RESUMO
Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds inâ vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31â µM and 0.41â µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.
Assuntos
Alcaloides , Antineoplásicos , Neoplasias Colorretais , Humanos , Alcaloides/farmacologia , Alcaloides/química , Linhagem Celular , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Estrutura MolecularRESUMO
Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.
Assuntos
Alcaloides de Berberina , Telomerase , Animais , Telomerase/metabolismo , RNA/químicaRESUMO
The first total synthesis of (S)-(+)-ovigerine, (S)-(+)-N-formylovigerine, and (6aS,6a'S)-(+)-ovigeridimerine of aporphine alkaloids with a benzo[d][1,3]dioxole structure feature was established. The strategy was based upon the well-known Pd-catalyzed arylation to set the aporphine framework, and Noyori asymmetric hydrogenation followed by diastereoselective resolution to achieve excellent enantioselectivity. By slightly modifying the total synthetic route and strategically combining it with a aza-Michael addition, Bischler-Napieralski reaction and N-arylation, this methodology was also applied to the total syntheses of benzo[d][1,3]dioxole-type benzylisoquinoline alkaloids of coptisines and dibenzopyrrocolines, including two impatiens, tetrahydrocoptisine, and quaternary coptisine bromide of coptisines and two dibenzopyrrocoline analogues, with the syntheses of all of these target compounds being efficient. Among the nine synthesized compounds, the total syntheses of the three aporphines and the two impatiens, all with ee values of greater than 99%, were reported for the first time. This work also represents the first unification of synthetic routes for the total synthesis of benzo[d][1,3]dioxole-type aporphines, coptisines, and dibenzopyrrocolines.
RESUMO
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.
Assuntos
Alcaloides , Colite Ulcerativa , Alcaloides/farmacologia , Humanos , Estrutura Molecular , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Clostridioides difficile/metabolismo , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
In this study, quaternary berberine chloride is used as a lead compound to design and synthesize a series of berberine-12-amine derivatives to evaluate the growth inhibition activity against human cancer cell lines. Forty-two compounds of several series were obtained. The quaternary berberine-12-N,N-di-n-alkylamine chlorides showed the targeted activities with the IC50 values of most active compounds being dozens of times those of the positive control. A significant structure-activity relationship (SAR) was observed. The activities of quaternary berberine-12-N,N-di-n-alkylamine chlorides are significantly stronger than those of the reduced counterparts. In the range of about 6-8 carbon atoms, the activities increase with the elongation of n-alkyl carbon chain of 12-N,N-di-n-alkylamino, and when the carbon atom numbers are more than 6-8, the activities decrease with the elongation of n-alkyl carbon chain. The activities of the tertiary amine structure are significantly higher than that of the secondary amine structure.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Berberina/síntese química , Berberina/farmacologia , Técnicas de Química Sintética , Antineoplásicos/química , Berberina/análogos & derivados , Berberina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Three previously undescribed (±)-3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives were isolated from Juglans regia flowers. Elucidation of the 2D structures of these first-reported compounds was completed via regular spectroscopic methods. The assignment of racemic nature of these compounds was achieved using the examination of their chiral HPLC profiles. (±)-2,3-Dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one, (±)-2,3-dihydro-4',5,8,8'-tetrahydroxy-(1,1'-binaphthalen)-4(1H)-one, and (±)-2,3-dihydro-1',5,5',8-tetrahydroxy-(1,2'-binaphthalen)-4(1H)-one were the structures of these racemic compounds, all taking on central chirality. The resolution of all the racemic compounds was conducted and achieved using a chiral HPLC procedure. The absolute configurations of the three isolated pairs of enantiomers were assigned via time-dependent density functional theory calculations from the electronic circular dichroism data. The findings in this paper demonstrated that the relevant biochemical reactions for the construction of these 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-one derivatives in the test plant are nonselective. The (±)-2,3-dihydro-4',8,8'-trihydroxy-(1,1'-binaphthalen)-4(1H)-one showed selective inhibitory activity on tumor cells growth, preliminarily supporting the application of Juglans regia flowers to protect against cancers in a few Chinese folk areas.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Flores/química , Juglans/química , Naftalenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Naftalenos/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologiaRESUMO
A method was developed to synthesize 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride. 1-Bromo-2-bromomethyl-3,4-alkylenedioxy benzenes and 6,7-alkylenedioxynaphthalen-1-amines were synthesized first. Reactions to construct the target compounds with these two series of synthons involved alterations on a published method for synthesizing 2,3,7,8-tetraoxygenated derivatives of benzo[c]phenanthridinium, substituting benzyl bromides for benzoic aldehydes, prolonging the radical annulation time, and conducting N-methylation with formic acid and NaBH4. All the target compounds showed the same or better in vitro growth inhibitory activities against cancer cell lines compared with the positive compound. The structure activity relationship relevant to cytotoxicity and lipophilicity of the target compounds was produced.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzofenantridinas/química , Isoquinolinas/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Antiulcerosos/farmacologia , Alcaloides de Berberina/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/uso terapêutico , Antiulcerosos/síntese química , Antiulcerosos/química , Antiulcerosos/uso terapêutico , Alcaloides de Berberina/síntese química , Alcaloides de Berberina/química , Alcaloides de Berberina/uso terapêutico , Peso Corporal/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Colo/metabolismo , Escherichia coli/efeitos dos fármacos , Levofloxacino/farmacologia , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfassalazina/farmacologia , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
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.
