三尖杉酯碱

摘要： 记述了我国著名有机合成化学家、兰州大学资深教授李裕林先生在祖国的大西北近半个世纪的学术生涯中的主要贡献,其中包括三尖杉酯碱类化合物的半合成,以及生物标志化合物、狼毒素、大环二萜类、桉烷类和沉香呋喃类天然产物的全合成研究.

摘要： 目的 评价高三尖杉酯碱、阿糖胞苷、柔红霉素或去甲氧柔红霉素(HAD/HAI)方案诱导治疗初治急性髓系白血病(AML)患者的长期疗效并探讨其影响因素.方法 观察HAD/HAI方案治疗1个疗程后初治143例AML患者的完全缓解(CR)、总生存(OS)及无复发生存(RFS)率,分析WHO2008标准诊断分型、遗传学预后分组及初始WBC等因素对患者OS、RFS率的影响,评估中剂量阿糖胞苷(MD-Ara-C)巩固治疗在提高AML患者长期生存中的作用.结果 143例患者中112例(78.3％)1个疗程获CR.仅1例患者在诱导化疗期早期死亡.高白细胞与非高白细胞组、FLT3-ITD突变型与野生型组患者CR率差异均无统计学意义(P值分别为0.266和0.528).遗传学预后良好、中等、不良组患者CR率分别为93.7％、71.4％和61.3％,组间差异有统计学意义(P=0.001).中位随访24(1～104)个月,中位生存时间为30(95％CI12～48)个月.所有患者的5年OS率为40.0％,5年RFS率为37.0％.1个疗程CR后接受巩固治疗的患者为96例,5年OS率为47.0％,5年RFS率为38.0％;其中序贯含MD-Ara-C方案(71例)和序贯标准剂量Ara-C(25例)巩固治疗组患者的5年OS率差异有统计学意义(58.0％对19.0％,P=0.004).在序贯含MD-Ara-C方案巩固治疗的患者中,高白细胞与非高白细胞组、FLT3-ITD突变型和野生型组患者的5年OS率差异均无统计学意义(P值分别为0.419和0.482),遗传学预后良好、中等、不良组患者5年OS率差异无统计学意义(P=0.332).结论 HAD/HAI方案诱导化疗缓解后序贯含MD-Ara-C方案巩固治疗的策略对初治AML患者,特别是高白细胞患者,可望获得满意的长期生存率.%Objective To estimate the long-term outcomes and the prognostic factors of homoharringtonine,cytarabine,daunorubicin or idarubicin (HAD/HAI) as induction chemotherapy in de novo acute myeloid leukemia (AML).Methods The CR rate,overall survival (OS) rate,relapse free survival (RFS) rate were retrospectively assayed in 143 de novo AML patients who received the HAD/ HAI induction chemotherapy.The outcomes were compared among prognostic groups according to world health organization (WHO) classification,genetic prognosis and initial white blood cell (WBC) count.The role of consolidation chemotherapy consisting of middle-dosage Ara-C (MD-Ara-C) on long term survival was evaluated.Results Of 143 patients,112 (78.3％) achieved CR after the first course of HAD/ HAI induction treatment,and early death occurred in only one case.Notably,the CR rate of patients with an initial WBC count ≥100× 109/L was not significantly different from those with an initial WBC count＜100× 109/L (70.4％ vs 80.2％,P=0.266).The CR rate for the patients with favorable,intermediate and unfavorable integrated genetics risk factors was 93.7％,71.4％ and 61.3％,respectively,the difference between groups was statistically significant (P=0.001).Patients with FLT3-ITD mutation obtained similar CR rate (70.6％)to that of patients with FLT3 wild type (79.3％,P=0.528).The estimated 5-year OS rate and 5-year RFS rate for all patients was 40.0％ and 37.0％,respectively,with a median follow-up of 24 (range 1-104) months.The median survival time was 30 [95％ CI (12,48)] months.5-year OS and 5-year RFS of the 96 patients who achieved CR after first course chemotherapy without undergoing allo-HSCT in complete remission was 47.0％ and 38.0％,respectively.5-year OS was significantly higher in MD-Ara-C consolidation group than in no MD-Ara-C consolidation group among CR patients without allo-HSCT (58.0％,19.0％,respectively,P=0.004).In patients who obtained CR after first course and received MD-Ara-C consolidation without allo-HSCT,the 5-year OS of patients with hyperleukocytosis was not significantly lower than that of patients without hyperleukocytosis (55.5％,58.8％,respectively,P=0.419).FLT3-ITD mutation patients showed similar 5-year OS to that of wild type FLT3 patients (51.4％,60.2％,respectively,P=0.482).And furthermore,5-year OS of favorable,intermediate and unfavorable integrated genetics groups were 59.1％,62.5％,51.9％,respectively (P=0.332) in this subgroup.Conclusion HAD/ HAI induction chemotherapy with sequential consolidation of MD-Ara-C could obtain satisfactory CR rate and long-term survival rate in de novo AML,especially for patients with hyperleukocytosis or FLT3-ITD mutation.It yet remains to be verified by large sample,prospective studies.

