RESUMEN
We report an indirect method for synthesis of previously inaccessible diazeniumdiolated carbamates. Synthesis involves use of previously reported triisopropylsilyloxymethylated isopropylamine diazeniumdiolate (TOM-ylated IPA/NO). These novel diazeniumdiolated carbamate prodrugs upon activation release nitric oxide (NO) similar to their secondary amine counterparts. They are also efficient sources of intracellular NO. These prodrugs may have potential applications as therapeutic NO-donors.
Asunto(s)
Carbamatos/química , Carbamatos/farmacología , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Profármacos/química , Profármacos/farmacología , Compuestos Azo/síntesis química , Compuestos Azo/química , Compuestos Azo/farmacología , Carbamatos/síntesis química , Línea Celular , Técnicas de Química Sintética/métodos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/síntesis química , Profármacos/síntesis químicaRESUMEN
JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.
Asunto(s)
Antineoplásicos/química , Compuestos Azo/química , Glutatión/metabolismo , Profármacos/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Compuestos Azo/farmacología , Estabilidad de Medicamentos , Semivida , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Cinética , Ratones , Neoplasias/tratamiento farmacológico , Óxido Nítrico/metabolismo , Profármacos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
This review summarizes research work carried out in India on domino metathesis reactions using ruthenium-carbene complexes. This reaction has been widely used by synthetic chemists in India for the synthesis of polycyclic systems and complex molecular architectures.
Asunto(s)
Metano/análogos & derivados , Compuestos Policíclicos/síntesis química , Rutenio/química , India , Metano/química , Estructura Molecular , Compuestos Policíclicos/químicaRESUMEN
Here we report a number of novel JS-K structural analogues with sub-micromolar anti-proliferative activities against human leukemia cell lines HL-60 and U937; JS-K is the anti-cancer lead compound O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. The ability of these compounds to generate intracellular nitric oxide correlated well with their observed anti-proliferative effects: analogues that had potent inhibitory activity against leukemia cells formed elevated levels of intracellular nitric oxide.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Azo/química , Piperazinas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Azo/síntesis química , Compuestos Azo/farmacología , Línea Celular Tumoral , Humanos , Óxido Nítrico/metabolismo , Piperazinas/síntesis química , Piperazinas/farmacologíaRESUMEN
An expedient and first tandem enyne/ring closing metathesis approach on a sugar furanose template leading to a novel angularly fused dioxa-triquinane is described here.
Asunto(s)
Alquinos/síntesis química , Compuestos Heterocíclicos/síntesis química , Alquinos/química , Ciclización , Estructura MolecularRESUMEN
Synthesis of previously inaccessible, potentially liver selective HNO donor V-IPA/NO ([iPrHN(3)-N(1)(O(1))=N(2)-O(2)-R], where R = vinyl) is reported here. A novel fluoride-labile TOM group at O-2 in conjunction with MOM protection at N-3 in IPA/NO is employed. The strategy developed is also extended to synthesis of other NO-releasing prodrugs and has applications in diversity-oriented synthesis of HNO- and NO-prodrugs.
Asunto(s)
Compuestos Azo/química , Compuestos de Vinilo/síntesis química , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Óxido Nítrico/química , Óxidos de Nitrógeno/química , Profármacos/síntesis química , Profármacos/química , Compuestos de Vinilo/químicaRESUMEN
Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
Asunto(s)
Factor de Transcripción Activador 3/fisiología , Antineoplásicos/síntesis química , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Donantes de Óxido Nítrico/síntesis química , Profármacos/síntesis química , Factor de Transcripción Activador 3/biosíntesis , Factor de Transcripción Activador 3/genética , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular , División Celular , Línea Celular Tumoral , Activación Enzimática , Fase G2 , Silenciador del Gen , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Profármacos/química , Profármacos/farmacología , Transducción de Señal , Relación Estructura-Actividad , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
GlcNAc-PROLI/NO prodrugs that are activated by N-acetylglucosaminidase to release nitric oxide (NO) are described. A classical acid-amine coupling is used to bifunctionalize these PROLI/NO prodrugs, which on activation generate up to 4 mol of NO, a peptide residue, and an N-acetylglucosamine residue. Many of the prodrugs synthesized are efficient sources of intracellular NO.
Asunto(s)
Acetilglucosaminidasa/metabolismo , Óxido Nítrico/metabolismo , Profármacos/síntesis química , Prolina/análogos & derivados , Glicosilación , Estructura Molecular , Óxido Nítrico/química , Profármacos/química , Prolina/síntesis química , Prolina/químicaRESUMEN
V-PYRRO/NO is a well studied nitric oxide (NO) prodrug which has been shown to protect human liver cells from arsenic, acetaminophen, and other toxic assaults in vivo. Its proline-based analogue, V-PROLI/NO, was designed to be a more biocompatible form that decomposes to the naturally occurring metabolites of proline, NO, and glycolaldehyde. Like V-PYRRO/NO, this cytochrome P450-activated prodrug was previously assumed to passively diffuse through the cellular membrane. Using (14)C-labeled proline in a competition assay, we show that V-PROLI/NO is transported through proline transporters into multiple cell lines. A fluorescent NO-sensitive dye (DAF-FM diacetate) and nitrite excretion indicated elevated intracellular NO release after metabolism over V-PYRRO/NO. These results also allowed us to predict and design a more permeable analogue, V-SARCO/NO. We report a proline transporter-based strategy for the selective transport of NO prodrugs that may have enhanced efficacy and aid in development of further NO prodrugs with increased permeability.
RESUMEN
The use of Cu(I)-catalyzed "click" reactions of alkyne-substituted diazeniumdiolate prodrugs with bis- and tetrakis-azido compounds is described. The "click" reaction for the bis-azide using CuSO(4)/Na-ascorbate predominantly gave the expected bis-triazole. However, CuI/diisopropylethylamine predominantly gave uncommon triazolo-triazole products as a result of oxidative coupling. Neither set of "click" conditions showed evidence of compromising the integrity of the diazeniumdiolate groups. The chemistry developed has applications in the synthesis of polyvalent and dendritic nitric oxide donors.
Asunto(s)
Compuestos Azo/química , Donantes de Óxido Nítrico/química , Azidas/química , Ciclización , Estructura MolecularRESUMEN
A facile synthesis of a 5,7,5-fused ring system that is present in thapsigargins belonging to a novel family of sesquiterpene lactones, guainanolides, using domino enyne-RCM is reported here.