Assuntos
Alcaloides/química , Chelidonium/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenômenos Ópticos , Teoria Quântica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Aldeídos/isolamento & purificação , Aldeídos/farmacologia , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Azepinas/isolamento & purificação , Azepinas/farmacologia , Flores/química , Indóis/isolamento & purificação , Indóis/farmacologia , Juglans/química , Fenóis/química , Aldeídos/química , Alcaloides/química , Azepinas/química , Linhagem Celular Tumoral , Dicroísmo Circular , Humanos , Indóis/química , Concentração Inibidora 50 , Estrutura MolecularRESUMO
Three new 14,15-secopregnane-type glycosides, stauntosides UA, UA1, and UA2, were isolated from the roots of Cynanchum stauntonii. The three compounds share the first reported and same basic structural features of 3ß-hydroxy-14:16,15:20,18:20-triepoxy-5α:9α-peroxy-14,15-secopregnane-6,8(14)-diene named as stauntogenin G as the aglycones. The structures of the new compounds were characterized on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR and MS methods and chemical analysis. The isolation and identification of the new compounds graced the structural diversity of pregnane-type steroids from C. stauntonii.
Assuntos
Cynanchum/química , Glicosídeos/química , Raízes de Plantas/química , Apocynaceae/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Esteroides/químicaRESUMO
Two new sugar-free 14,15-secopregnane-type steroids, 14-O-methyl-3-epi-hirundigenin (1) and 2-deoxyamplexicogenin A (2), along with two known sugar-free pregnane-type steroids, were isolated from the 95% ethanol extract of the roots of Cynanchum stauntonii. The structures of the new compounds were characterized on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR methods, albeit the MS experiments did not display the molecular ion peaks. Compound 2 was the aglycones of stauntosides J and K, etc., previously isolated from C. stauntonii. The isolation and identification of the new compounds graced the structural diversity of pregnane-type steroids from C. stauntonii.
Assuntos
Cynanchum/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Raízes de Plantas/química , Pregnanos/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pregnanos/químicaRESUMO
Nine 14,15-secopregnane-type C21-steriosides, stauntosides U, V, V1-V3, W and C1-C3, as well as two known C21-steriosides, were isolated from the roots of Cynanchum stauntonii. Stauntosides U, V and V1-V3 share the same basic structural features of 8α:14α,14:16,15:20,18:20-tetraepoxy-14,15-secopregn-6-ene-3ß,5α,9α-triol, with the numbering system following that of C21-pregnanes. The aglycones of stauntosides U, V and V1-V3 are classified into two subcategories, the 5,9-dihydroxy groups and 5α:9α-peroxy bridge, according to the oxidative states of the two hydroxy groups at the C-5 and C-9 positions. The anti-inflammatory activity of the major compounds was assessed in an in vitro inflammatory model of mouse peritoneal macrophages using IC50 values of the inhibition of nitric oxide (NO) production as an indicator. Stauntosides V1 and V3 exhibited target activity with IC50 values of 9.3 µM and 12.4 µM, respectively, compared with dexamethasone, which was used as a positive control.
Assuntos
Cynanchum/química , Raízes de Plantas/química , Pregnanos/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Óxido Nítrico/metabolismo , Pregnanos/isolamento & purificaçãoRESUMO
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.
Assuntos
Berberina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Berberina/síntese química , Berberina/química , Berberina/farmacologia , Hydrastis/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fatores de Transcrição de Fator Regulador X/metabolismo , SaisRESUMO
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.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Aminas/síntese química , Aminas/farmacologia , Colite Ulcerativa/tratamento farmacológico , Proteínas de Ligação a DNA/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Amidas/química , Aminas/química , Animais , Berberina/análogos & derivados , Masculino , Estrutura Molecular , Fatores de Transcrição de Fator Regulador X , Relação Estrutura-AtividadeRESUMO
Two new compounds of phenylpropanoids, (S)-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-5-oxopyrrolidine-2-carboxamide (1) and (3R)-3-O-ß-d-glucopyranosyl-3-phenylpropanoic acid (2), were isolated from the stems of Ephedra sinica. Their structures were elucidated by in-depth examination of spectroscopic data, mainly including those from the 1D and 2D NMR and HRESIMS techniques, and chemical method. The absolute configurations of the two compounds were also corroborated through CD procedure.