摘要： 目的 采用固相萃取-高效液相色谱(SPE-HPLC)法测定三尖杉Cephalotaxus fortunei Hook.f.中的三尖杉酯碱和高三尖杉酯碱.方法 三尖杉90％乙醇提取液的分析采用迪马Diamonil C18色谱柱(250 mm×4.6 mm,5μm);流动相为乙腈∶水(含0.1g十二烷基磺酸钠和0.1％磷酸,42∶58),等度洗脱;体积流量为0.5 mL/min;检测波长为291 nm.结果 三尖杉酯碱、高三尖杉酯碱在2.48～49.60、2.51～50.20 μg/mL范围内线性关系良好,平均回收率(n=5)分别为95.4％、95.1％,RSD分别为1.83％、1.91％.两种成分的含有量在茎中最高,而在叶中最低.结论 该方法可用于测定该植物中的三尖杉酯碱和高三尖杉酯碱,效果理想.

摘要： 为了研究海南粗榧细胞的固定化条件及其对细胞的生长和三尖杉酯碱合成的影响,本研究利用海藻酸钠凝胶包埋法对海南粗榧悬浮细胞进行固定化,并改变了其固定化条件,同时测定了生物量、PAL酶活性、凝胶球硬度、蔗糖含量和三尖杉酯碱产量等指标,结果显示:海南粗榧固定化细胞的生长周期为40 d,其中,在0～15d其细胞生长停滞,在15～30 d其细胞生长缓慢,而30 ～40 d为缓慢衰亡期;海南粗榧细胞固定化培养的最佳产物提取时间为第15 d;包埋过程中CaCl2的最适质量浓度为0.023 g/mL;鲜重细胞的最适接种量为10％.由此得出结论:海南粗榧细胞固定化培养抑制了细胞的生长,延长了细胞的生长周期,但缩短了细胞生产三尖杉酯碱的周期.

