RESUMEN
Ulcerative colitis (UC) is a chronic recurrent inflammatory disease affecting the rectum and colon. Numerous epidemiological studies have identified smoking as a protective factor for UC. Dysbiosis of intestinal microbiota and release of inflammatory factors are well-established characteristics associated with UC. Therefore, we have observed that nicotine exhibits the potential to ameliorate colitis symptoms in UC mice. Additionally, it exerts a regulatory effect on colonic microbiota dysbiosis by promoting the growth of beneficial bacteria while suppressing harmful bacteria. Combined in vivo and in vitro investigations demonstrate that nicotine primarily impedes the assembly of NLRP3, subsequently inhibiting downstream IL-1ß secretion.
Asunto(s)
Sulfato de Dextran , Microbioma Gastrointestinal , Proteína con Dominio Pirina 3 de la Familia NLR , Nicotina , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nicotina/farmacología , Ratones , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Ratones Endogámicos C57BL , Interleucina-1beta/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Estructura Molecular , Masculino , Disbiosis/tratamiento farmacológico , HumanosRESUMEN
In order to obtain new dihydrocoptisine-type compounds with stable structure and activating XBP1 transcriptional activity, (±)-8-trifluoromethyldihydrocoptisine derivatives as target compounds were synthesized from quaternary ammonium chlorides of coptisine alkaloids as starting materials by a one-step reaction. The structures of the synthesized compounds were confirmed by 1H-, 13C-, and 19F-NMR as well as HRESIMS methods. These compounds showed more significant structural stability and activating XBP1 transcription activity in vitro than dihydrocoptisine as positive control. No obvious cytotoxicity on normal cell in vitro was observed with (±)-8-trifluoromethyldihydrocoptisines. Trifluoromethylation can be used as one of the fluorine modification strategies for dihydrocoptisines to guide follow-up studies on structural modification of coptisine-type alkaloids and on anti-Ulcerative colitis drugs with coptisines.
Asunto(s)
Alcaloides , Colitis Ulcerosa , Alcaloides/farmacología , Humanos , Estructura Molecular , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
13-[(N-Alkylamino)methyl]-8-oxodihydrocoptisines were synthesized to evaluate antibacterial activity against Clostridium difficile and activating x-box-binding protein 1 (XBP1) activity, biological properties both associated with ulcerative colitis. Improving structural stability and ameliorating biological activity were major concerns. Different substituents on the structural modification site were involved to explore the influence of diverse structures on the bioactivities. The target compounds exhibited the desired activities with definite structure-activity relationship. In the series of 13-[(N-n-alkylamino)methyl]-8-oxodihydrocoptisines, the length of n-alkyl groups has a definite effect on the bioactivity, elongation of the length increasing the antibacterial activity. The synthesized compounds were determined to display strong or weak XBP1-activating activity inâ vitro. The preliminary results of this study warrant further medicinal chemistry studies on these synthesized compounds.
Asunto(s)
Antibacterianos/farmacología , Clostridioides difficile/efectos de los fármacos , Proteína 1 de Unión a la X-Box/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/química , Clostridioides difficile/metabolismo , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
In this study, quaternary palmatine is used as a lead compound to design and synthesize derivatives to evaluate bioactivities, with twenty-seven compounds of four series being obtained. Antibacterial activity was examined by determining the minimal inhibitory concentration (MIC) values on Staphylococcus aureus, Escherichia coli, and Candida albicans, three series of derivatives being found to exhibit activity in vitro with significant structure-activity relationship (SAR). Elongating the carbon chain led to the antibacterial activity increased, with quaternary 13-hexanoylpalmatine chloride, quaternary 13-(ω-ethoxycarbonyl)heptylpalmatine chloride, and 8-oxo-13-(N-n-nonyl)aminomethyldihydropalmatine, all of which possess the longest aliphatic carbon chain in the corresponding series of derivatives, showing the MIC values of 62.5, 7.81, and 15.63⯵g/ml against S. aureus, respectively. The property of anti-ulcerative colitis (anti-UC) was assessed at the levels of both in vitro and in vivo, with X-box-binding protein 1 (XBP1) being targeted in vitro. Seven compounds were found not only to be hypocytotoxic toward intestinal epithelial cells, but also to exhibit activity of activating the transcription of XBP1 in vitro. Five compounds were found to possess significant dose-effect relationship with EC50 values at a level of 10-7⯵M in vitro. 8-Oxo-13-formyldihydropalmatine as an intermediate was found to display significant curative effect on UC in vivo based on the biomarkers of body weight change, colon length change, and calculated values of disease activity index and colon macroscopic damage index of the experimental animals, as well as the examination into the pathological changes of the colon tissue of the modeled animals.
