions in biology will require additional development of these techniques, which are reviewed in this Current Topics article.
Asunto(s)
Colorantes Fluorescentes/química , Homeostasis/fisiología , Metales/metabolismo , Animales , Cationes/metabolismo , Humanos , Procesos Fotoquímicos , Fotoquímica/métodosRESUMEN
By utilizing thioether ligands, CuproCleav-1 stabilizes Cu(+) complexes in aqueous solution and releases the guest metal ion upon photolysis of the nitrobenzyl group. The photocage has an apparent K(d) of 54 pM for Cu(+), and metal ion release has been demonstrated using the fluorescent sensor CS1.
Asunto(s)
Quelantes/química , Cobre/química , Quelantes/síntesis química , Complejos de Coordinación/química , Colorantes Fluorescentes/química , Luz , Fotólisis , Espectrometría de Fluorescencia , Agua/químicaRESUMEN
ArgenCast-1 (1), a photocage for silver utilizing acyclic polythioether 3,6,12,15-tetrathia-9-azaheptadecane receptor and 4,5-dimethoxy-2-nitrobenzyl (DMNB) chromophore has been prepared using trimethylsilyl trifluoromethanesulfonate-assisted electrophilic aromatic substitution. Metal binding studies with ArgenCast-1 reveal interactions with Ag(+), Hg(2+) and Cu(+), but only Ag(+) coordinates in both aqueous and organic solvents. The uncaging mechanism of ArgenCast-1 metal complex involves a photoreaction that converts the nitrobenzydrol into the electron withdrawing nitrosobenzophenone that participates in a resonance interaction with a metal-bound aniline nitrogen atom. The structural change following photolysis decreases availability of the nitrogen lone pair for Ag(+) coordination, but strong interactions between Ag(+) and the thioether ligands mitigates metal ion release. A resonance interaction with a key aci-nitro intermediate reduces the photolysis quantum yield of ArgenCast-1, so several naphthyl-based nitrobenzyl groups were screened as alternatives to DMNB. The naphthyl Ag(+) photocages, ArgenCast-2 and -3, exhibit nearly identical quantum yield to ArgenCast-1 owing to the dominance of resonance between aci-nitro intermediate and the aniline nitrogen atom.
Asunto(s)
Compuestos de Anilina/química , Complejos de Coordinación/química , Colorantes Fluorescentes/química , Plata/química , Cobre/química , Cinética , Ligandos , Mercurio/química , Mesilatos/química , Fotólisis , Solventes , Análisis Espectral , Compuestos de Trimetilsililo/química , AguaRESUMEN
A highly crystalline iodinating reagent, {[K·18-C-6]ICl(2)}(n), was synthesized in high yield (93%). The trihalide is supported by an 18-crown-6 macrocycle and forms a coordination polymer in the solid state. This reagent iodinates anilines and phenols efficiently under mild conditions. Controlled mono-iodination with anilines was easily achieved while poly-iodination was observed with phenols.