苯氧丙胺类化合物的合成与抑酸活性的研究

目的:合成H_2受体阻滞剂罗沙替丁乙酸酯盐酸盐;设计合成具有抑酸活性的苯氧丙胺类化合物,并考察其体外抑酸活性。方法:以间羟基苯甲醛为起始原料,经Leukart、酰化、SN_2取代反应得罗沙替丁乙酸酯盐酸盐;以中间体N-{3-[3-(1-哌啶甲基)苯氧]丙基}氯乙酰胺为原料,在强碱性条件下,选取3个伯胺,经胺解得到3个苯氧丙胺类化合物。测定离体豚鼠胃粘膜胃酸分泌量,考察苯氧丙胺类化合物的抑酸活性。结果:合成了罗沙替丁乙酸酯盐酸盐,以间羟基苯甲醛计,4步反应总收率为28.8%;经核磁和质谱,确证了3个苯氧丙胺类化合物(Z1,Z2,Z3)化学结构。初步药理筛选实验表明,化合物Z1和Z2表现出较高的抑制胃酸分泌百分率。结论:合成反应条件温和,原料价廉易得,适合工业化生产。

雷贝拉唑的抑酸活性对提高胃癌化疗效果的临床研究

目的探讨雷贝拉唑的抑酸活性对提高胃癌化疗的效果以及其最佳给药时间。方法将30例胃癌患者随机分为对照组、试验A组和试验B组,每组10例。对照组予以口服2000 mg·m^-2·d^-1卡培他滨,每日2次,第1-14天加静脉滴注130 mg·m^-2·d^-1奥沙利铂,第1天;试验A组在对照组的基础上,加用口服雷贝拉唑20 mg,每天1次,第1-14天;试验B组在对照组的基础上,加用口服雷贝拉唑20 mg,每天1次,第-7-13天（即在化疗药开始前7天即开始使用）。3组患者均接受2个周期的治疗,每个周期21 d。比较3组患者治疗后的临床疗效和不良反应发生率。结果对照组、试验A组、试验B组的有效率分别为25.00%,33.33%和30.00%,疾病控制率分别为62.50%、77.78%和70.00%,组间比较差异无统计学意义（P〉0.05）,但试验组的有效率和疾病控制率较对照组呈增高的趋势。治疗期间,3组患者的主要不良反应为消化道反应、血液学毒性和手足综合征,但组间比较差异无统计学意义（P〉0.05）。试验A组与试验B组的雷贝拉唑血药浓度比较差异无统计学意义（P〉0.05）。结论卡培他滨联合奥沙利铂的临床疗效较好,不良反应较轻,雷贝拉唑提前1 d给药即可达稳态。

1-(取代)苯磺酰基-3-烷胺基甲基吲哚衍生物的设计合成及其抑酸活性研究

目的设计合成系列1-(取代)苯磺酰基-3-烷胺基甲基吲哚衍生物,评价其对大鼠胃酸分泌的抑制能力,并初步探讨其构效关系。方法以取代吲哚为起始原料,经Vilsmeier反应在吲哚3位引入醛基,再与取代苯磺酰氯反应,最后经还原胺化并成盐制得目标化合物;采用组胺刺激的大鼠胃酸分泌模型评价目标化合物的抑酸活性。结果与结论合成了20个未见文献报道的苯基磺酰基类化合物,目标化合物的结构均经1H-NMR、13C-NMR和HRMS谱确证。活性测试结果表明,所合成的目标化合物均具有一定的抑酸活性,部分化合物的活性优于阳性药vonoprazan,其中有8个化合物的抑酸率大于80%。

苯氧丙胺类化合物(Ⅱ)的合成与药理活性研究

目的:合成7个苯氧丙胺类化合物,并进行药理活性研究。方法:以中间体N-{3-[3-(1-哌啶甲基)苯氧]丙基}氯乙酰胺为厚料,在强碱性条件下,选取伯胺,经胺解、柱层析纯化得到目标化合物。结果:确证了苯氧丙胺类化合物化学结构。药理筛选实验表明,化合物Z1和Z2抑酸活性较高,化合物Z1和Z4对组胺H_2受体的阻滞作用较强。结论:苯氧丙胺类化合物合成方法简易,化合物Z1和Z4表现出较好的抗消化性溃疡活性。

Cantharidin and Its Analogues:Anticancer and Ser/Thr Protein Phosphatase Inhibitory Activities

This paper mainly describes the anticancer activities and Ser/Thr protein phosphatase inhibitory activities of cantharidin and its analogues.

