A novel hepatoprotective oleanolic acid derivative, 3-oxours-oleana-9(11), 12-dien-28-oic acid (Oxy-Di-OA), has been reported. In previous studies, we found that Oxy-Di-OA presented the anti-HBV ...(Hepatitis B Virus) activity (IC sub(50)= 3.13 mu g/mL). Remarkably, it is superior to lamivudine in the inhibition of the rebound of the viral replication rate. Furthermore, Oxy-Di-OA showed good performance of anti-HBV activity in vivo. Some studies showed that liver fibrosis may affiliate with HBV gene mutations. In addition, the anti-hepatic fibrosis activity of Oxy-Di-OA has not been studied. Therefore, we evaluated the protective effect of Oxy-Di-OA against carbon tetrachloride (CCl sub(4))-induced liver injury in rats. Daily intraperitoneally administration of Oxy-Di-OA prevented the development of CCl sub(4)-induced liver fibrosis, which was evidenced by histological study and immunohistochemical analysis. The entire experimental protocol lasted nine weeks. Oxy-Di-OA significantly suppressed the increases of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (p< 0.05). Furthermore, Oxy-Di-OA could prevent expression of transforming growth factor beta 1 (TGF- beta 1). It is worth noting that the high-dose group Oxy-Di-OA is superior to bifendate in elevating hepatic function. Compared to the model group, Oxy-Di-OA in the high-dose group and low-dose group can significantly reduce the liver and spleen indices (p< 0.05). The acute toxicity test showed that LD sub(50) and a 95% confidence interval (CIs) value of Oxy-Di-OA were 714.83 mg/kg and 639.73-798.73 mg/kg via intraperitoneal injection in mice, respectively. The LD sub(50) value of Oxy-Di-OA exceeded 2000 mg/kg via gavage in mice. In addition, a simple and rapid high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated to study the pharmacokinetic characteristics of the compound. After single-dose oral administration, time to reach peak concentration of Oxy-Di-OA (C sub(max)= 8.18 + or - 0.66 mu g/mL) was 10 + or - 2.19 h; the elimination half-life and area under the concentration-time curve from t= 0 to the last time of Oxy-Di-OA was 2.19 h and 90.21 mu g times h/mL, respectively.
A new anticancer ligustrazine derivative, 3β-hydroxyolea-12-en-28-oic acid- 3,5,6-trimethylpyrazin-2-methylester (T-OA, C38H58O3N2), was previously reported. It was synthesized via conjugating ...hepatoprotective and anticancer ingredients of traditional Chinese medicine. We found that T-OA exerted its anticancer activity by preventing the expression of nuclear transcription factor NF-κB/p65 and COX-2 in S180 mice. However, the selective cytotoxicity of T-OA on various kinds of cell lines has not been studied sufficiently. In the present study, compared with Cisplatin, T-OA was more toxic to human hepatoma cell line Bel-7402 (IC50 = 6.36 ± 1.56 µM) than other three cancer cell lines (HeLa, HT-29, BGC-823), and no toxicity was observed toward Madin-Darby canine kidney cell line MDCK (IC50 > 150 µM). The morphological changes of Bel-7402 cells demonstrated that T-OA had an apoptosis-inducing effect which had been substantiated using 4',6-diamidino-2-phenylindole (DAPI) staining, acridine orange (AO)/ethidium bromide (EB) staining, flow cytometry and mitochondrial membrane potential assay. Combining the immumohistochemical staining, we found T-OA could prevent the expression of NF-κB/p65 and COX-2 in Bel-7402 cells. Both of the proteins have been known to play roles in apoptosis and are mainly located in the nuclei. Moreover subcellular localization was performed to reveal that T-OA exerts in nuclei of Bel-7402 cells. The result was in accordance with the effects of down-regulating the expression of NF-κB/p65 and COX-2.