摘要： AIM:To study whether inhibition of forkhead box protein M1(FoxM1) sensitizes leukemia K562 cells to homoharringtonine ( HHT ) .METHODS: K562 cells were incubated with HHT at different concentrations ( 0μmol/L, 0.015 μmol/L, 0.030μmol/L and 0.045μmol/L) for different time (0 h, 24 h, 48 h and 72 h).The mRNA and protein levels of FoxM1 were detected by real-time PCR and Western blot.FoxM1 siRNA was transfected into K562 cells with 0.015μmol/L HHT after 6 h.After 72 h incubation, the cell proliferation was detected by cell counting and soft agar assay, and the proportion of apoptotic K562 cells was determined by flow cytometry.The expression of c-Myc and Sp1 were detected by real-time PCR and Western blot.RESULTS:FoxM1 expression was reduced time-dependently and dose-dependently, suggesting that HHT mediated the downregulation of FoxM1 in K562 cells.In K562 cells, treatment with FoxM1 siRNA and HHT inhibited the cell proliferation and promoted the apoptosis significantly.Therefore, inhibition of FoxM1 sensitized leukemia K562 cells to HHT.The expression of c-Myc and Sp1 was positively regulated by FoxM1. CONCLUSION:HHT inhibits Forkhead box protein M1 expression in K562 cells.Inhibition of FoxM1 sensitizes K562 cells to HHT.%目的：探讨抑制白血病K562细胞叉头框蛋白M1（FoxM1）是否增强细胞对高三尖杉酯碱（HHT）的敏感性。方法：HHT以不同浓度（0、0．015、0．030和0．045μmol／L）和最低起效浓度不同时间（0．015μmol／L，0、24、48和72 h）作用于K562细胞，real－time PCR和Western blot检测FoxM1 mRNA和蛋白表达；以0．015μmol／L HHT作用K562细胞后转染FoxM1 siRNA，观察沉默K562细胞FoxM1后细胞对HHT的敏感性、细胞增殖和凋亡效应以及FoxM1相关靶分子c－Myc和Sp1表达状况。结果：随着HHT浓度增加和时间延长FoxM1表达逐渐降低，说明HHT抑制K562细胞FoxM1表达；HHT处理K562细胞后转染FoxM1 siRNA，细胞生长和克隆形成显著下降，细胞凋亡增加，因此抑制FoxM1可增加K562细胞对HHT的敏感性；FoxM1 siRNA组c－Myc和Sp1表达显著降低，表明FoxM1可正性调控c－Myc和Sp1表达。结论：HHT可以抑制白血病K562细胞FoxM1表达，干扰FoxM1可增强细胞对HHT的敏感性。

摘要： Objective To compare the clinical effects of three harringtonine and chemotherapy on cerebral vascular BCNU malignancies.Methods From March 2009 to June 2011,in the second people's hospital of Changzhi,19 patients with cancer treatment were analyzed retrospectively.Ten patients underwent treatment with three harringtonine as the experimental group,and the other 9 cases were treated with chemotherapy within BNCU cerebrovascular as the control group,the differences of the two groups in age,gender,disease and other aspects were not obvious,there was no significant difference (P ＞ 0.05).The complications and prolong the lives of patients differences in terms of time was compared.Results There were 6 patients with effective results in the control group,the treatment effective rate was 66.67％,and 7 patients were effective in the test group,the treatment effective rate was 70％,treatment efficiency difference was not statistically significant (P ＞ 0.05).The average life extension of time in the control group was 18.5 months,the average life span of patients was 22.3 months.The average life span had obvious difference with statistical significance (P ＜ 0.05).Conclusions Three harringtonine in the treatment of malignant tumors has good cerebrovascular chemotherapy effects,can prolong the life time of the patient,so it can be used in clinical practice.%目的 比较三尖杉酯碱和BCNU脑血管内化疗治疗恶性肿瘤的临床效果.方法 随机选取2009年3月至2011年6月在长治市第二人民医院进行恶性肿瘤治疗的19例患者为观察对象,对其临床资料进行回顾性分析.选取其中10例采用三尖杉酯碱进行治疗的患者作为试验组,另9例采用BNCU脑血管内化疗法的患者作为对照组,两组患者在年龄、性别、病情等方面比较差异无统计学意义(P＞0.05).比较两组在治疗效果、并发症发生以及患者生命延长时间等方面的差异.结果 对照组6例治疗有效,治疗有效率为66.67％,试验组7例治疗有效,治疗有效率为70％,两组比较差异无统计学意义(P＞0.05).对照组平均生命延长时间为18.5个月,试验组为22.3个月,差异有统计学意义(P＜0.05)结论 三尖杉酯碱较BNCU脑血管内化疗治疗恶性肿瘤效果明显,更能延长患者的生命时间,可以在临床中推广应用.