PTEN induces anoikis through its phosphatase activity in human bladder transitional carcinoma cells BIU-87

Objective:To investigate the effects and mechanisms of tumor suppressor gene PTEN on the induction of anoikis of human bladder transitional carcinoma cells BIU-87.Methods:BIU-87 cells were transfected with GFP plasmids containing wild-type PTEN or phosphatase inactivating mutant PTEN(C124A-PTEN)in vitro.The PTEN expression and the phosphorylation levels of focal adhesion kinase(FAK)and protein kinase B(PKB/Akt)were detected by Western blotting.Flow cytometry assay and laser scanning confocal microscopy were used to analyze apoptosis in adherent and non-adherent cells.Results: Compared with the control group,PTEN expression in the cells transfected with wild-type PTEN increased to 210%–260%, while the phosphorylation level of FAK and Akt decreased 59%(P<0.01)and 89%(P<0.01),respectively.And the anoikis percentage increased from 8.32±0.57%to 37.62±2.12%.In the cells transfected with C124A-PTEN,neither the phos- phorylation of FAK and Akt nor the anoikis percentage had obviously changed,although the PTEN expression enhanced remarkably in comparison with the control.Conclusion:Through its phosphatase activity,tumor suppressor gene PTEN can suppress the phosphorylation of FAK and Akt,and induce anoikis in human bladder transitional carcinoma cells BIU-87.

Cysteine peptidase and its inhibitor activity levels and vitamin E concentration in normal human serum and colorectal carcinomas

AIM: Cysteine peptidase (CP) and its inhibitor (CPI) are a matrix protease that may be associated with colorectal carcinoma invasion and progression, and vitamin E is also a stimulator of the immunological system. Our purpose was to determine the correlation between the expression of cysteine peptidases and their endogenous inhibitors,and the level of vitamin E in sera of patients with colorectal cancer in comparison with healthy individuals.METHODS: The levels of cysteine peptidases and their inhibitors were determined in the sera of patients with primary and metastatic colorectal carcinoma and healthy individuals using fluorogenic substrate, and the level of vitamin E was determined by HPLC.RESULTS: The levels of cysteine peptidases and their inhibitors were significantly higher in the metastatic colorectal cancer patients than that in the healthy controls (P＜0.05).The activity of CP increased 2.2-fold, CPI 2.8-fold and vitamin E decreased 3.4-fold in sera of patients with metastasis in comparison with controls. The level of vitamin E in healthy individuals was higher, whereas the activity of cysteine peptidases and their inhibitors associated with complexes was lower than that in patients with cancer of the digestive tract.CONCLUSION: These results suggest that the serum levels of CP and their inhibitors could be an indicator of the prognosis for patients with metastatic colorectal cancer. Vitamin E can be administered prophylactically to prevent digestive tract neoplasmas.

Chemical constituents of marine mangrove-derived endophytic fungus Alternaria tenuissima EN-192

A chemical investigation of the ethyl acetate extract of the fermentation broth of Alternaria tenuissima EN- 192, an endophytic fungus obtained from the stems of the marine mangrove plant Rhizophora stylosa, resulted in the isolation of nine known secondary metabolites, including four indole-diterpenoids： penijanthine A （1）, paspaline （2）, paspalinine （3）, and penitrem A （4）; three tricycloalternarene derivatives： tricycloalternarene 3a （5）, tricycloalternarene lb （6）, and tricycloalternarene 2b （7）; and two alternariol congeners： djalonensone （8） and alternariol （9）. The chemical structures of these metabolites were characterized through a combination of detailed spectroscopic analyses and their comparison with reports from the literature. The inhibitory activities of each isolated compound against four bacteria were evaluated and compounds 5 and 8 displayed moderate activity against the aquaculture pathogenic bacterium Vibrio anguillarum, with inhibition zone diameters of 8 and 9 mm, respectively, at 100 gg/disk. To the best of our knowledge, this is the first report on the secondary metabolites of mangrove-derived Alternaria tenuissima and also the first report of the isolation ofindole-diterpenoids from fungal genus Alternaria.

