Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

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 in vitro.

Chemoproteomics Reveals That Quaternary Protoberberine Alkaloids Inhibit Telomerase Activity Oncologically by Binding to PES1.

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.

A unified total synthesis of benzo[][1,3]dioxole-type benzylisoquinoline alkaloids of aporphines, coptisines, and dibenzopyrrocolines.

The first total synthesis of ()-(+)-ovigerine, ()-(+)--formylovigerine, and (6a,6a')-(+)-ovigeridimerine of aporphine alkaloids with a benzo[][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 -arylation, this methodology was also applied to the total syntheses of benzo[][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.

Trifluoromethylation of dihydrocoptisines and the effect on structural stability and XBP1-activating activity.

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 H-, C-, and F-NMR as well as HRESIMS methods. These compounds showed more significant structural stability and activating XBP1 transcription activity than dihydrocoptisine as positive control.

Syntheses and Structure-Activity Relationships in Antibacterial Activity against Clostridium difficile and XBP1 Activation Property of 13-[(N-Alkylamino)methyl]-8-oxodihydrocoptisines.

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.

Syntheses and Structure-Activity Relationships in Growth Inhibition Activity against Human Cancer Cell Lines of 12 Substituted Berberine Derivatives.

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--di--alkylamine chlorides showed the targeted activities with the IC values of most active compounds being dozens of times those of the positive control.

Butyric Acid Increases the Therapeutic Effect of EHLJ7 on Ulcerative Colitis by Inhibiting JAK2/STAT3/SOCS1 Signaling Pathway.

Ulcerative colitis (UC) is a refractory chronic disease characterized by bloody diarrhea and mucosal or submucosal ulcers. There is an urgent need of new drugs for the treatment of ulcerative colitis. EHLJ7 is a quaternary coptisine derivative.

Racemic 3,4-dihydro-4-naphthyl-naphthalen-1(2H)-ones from Juglans regia flowers.

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.

Re-engineering and synthesis of cytotoxic 2,3:7,8-di(alkylenedioxy)-extended analogs of quaternary sanguinarine chloride.

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 NaBH.

Syntheses and structure-activity relationships on antibacterial and anti-ulcerative colitis properties of quaternary 13-substituted palmatines and 8-oxo-13-substituted dihydropalmatines.

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.

Six scalemic mixtures of 6-monosubstituted dihydrobenzophenanthridine alkaloids from Chelidonium majus and optically active structures of enantiomers.

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.

Colitis Is Effectively Ameliorated by (±)-8-Acetonyl-dihydrocoptisine via the XBP1-NF-κB Pathway.

Ulcerative colitis (UC) is a recurrent, chronic intestinal disease. Available treatments for UC are poor effective and/or cause severe adverse events. X-box binding protein 1 (XBP1) and nuclear factor-κB (NF-κB) have been reported to play important roles in UC.

Development of an XBP1 agonist, HLJ2, as a potential therapeutic agent for ulcerative colitis.

There is a severe lack of effective treatments for ulcerative colitis (UC), a recurrent and intractable inflammatory bowel disease. The identification of valid targets and new drugs is an urgent need. In this study, we identified the XBP-1 agonist HLJ2 as a promising treatment candidate.

Azacyclo-indoles and Phenolics from the Flowers of Juglans regia.

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.

14,15-Secopregnane-Type Glycosides with 5α:9α-Peroxy and Δ-diene Linkages from the Roots of Cynanchum stauntonii.

Three new 14,15-secopregnane-type glycosides, stauntosides UA, UA₁, and UA₂, were isolated from the roots of . The three compounds share the first reported and same basic structural features of 3β-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.

Sugar-free pregnane-type steroids from the roots of Cynanchum stauntonii.

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.

14,15-Secopregnane-type C-steriosides from the roots of Cynanchum stauntonii.

Nine 14,15-secopregnane-type C-steriosides, stauntosides U, V, V-V, W and C-C, as well as two known C-steriosides, were isolated from the roots of Cynanchum stauntonii. Stauntosides U, V and V-V share the same basic structural features of 8α:14α,14:16,15:20,18:20-tetraepoxy-14,15-secopregn-6-ene-3β,5α,9α-triol, with the numbering system following that of C-pregnanes. The aglycones of stauntosides U, V and V-V 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.

Versatile methods for synthesizing organic acid salts of quaternary berberine-type alkaloids as anti-ulcerative colitis agents.

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.

[Constituents with anti-oxidative activity from seeds of Jufeng grape].

Taking application of some isolation and purification technologies, including crushing, solvent extraction, preliminary solvent isolation, column chromatographies over silica gel and Sephadex LH-20 gel and preparative HPLC, 8 compounds were obtained from the seeds of Jufeng grape sourced from market. Their structures were identified by spectroscopic methods and comparison with literature values as Catechin (1), Epicatechin (2), quercetin (3), ethylgallate (4), rel-(2S, 3R) -2-(4-hydroxy-3-methoxyphenyl) -3- (hydroxymethyl)-5-(3-hydroxypropyl)-2,3-dihydrobenzofuran-7-ol (5), rel-(2α, 3β)-7-O-methylcedrusin (6), rel-(1R,2S)-1-(4-hydroxy-3-methoxyphenyl) -2-(4-(3-hydroxypropyl) -2-methoxyphenoxy) propane-1,3-diol (7), and (+) -isolariciresinol (8), respectively. Compounds 5-8 were serial lignans isolated from the seeds of grape for the first time.

[Lignans from cultivated Gynura nepalensis].

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.

Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1.

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.

The protective effect of epicatechin on experimental ulcerative colitis in mice is mediated by increasing antioxidation and by the inhibition of NF-κB pathway.

Background: Ulcerative colitis (UC) is a chronic inflammatory intestinal disease. It is necessary to find out new effective drugs for UC. In our study epicatechin extracted from grape seed by our institute for the first time could treat UC effectively.

Phenylpropanoids from the stems of Ephedra sinica.

Two new compounds of phenylpropanoids, (S)-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-5-oxopyrrolidine-2-carboxamide (1) and (3R)-3-O-β-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.

Synthesis and Structure-Activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents.

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.

[Chemical constituents of the roots of Macleaya microcarpa and activation efficacy of benzophenanthridine alkaloids for the transcription of xbp1 gene].

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), 3β-hydroxy-12-oleanen-30-oic acid (4), ferulic acid (5), ferulic acid 4-O-β-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.