The lead compound T-OA, 3
β
-hydroxyolean-12-en-28-oic acid-(3,5,6-trimethylpyrazine-2-yl) methyl ester, which exhibited promising anticancer effects in vitro and in vivo, has previously been ...reported. According to the structural features, a series of novel T-OA analogues were synthesized via amino condensation reaction. These analogues’ cytotoxic activities were evaluated on five cancer cell lines (Bel-7402, HepG-2, HT-29, Hela, BGC-823) and hepatic stellate cell line (HSC-6). Among the candidates, compounds
8
and
16
showed promising effects; 3
β
-hydroxy-lup-20(29)-ene-28-oic acid-(3,5,6-trimethylpyrazin-2-yl) methyl amine (
16
) even possessed superior bioactivities to positive drugs (cisplatin and ursolic acid), which was worthy of further study. In addition, structure–activity relationships and Clog
P
values of T-OA analogues were briefly discussed.
Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity. To continue our research, a simple and ...regioselective methodology, using Eosin Y as a clean photosensitized oxidation catalyst, was developed for the synthesis of a peroxide bridge in steroids. The method that using Eosin Y as the catalyst was exposed to visible light and furbished in high yields, did not involve tedious work-up or purification, and avoided using environmentally hazardous solvents. It can be regarded as a green protocol. Moreover, a series of cholesterol and β-sitosterol derivatives containing a peroxide bridge were synthesized using this method and screened for their anti-HBV activity. Among the compounds synthesized in this research, 5α,8α-cyclicobioxygen-6-vinyl-3-oxo-cholesterone (
, 3.13 μg ml
) had the most potent activity with inhibition rates of 77.45% ± 6.01% and 58.73% ± 8.64% on the secretion of HBsAg and HBeAg antigens, respectively, after 8 days. Further acute toxicity test showed that the LD
value of compound
was 362.46 mg kg
after an intraperitoneal injection in mice. Moreover, structure-activity relationships of cholesterol and β-sitosterol derivatives were briefly discussed.
Previous studies display that bile acids (Bas) could be used as carriers and pharmaceutical excipients. In this study, the selective cytotoxicity of 6 bile acids (BAs) was evaluated against hepatoma ...cell line HepG2, human colon carcinoma cell line HT-29, gastric cancer cell line BGC823,
cervical cancer cell line Hela and hepatocyte line L02. Our study suggested that most of the BAs showed cytotoxicity against a broader spectrum of tumor cells and display high cell selectivity toward HepG2. In particular, chenodeoxycholic acid (CDCA) exerted the most potent selective cytotoxicity
against HepG2 (IC50 = 54.62 ± 3.5 μM) and low toxicity on L02 cells (IC50 > 200 μM). According to the structure-activity relationship, the position, configuration and number of OH groups in BAs could affect cell proliferation and selectivity. Moreover,
the pre-mechanism of CDCA on HepG2 cells was studied by Giemsa staining, DAPI staining, AO/EB staining, apoptosis analysis and mitochondrial membrane potential assay. Results showed that CDCA could induce apoptosis and loss of mitochondrial transmembrane potential in HepG2 cells. The study
inferred that CDCA might be a carrier and parent pharmaceutical excipient for hepatic carcinoma targeting drug.
Ligustrazine-benzoic acid derivatives which exhibited promising neuroprotective activities have previously been reported. To further improve the neuroprotective effect of ligustrazine, a series of ...new ligustrazine derivatives was synthesized and evaluated for their protective effect against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. Most compounds exhibited higher activity than ligustrazine, of which, we found compound ( E )-(3,5,6-trimethylpyrazin-2-yl)methyl 3-(2,3,4-trimethoxyphenyl)acrylate ( 9 ) displayed the highest protective effect on the PC12 cells damaged by CoCl 2 (EC 50 = 0.719 μM). Structure–activity relationships are briefly discussed.
Background
Ligustrazine has potent effects of thrombolysis, neuroprotection and vascular protection, which were important for effectively protecting the nervous system. Previous study in our ...laboratory reported that ligustrazine-benzoic acid derivatives have been shown to exhibit beneficial effect against CoCl
2
-induced neurotoxicity in differentiated PC12 cells. To further improve ligustrazine’s neuroprotection, we integrated the ligustrazine and phenolic acid fragments into one molecule via an amide bond based on structural combination.