Asunto(s)
Antibacterianos/farmacología , Antiulcerosos/farmacología , Alcaloides de Berberina/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/uso terapéutico , Antiulcerosos/síntesis química , Antiulcerosos/química , Antiulcerosos/uso terapéutico , Alcaloides de Berberina/síntesis química , Alcaloides de Berberina/química , Alcaloides de Berberina/uso terapéutico , Peso Corporal/efectos de los fármacos , Candida albicans/efectos de los fármacos , Colitis Ulcerosa/tratamiento farmacológico , Colon/metabolismo , Escherichia coli/efectos de los fármacos , Levofloxacino/farmacología , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Sulfasalazina/farmacología , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Six pairs of previously undescribed 6-monosubstituted dihydrobenzophenanthridine alkaloids were separated as corresponding six scalemic mixtures from the aerial part of Chelidonium majus. The elucidation for the 2D structures of these alkaloids was achieved using regular spectroscopic and chemical methods. The assignment of scalemic-mixture nature was achieved using combined examinations of their NMR data, CD spectra, calculation of specific rotations, and chiral HPLC profiles. The identification for the relative configurations of alkaloids possessing two asymmetric carbons directly connected up by a rotatable sp3-sp3 carbon-carbon single bond was significantly facilitated by discussing the erythro and threo relative configurations defined by the mutuality of the orders of decreasing steric hindrances between the two sets of ligands linked to the two chiral centers. Two scalemic mixtures were assigned as (1'R,6R/1'S,6S)- and (1'S,6R/1'R,6S)-1-(dihydrochelerythrine-6-yl)ethanols, two as (1'R,6R)/(1'S,6S)- and (1'S,6R)/(1'R,6S)-1-(dihydrosanguinarine-6-yl)ethanols, one as (±)-ethyl 2-(dihydrosanguinarine-6-yl)acetate, and one as (±)-ethyl dihydrosanguinarine-6-carboxylate, respectively. The resolution of three scalemic mixtures was achieved and the absolute configurations of the three pairs of enantiomers were assigned via time-dependent Density Functional Theory calculations of electronic circular dichroism (ECD) data. The assignment for the absolute configurations of the other three scalemic mixtures was achieved via a chiral HPLC-UV/CD method plus analyzing their ECD data. The findings of this paper demonstrated that the relevant biochemical reactions concerning the construction of these 6-monosubstituted dihydrobenzophenanthridine alkaloids in the test plant are very nonselective. Scalemic mixture of (1'R,6R)/(1'S,6S)-1-(dihydrosanguinarine-6-yl)ethanol exhibited biological activity. It inhibited the growth of human MDA-MB-231 cell line at a moderate level with IC50 value of 5.12 µM.
Asunto(s)
Alcaloides/química , Chelidonium/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fenómenos Ópticos , Teoría Cuántica , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Seven new azacyclo-indoles and phenolics and four known alkaloids were isolated from the flowers of Juglans regia. Spectroscopic and chromatographic data revealed that the structures of the new compounds are 5,6,11,12-tetrahydropyrrolo[1',2':1,2]azepino[4,5-b]indole-3-carbaldehyde (1), (±)-5,6,7,11c-tetrahydro-1H-indolizino[7,8-b]indol-3(2H)-one (2), (±)-9-hydroxy-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxamide (3), 5-(ethoxymethyl)-1-(4-hydroxyphenethyl)-1H-pyrrole-2-carbaldehyde (4), (±)-5,8-dihydroxy-4-(1H-indol-3-yl)-3,4-dihydronaphthalen-1(2H)-one (5), (±)-4-(6-amino-9H-purin-9-yl)-5,8-dihydroxy-3,4-dihydronaphthalen-1(2H)-one (6), and (±)-4-(6-amino-9H-purin-9-yl)-5-hydroxy-3,4-dihydronaphthalen-1(2H)-one (7). The five pairs of enantiomers were resolved, and the absolute configurations of the enantiomers were assigned via electronic circular dichroism data. Compound 1 exhibited significant in vitro growth inhibition against the HCT-116, HepG2, BGC-823, NCI-H1650, and A2780 cancer cell lines, with IC50 values of 2.87, 1.87, 2.28, 2.86, and 0.96 µM, respectively, and low cytotoxicity toward normal IEC-6 cells, with a 79.6% survival rate at a 10 µM concentration.