Improvement of Propionic Acid Production for Antifungal Activity from Whey by Calcium Alginate Immobilization of Propionibacterium acidipropionici TISTR 442

The improvement of propionic acid production for antifungal activity, as fermenting by calcium alginate immobilized cells of Propionibacterium acidipropionici TISTR 442 was investigated by using whey as substrate. Optimal condition for immobilization was performed by adjusting tube distance to CaCI2 solution to be 4-6 cm and 7 mL/min flow rate of alginate gel. The production of propionic acid by immobilized cells in a 2 L fermentor using 1% CaCO3 and 5 N KOH to control the pH at 6.5 gave maximum propionic acid and they had consistent potential to recycle 2 rounds of fermentation and produced the total of 29.24 g/L propionic acid （15.85 ± 0.25 g/L and 13.39 ± 0.25 g/L propionic acid from Batch 1 and Batch 2 fermentation, respectively）. Compared to free-cell fermentation, propionic acid productivity increased 20% （0.083 g/h vs. 0.070 g/h） and fermentation time reduced 11% （192 h vs. 216 h） in 2 L fermentor with 40 g/L initial total sugar from whey. The fermented propionic acid as well as the commercial propionic acid from chemical process was able to inhibit the growth of the fungal tested.

Activation of phospholipase D activity in transforming growth factor-beta-induced cell growth inhibition

Cells regulate phospholipase D (PLD) activity in response to numerous extracellular signals. Here, we investigated the involvement of PLD activity in transforming growth factor-β(TGF-β1)-mediated growth inhibition of epithelial cells. TGFβ1 inhibits the growth of MDCK, Mv1Lu, and A-549 cells. In the presence of 0.4 % butanol, TGF-β1 induces an increase in the formation of phosp hat idylbutanol, a unique product catalyzed by PLD. TGF-β1 also induces an increase in phosphatidic acid (PA) level in A-549 and MDCK cells. TGF-β1 induces an increase in the levels of DAG labeled with [~3H]-myristic acid in A-549 and MDCK cells but not in Mv1Lu cells- No increase of DAG was observed in cells prelabeled with [~3H]-arachidonic acid.The data presented suggest that PLD activation is involved in the TGF-β1-induced cell growth inhibition.

Screening and Characterization of the Alkaline Protease Isolated from PLI-1, a Strain of Brevibacillus sp. Collected from Indonesia's Hot Springs

A total of 69 strains of thermophilic bacteria were isolated from water, soil and sediment samples from three Indonesia's hot spring areas (Pantai cermin, Kalianda and Banyu wedang) by using Minimal Synthetic Medium (MSM). The extreme thermophile Brevibacillus sp. PLI-1 was found to produce extracellular thermophilic alkaline protease with optimal activity at 70℃ and pH 8.0-9.0. The molecular weight of the protease was estimated to be around 56 kD by SDS-PAGE. The maximum activity of the protease was 26.54 U mL-1. The protease activity did not decrease after 30 min and still retained more than 70% of relative activity after 60 min at 70℃ and pH 8.0. The ion Mg2+ was found to promote protease activity at both low and high concentrations, whereas Cu2+ and Zn2+ could almost completely inhibit the activity. Divalent cation chelator EDTA inhibited the enzyme activity by 55.06% ± 0.27%, while the inhibition caused by PMSF, Leupeptin, Pepstain A and Benzamidine were 66.78% ± 3.25%, 52.37% ± 0.25%, 62.47% ± 2.96% and 50.99% ± 0.24%, respectively. Based on these observations, the enzyme activity was conspicuously sensitive to the serine and cysteine protease inhibitors. All these results indicated that the protease isolated from the strain PLI-1 was a thermophilic protease and had a high-temperature stability and a pH stability.

Inhibitory effect of Cr(Ⅵ) on activities of soil enzymes

To evaluate the influence of various Cr(Ⅵ) concentrations (0.05, 0.25, 0.50, 1.00 and 2.00 g/kg) on the activity of soil enzymes, the activities of catalase, polyphenol oxidase, dehydrogenase, alkaline phosphatase in soils were investigated in the incubation experiment with a period of 35 d. The results indicate that all the tested Cr(Ⅵ) concentrations significantly inhibit dehydrogenase activity by over 70% after 35 d. The activity of alkaline phosphatase is slightly inhibited during the whole experiment except for on the day 7. Cr(Ⅵ) has no obvious effect on the activity of catalase in soil. On the contrary, Cr(Ⅵ) stimulates the activity of polyphenol oxidase. The results suggest that dehydrogenase activity can be used as an indicator for assessing the severity of chromium pollution.