Results
In this study, 12 novel ligustrazine-phenolic acid derivatives were synthesized and nine others were prepared by improved methods. Furthermore, these compounds were evaluated for their protective effects against CoCl
2
-induced neurotoxicity in differentiated PC12 cells. The amides conjunctional derivatives exhibited promising neuroprotective activities in comparison with ligustrazine. In addition, the most active congener (E)-3-(2,3,4-trimethoxyphenyl)-N-((3,5,6-trimethylpyrazin-2-yl)methyl)acrylamide (
L10
, EC
50
= 25 μM), which is 2 times higher than that of ligustrazine, may be a potential candidate for intervention in neurological diseases. Structure-activity relationship was discussed briefly.
Conclusions
Results of series of ligustrazinyl amides enrich the study of ligustrazine derivatives with neuroprotective effects. Our completed work supports that the attempt to apply structure combination to discover more efficient neuroprotection lead compounds is viable.
Graphical Abstract
Ligustrazinyl Amides
L1-L21
with Neuroprotective Effects.
Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity. To continue our research, a simple and ...regioselective methodology, using Eosin Y as a clean photosensitized oxidation catalyst, was developed for the synthesis of a peroxide bridge in steroids. The method that using Eosin Y as the catalyst was exposed to visible light and furbished in high yields, did not involve tedious work-up or purification, and avoided using environmentally hazardous solvents. It can be regarded as a green protocol. Moreover, a series of cholesterol and β-sitosterol derivatives containing a peroxide bridge were synthesized using this method and screened for their anti-HBV activity. Among the compounds synthesized in this research, 5α,8α-cyclicobioxygen-6-vinyl-3-oxo-cholesterone (
1f
, 3.13 μg ml
−1
) had the most potent activity with inhibition rates of 77.45% ± 6.01% and 58.73% ± 8.64% on the secretion of HBsAg and HBeAg antigens, respectively, after 8 days. Further acute toxicity test showed that the LD
50
value of compound
1f
was 362.46 mg kg
−1
after an intraperitoneal injection in mice. Moreover, structure-activity relationships of cholesterol and β-sitosterol derivatives were briefly discussed.
Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity.
Previous studies have demonstrated that natural steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity.
Previous studies have demonstrated that natural ...steroid compounds containing a peroxide bridge exhibited potential anti-hepatitis B virus activity. To continue our research, a simple and regioselective methodology, using Eosin Y as a clean photosensitized oxidation catalyst, was developed for the synthesis of a peroxide bridge in steroids. The method that using Eosin Y as the catalyst was exposed to visible light and furbished in high yields, did not involve tedious work-up or purification, and avoided using environmentally hazardous solvents. It can be regarded as a green protocol. Moreover, a series of cholesterol and β-sitosterol derivatives containing a peroxide bridge were synthesized using this method and screened for their anti-HBV activity. Among the compounds synthesized in this research, 5α,8α-cyclicobioxygen-6-vinyl-3-oxo-cholesterone (
1f
, 3.13 μg ml
–1
) had the most potent activity with inhibition rates of 77.45% ± 6.01% and 58.73% ± 8.64% on the secretion of HBsAg and HBeAg antigens, respectively, after 8 days. Further acute toxicity test showed that the LD
50
value of compound
1f
was 362.46 mg kg
–1
after an intraperitoneal injection in mice. Moreover, structure–activity relationships of cholesterol and β-sitosterol derivatives were briefly discussed.
Ligustrazine-benzoic acid derivatives which exhibited promising neuroprotective activities have previously been reported. To further improve the neuroprotective effect of ligustrazine, a series of ...new ligustrazine derivatives was synthesized and evaluated for their protective effect against cobalt chloride-induced neurotoxicity in differentiated PC12 cells. Most compounds exhibited higher activity than ligustrazine, of which, we found compound (
E
)-(3,5,6-trimethylpyrazin-2-yl)methyl 3-(2,3,4-trimethoxyphenyl)acrylate (
9
) displayed the highest protective effect on the PC12 cells damaged by CoCl
2
(EC
50
= 0.719 μM). Structure-activity relationships are briefly discussed.
The novel ligustrazine derivatives were synthesized and displayed the remarkable protective effect (highest EC
50
= 0.719 μM) on PC12 cells damaged by CoCl
2
.
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