RESUMEN
The inflammatory response is an essential process for the host defence against pathogens. Lipid mediators are important in coordinating the pro-inflammatory and pro-resolution phases of the inflammatory process. However, unregulated production of these mediators has been associated with chronic inflammatory diseases such as arthritis, asthma, cardiovascular diseases, and several types of cancer. Therefore, it is not surprising that enzymes implicated in the production of these lipid mediators have been targeted for potential therapeutic approaches. Amongst these inflammatory molecules, the 12-hydroxyeicosatetraenoic acid (12(S)-HETE) is abundantly produced in several diseases and is primarily biosynthesized via the platelet's 12-lipoxygenase (12-LO) pathway. To this day, very few compounds selectively inhibit the 12-LO pathway, and most importantly, none are currently used in the clinical settings. In this study, we investigated a series of polyphenol analogues of natural polyphenols that inhibit the 12-LO pathway in human platelets without affecting other normal functions of the cell. Using an ex vivo approach, we found one compound that selectively inhibited the 12-LO pathway, with IC50 values as low as 0.11 µM, with minimal inhibition of other lipoxygenase or cyclooxygenase pathways. More importantly, our data show that none of the compounds tested induced significant off-target effects on either the platelet's activation or its viability. In the continuous search for specific and better inhibitors targeting the regulation of inflammation, we characterized two novel inhibitors of the 12-LO pathway that could be promising for subsequent in vivo studies.
Asunto(s)
Araquidonato 12-Lipooxigenasa , Araquidonato 5-Lipooxigenasa , Humanos , Araquidonato 5-Lipooxigenasa/metabolismo , Ácidos Cafeicos/farmacología , Lípidos , Inhibidores de la Lipooxigenasa/farmacologíaRESUMEN
The hydroxycinnamic acid scaffold is extremely versatile with various biological activities. This review will highlight the progress of the biological activities of hydroxycinnamic acids and their related synthetic analogs, including recently reported anti-cancer, anti-inflammatory, and antioxidant activities.
Asunto(s)
Alcohol Feniletílico , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Ácidos Cafeicos/farmacología , Ácidos Cumáricos/farmacología , Alcohol Feniletílico/farmacologíaRESUMEN
Caffeic acid phenethyl ester (CAPE, 2), a natural compound from propolis, is a well-documented antitumor agent with nuclear factor kappa B (NF-κB) inhibitory activity. Key transcription factors regulated by NF-κB, namely, interferon regulatory factor-4 (IRF4) and octameric binding protein-2 (OCT2), are implicated in the tumorigenesis of multiple myeloma (MM), an incurable bone marrow cancer. Adverse effects and resistance to current chemotherapeutics pose a great challenge for MM treatment. Hence, the structure-activity relationships of CAPE (2) and 21 of its analogues were evaluated for their antimyeloma potential. Preclinical evaluation revealed that CAPE (2) and the 3-phenylpropyl (4), 2,5-dihydroxycinnamic acid 3-phenylpropyl ester (17), and 3,4-dihydroxycinnamic ether (22) analogues inhibited human myeloma cell growth. Analogue 4 surpassed CAPE (2) and lenalidomide in showing strong apoptotic effects with a remarkable decrease in IRF4 levels. The analogue 17 exhibited the most potent anti-MM activity. The downregulation of specificity protein 1 (Sp1) and the IKZF1-IRF4-MYC axis by CAPE (2) analogues 4 and 17 revealed their novel mechanism of action. The analogues showed no adverse cytotoxic effects on normal human cells and exhibited appropriate in silico pharmacokinetic properties and drug-likeness. These findings suggest the promising application of CAPE (2) analogues to target Ikaros (IKZF1)/IRF4 addiction, the so-called Achilles heel of myeloma, for better treatment outcomes.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Ácidos Cafeicos/farmacología , Regulación hacia Abajo , Genes myc , Factor de Transcripción Ikaros/metabolismo , Factores Reguladores del Interferón/metabolismo , Mieloma Múltiple/patología , Alcohol Feniletílico/análogos & derivados , Factor de Transcripción Sp1/metabolismo , Apoptosis/efectos de los fármacos , Ácidos Cafeicos/química , Línea Celular Tumoral , Humanos , Lenalidomida/farmacología , Mieloma Múltiple/metabolismo , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Relación Estructura-ActividadRESUMEN
5-lipoxygenase (5-LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5-LO and the leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor of 5-LO and leukotriene biosynthesis but is susceptible to hydrolysis by esterases. In this study a number of CAPE analogues were synthesized with modifications to the caffeoyl moiety and the replacement of the ester linkage with a ketone. Several new molecules showed better inhibition of leukotriene biosynthesis than CAPE in isolated human neutrophils and in whole blood with IC50 values in the nanomolar (290-520 nmol/L) and low micromolar (1.0-2.3 µmol/L) ranges, respectively. Sinapic acid and 2,5-dihydroxy derivatives were more stable than CAPE in whole blood, and ketone analogues were degraded more slowly in HepaRG hepatocyte cultures than esters. All compounds underwent modification consistent with glucuronidation in HepaRG cultures as determined using LC-MS/MS analysis, though the modified sinapoyl ketone (10) retained 50% of its inhibitory activity after up to one hour of incubation. This study has identified at least one CAPE analogue, compound 10, that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Hidroxibenzoatos/síntesis química , Cetonas/síntesis química , Inhibidores de la Lipooxigenasa/síntesis química , Análisis Químico de la Sangre , Ácidos Cafeicos/química , Línea Celular , Estabilidad de Medicamentos , Ésteres/química , Células HEK293 , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacología , Concentración 50 Inhibidora , Cetonas/química , Cetonas/farmacología , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Simulación del Acoplamiento Molecular , Neutrófilos/química , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/químicaRESUMEN
The inhibition of 5-lipoxygenase (5-LO), the key enzyme for the biosynthesis of leukotrienes (LTs), has generated increasing enthusiasm as anti-inflammatory and antitumor strategies in recent years. Based on our previous studies, we synthesized a series of dihydroxycinnamic acid-based analogs that might be 5-LO inhibitors. LTs biosynthesis inhibition in HEK293â¯cells and polymorphonuclear leukocytes (PMNL) was measured and antitumor activities were investigated in Renal Cell Carcinoma (RCC). Results showed that the 2,5-dihydroxycinnamic acid phenethyl ester (10b) was the best 5-LO inhibitor and was 7-fold more potent than Zileuton (1), the only clinically approved 5-LO inhibitor. 2,5-Dihydroxy substitution was more favorable to 5-LO inhibition since compound 10b is twice as active as CAPE (2) which is a 3,4-dihydroxylcinnamic acid ester. Meanwhile, 10b reduced the cell viability of renal cancer cells â¯and was more selective toward RCC4 and 786.0â¯cells which are deficient for the Von Hippel-Lindau (VHL) tumor suppressor gene. As to the underlying cell-death mechanisms, 10b induced apoptosis in VHL-deficient RCC4 cells. Also, increases in LC3B and p62 expression suggest a blockage of the autophagic flux in RCC in response to 10b.