Combination of telomerase antisense oligonucleotides simultaneously targeting hTR and hTERT produces synergism of inhibition of telomerase activity and growth in human colon cancer cell line

AIM: To investigate synergism of inhibition of telomerase activity and proliferation of human colon cancer cells by combination of telomerase antisense oligonucleotides (ASODNs) simultaneously targeting human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) in vitro. METHODS: ASODN of hTR and ASODN of hTERT were transfected into human colon cancer SW480 cells by liposomal transfection reagents. Telomerase activity of SW480 cells was examined using telomeric repeat amplification protocol (TRAP)-enzyme-linked immunosorbent assay (PCR-ELISA). Proliferation activity of SW480 cells was tested by methyl thiazolyl tetrazolium assay. Apoptosis and cell cycle were analyzed by flow cytometry. RESULTS: The telomerase activity and cell survival rate in SW480 cells transfected with 0.2 μmol/L of ASODN of hTR or ASODN of hTERT for 24-72 h were significantly decreased in a time-dependent manner compared with those after treatment with sense oligonucleotides and untreated (telomerase activity: 24 h, 73%, 74% vs99%, 98%; 48 h, 61%, 55% vs98%, 99%; 72 h, 41%, 37% vs 99%, 97%; P<0.01; cell survival rate: 24 h, 88%, 86% vs594%, 98%; 48 h, 49%, 47% vs94%, 97%; 72 h, 44%, 42% vs92%, 96%; P<0.01). Moreover, the telomerase activity and the cell survival rate in SW480 cells treated by the combination of telomerase anti-hTR and anti-hTERT were more significantly suppressed than single anti-hTR or anti-hTERT (telomerase activity: 24 h, 59% vs 73%, 74%; 48 h, 43% vs61%, 55%; 72 h, 18% vs41%, 37%; P<0.01; cell survival rate: 24 h, 64% vs88%, 86%; 48 h, 37% vs49%, 47%; 72 h, 25% vs44%, 42%; P<0.01). Meanwhile, the apoptosis rates in the combination group were markedly increased compared with those in the single group (24 h, 18.0% vs7.2%, 7.4%; 48 h, 23.0% vs13.0%, 14.0%; 72 h, 28.6% vs 13.2%, 13.75; P<0.01). Cells in combination group were arrested at G0/G1 phase. CONCLUSION: Telomerase anti-hRT and anti-hTERT suppress telomerase activity, and inhibit growth of human colon cancer cells probably via induction of apoptosis and retardation of cell cycle. Additionally, combined use of telomerase ASODNs targeting both hTR and hTERT yields synergistic action selective for human colon cancer.

质子泵抑制剂研究新进展

质子泵抑制剂是一类用于治疗胃、十二指肠溃疡,反流性食管炎和卓-艾综合征等酸相关性疾病的抑酸药物,且具抗氧化、抗炎、抗凋亡及抗癌等多重药理活性。综述质子泵抑制剂的分子作用机制、药理作用和药动学特性及其影响因素,并介绍若干新型质子泵抑制剂。

Synthesis and evaluation of 8-deaza-5,6,7,8-tetrahydromethotrexate derivatives as dihydrofolate reductase inhibitors

A series of N5-substituted 8-deaza-5,6,7,8-tetrahydromethotrexate derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase（DHFR）.The results indicated that modification of the pteridine ring of methotrexate（MTX） rendered poor activity against human DHFR.

Synthesis of prenylated and geranylated xanthones and their bioactivities

Nine prenylated and geranylated xanthones were synthesized in two steps with total yields ranging from 11%to 36%.All of the compounds were first reported.Then,the antitumor,anti-tyrosinase,anti-pancreatic lipase,antifungal and antibacterial activities of all or part of compounds 1–9 were evaluated.Compound 9 exhibited clear antitumor activity,and its cytotoxicity against MCF-7 and MDA-MB-231 cells was stronger compared with cisplatin.Compounds 1–4 and 6–7 also exhibited certain activity other than the antitumor activity described above.These results demonstrated that compounds 1–4,6–7 and 9 were very promising leads for further structural modification.