Asunto(s)
Aldehídos/aislamiento & purificación , Aldehídos/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Azepinas/aislamiento & purificación , Azepinas/farmacología , Flores/química , Indoles/aislamiento & purificación , Indoles/farmacología , Juglans/química , Fenoles/química , Aldehídos/química , Alcaloides/química , Azepinas/química , Línea Celular Tumoral , Dicroismo Circular , Humanos , Indoles/química , Concentración 50 Inhibidora , Estructura MolecularRESUMEN
OBJECTIVE To identify the valid targets and new drugs of ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. METHODS and RESULTS In an in vivo mouse model of DSS-induced colitis, HLJ2 decreased weight loss, colon contracture, disease activity index (DAI), colon mucosa damage index (CMDI) and histopathological index (HI). HLJ2 also decreased myelo?peroxidase(MPO) activity and reduced production of the inflammatory cytokines TNF- α, IL- 1β, andIL- 6. HLJ2 improved intestinal mucosa damage induced by dextran sodium sulfate (DSS) and increased the expression of ZO-1 and claudin-1. Fecal 16s rRNA high-throughput sequencing demon?strated a significant improvement in UC intestinal dysbacteriosis in mice treated with HLJ2, including increased abundance of probiotics such as Lachnospiraceae, Prevotellaceae, and Lactobacillaceae. At the same time there was a reduction in the abundance of pathogenic or conditional pathogenic microor?ganisms such as Bacteroidaceae, Porphyromonadaceae, Deferribacteraceae, and Pseudomonadaceae in HLJ2- treated mice compared with untreated mice. CONCLUSION Our results demonstrated that the XBP1 agonist HLJ2 inhibits inflammation, regulates the intestinal flora, and protects the intestinal mucosa. It is thus a potential therapeutic agent for ulcerative colitis.
RESUMEN
Two versatile methods to synthesize kinds of organic acid salts of quaternary berberine-type alkaloids were investigated in order to determine which is more efficient to improve the liposolubility of the target compounds and to explore the efficacy of the target compounds as anti-ulcerative colitis (UC) agents. Overall evaluation according to the reaction results and yields of the final products indicated that the synthetic method using tertiary (±)-8-acylmethyldihydroberberine-type alkaloids as key intermediates is superior to that of using tertiary dihydroberberine-type alkaloids as intermediates. Ten target compounds were synthesized using quaternary berberine chloride and quaternary coptisine chloride as starting materials, respectively, and the anti-UC activity of some target compounds was evaluated in an in vitro x-box-binding protein 1 (XBP1) transcriptional activity assay using dual luciferase reporter detection. At 10 µM, the tested compounds were found to activate the transcription of XBP1 target at almost the same level as that of quaternary coptisine chloride. The synthesized target compounds were also found to share higher liposolubility than the inorganic acid salts of quaternary berberine-type alkaloid.
Asunto(s)
Berberina/análogos & derivados , Colitis Ulcerosa/tratamiento farmacológico , Berberina/síntesis química , Berberina/química , Berberina/farmacología , Hydrastis/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Factores de Transcripción del Factor Regulador X/metabolismo , Sales (Química)RESUMEN
In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 µM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Aminas/síntesis química , Aminas/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Proteínas de Unión al ADN/efectos de los fármacos , Factores de Transcripción/efectos de los fármacos , Amidas/química , Aminas/química , Animales , Berberina/análogos & derivados , Masculino , Estructura Molecular , Factores de Transcripción del Factor Regulador X , Relación Estructura-ActividadRESUMEN
Four phenylpropanoid glucosides (1-4) and five lignan glycosides (5-9) were isolated from the aerial parts of Lespedeza cuneata, together with three known lignan glycosides (10-12). Their structures were elucidated on the basis of spectroscopic analyses, and the absolute configurations of compounds 5-9 were determined from the CD spectra. In addition, the compounds were tested for their ability to activate the transcription effect on xbp1 promoter. Compounds 4, 5, 7, 9, 10, and 12 could activate the transcription of xbp1 to varying degrees, with EC50 values ranging from 0.18 to 0.64 µM.