Assuntos
Medicamentos de Ervas Chinesas/isolamento & purificação , Ephedra sinica/química , Fenilpropionatos/isolamento & purificação , Medicamentos de Ervas Chinesas/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenilpropionatos/química , Caules de Planta/químicaRESUMO
Taking application of some isolation and purification technologies, including solvent extraction, rude solvent isolation, column chromatographies on silica gel and Sephadex LH-20 , and preparative HPLC , 4 compounds were obtained from Gynura nepalensis cultivated in a suburban area of Beijing. Their structures were identified by spectroscopic methods in conjunction with comparison of the NMR data with literature values as 7S,8R-9'-O-ethyl-dehydrodiconiferyl-9-acetate (1), 9'-O-ethyl-dehydrodiconiferyl alcohol (2), dehydrodiconiferyl-9,9'-diacetate(3), and (+)-medioresinol(4), respectively. 1 is a new 2,3-dihydrobenzofuran-8,3'-neolignane type compound, and 2-4 were isolated from G.nepalensis for the first time. The complete assignment of the 1H- and 13C-NMR spectroscopic data of the four compounds recorded in DMSO-d6 was achieved.
Assuntos
Asteraceae/química , Lignanas/química , Cromatografia Líquida de Alta Pressão , Dextranos , Lignanas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Thirty quaternary coptisine derivatives from a synthesized library were found to activate the in vitro transcription of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines were demonstrated by in vitro XBP1 transcriptional activity assays and animal experiments to be much more active anti-ulcerative colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines, and the positive control. Unsubstituted dihydrocoptisine exhibited more significant anti-UC efficacy than dihydrocoptisines substituted at the C-8 or C-13 position. The EC50 value of dihydrocoptisine for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine exhibited a significant dose-effect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting material's reductive states and the substitution patterns of the dihydrocoptisines were determined to be the critical parameters for modulating their anti-UC efficacy, and the dihydrocoptisine skeleton was designated as the key pharmacophore. The synthesized dihydrocoptisine is a promising lead for developing anti-UC drugs.
Assuntos
Anti-Inflamatórios/síntese química , Berberina/análogos & derivados , Colite Ulcerativa/tratamento farmacológico , Doença Aguda , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Berberina/química , Berberina/farmacologia , Berberina/uso terapêutico , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/fisiopatologia , Colo/efeitos dos fármacos , Colo/fisiopatologia , Proteínas de Ligação a DNA/agonistas , Proteínas de Ligação a DNA/genética , Sulfato de Dextrana , Camundongos Endogâmicos C57BL , Contração Muscular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Ratos , Fatores de Transcrição de Fator Regulador X , Estereoisomerismo , Relação Estrutura-Atividade , Fatores de Transcrição/agonistas , Fatores de Transcrição/genética , Ativação Transcricional , Proteína 1 de Ligação a X-BoxRESUMO
Ongoing study on the chemical constituents of the roots of Macleaya microcarpa led to the isolation of eight compounds of derivatives of triterpenes and organic acids in addition to some previously identified benzophenanthridines. The eight compounds were identified by spectroscopic methods as well as comparison with literature values as 1-oxo-2, 22 (30)-hopandien-29-oic acid (1), 3-oxo-12-oleanen-30-oic acid (2), 3α-hydroxy-12-oleanen-30-oic acid (3), 3ß-hydroxy-12-oleanen-30-oic acid (4), ferulic acid (5), ferulic acid 4-O-ß-D-glucoside (6), 3-O-feruloylquinic acid (7), and methyl 3-O-feruloylquinate (8). Of which, 1 is a new triterpenoid of hopanes and 2-8 are isolated from M microcarpa for the first time. In order to discover natural active compounds as potential agents of anti-ulcerative colitis (UC), an in vitro drug high-throughput screening model targeted x-box-binding protein 1 (xbp1) was employed to evaluate the activity of the major chemical constituents of M microcarpa. The result confirmed that two dihydrobenzophenanthridines, dihydrosanguinarine (9) and dihydrochelerythrine (10), showed a certain activity on activating the transcription of xbpl, a transcription factor (TF) associated with the occurrence, development, and potential treatment of UC, with their relative activating ratios being 1.76 and 1.77 times, respectively, as compared with control group.