摘要： 采用色谱柱为 ODS-C18（4.6mm ×250mm ，5μm），以甲醇∶0.02mol ・ L -1乙酸铵水溶液（体积比48∶52）为流动相，流速为1.0ml ・ min -1，柱温40°C，检测波长296nm ，进样量20μl ，外标法进行定量分析，探讨了测定三尖杉（Cephalotaxus fortunei Hook. f.）中的三尖杉酯碱（Harringtonine ， HT ）的高效液相色谱分析方法。结果表明，0.5～10mg ・ L -1的三尖杉酯碱化合物的标准曲线呈良好的线性关系（r ＝0.9998）；平均回收率在88.1％～95.4％之间，相对标准偏差＜3.6％。该方法测定结果准确，操作简便，适用于 HT 原料中药的测定。

摘要： Asymmetric synthesis of harringtonine side-chain acid was accomplished by a se-quence of Wittig and Meisenheimer rearrangements plus catalytic hydrogenation reaction in the presence of N-Boc amino aldehyde as the starting material .The structure of the intermediates and as-synthesized target product was characterized by means of nuclear magnetic resonance spectrometry (1 H NMR and 13 C NMR) ,infrared spectrometry and mass spectrometry .Results indicate that the methods adopted have the advantages of high yield ,mild reaction condition , and simple operation ,and the overall yield of target compound is as much as 30% .%　　以N-Boc苏氨醛为起始原料，经Wittig、Meisenheimer重排和催化氢化系列反应，不对称合成了天然产物三尖杉酯碱的侧链酸，中间体及目标产物结构经核磁共振（1 H NMR、13 C NMR）、红外光谱和质谱表征。结果表明，所用合成方法具有产率高、反应条件温和、操作简单等优点；目标化合物的总收率达30％。

摘要： AIM: To investigate the effects of P — glycoprotein ( multidrug resistance protein 1, MDR1 ) shR-NA on harringtonine - induced apoptosis of human harringtonine - resistant actue promyelocytic leukemia HT9 cells. METHODS: MDR1 shRNA expression plasmid pSilencer 3. 1 - H1 neo - MDR1 was constructed and introduced into HT9 cells ( HT9/sh —3.1 — 1 cells ). The mRNA of MDR1 was detected by real — time fluorescent quantitative PCR. The protein level of MDR1 was assayed by Western blotting. The viability of HT9 cells was determined by MTT method. After the cells were treated with harringtonine, the DNA fragmentation of the cells were observed by gel electrophoresis. The morphological alteration of the cells was observed under confocal laser scanning microscope. The cell cycle was also analyzed by flow cytometry. RESULTS: MDR1 shRNA expression plasmid was successfully constructed. The expression of MDR1 at mRNA and protein levels was significantly decreased after pSilencer 3.1 - H1 neo - MDR1 was transfected into HT9 cells, and IC50 of harringtonine was decreased from ( 1. 184 ± 0. 130 ) mg/L to ( 0. 711 ± 0. 010 )mg/L. Compared with HT9 cells, DNA ladder was observed in HT9/sh — 3.1 — 1 cells treated with harringtonine, and the typical apoptotic morphology was also found under a confocal laser scanning microscope. The cells in S phase were increased, and apoptotic peak was observed. CONCLUSION: shRNA expression plasmid pSilencer 3.1 - H1 neo - MDR1 permanently and stablely inhibits MDR1 gene expression and promotes the sensitivity of HT9 cells to harringtonine - induced apoptosis.%目的:探讨靶向P-糖蛋白(又称多药耐药蛋白1,MDR1)基因的shRNA对三尖杉酯碱诱导人耐三尖杉酯碱的前髓细胞白血病HT9细胞凋亡的影响.方法:构建MDR1基因特异的shRNA表达载体pSilencer 3.1-H1 neo-MDR1,稳定电转染HT9细胞,实时荧光定量PCR分析MDR1 mRNA的表达,Western blotting检测细胞MDR1蛋白表达,MTT法检测细胞活力,经三尖杉酯碱处理后琼脂糖凝胶电泳检测凋亡细胞DNA片段化,激光共聚焦观察细胞形态变化,流式细胞术检测细胞周期变化.结果:成功构建了shRNA表达载体pSilencer 3.1-H1 neo-MDR1,稳定转染后,HT9细胞MDR1 mRNA和蛋白表达均显著降低,HT9细胞三尖杉酯碱的 IC50由(1.184±0.130)mg/L降至(0.711±0.010)mg/L.与HT9细胞相比,经三尖杉酯碱处理后稳定转染细胞HT9/sh-3.1-1的DNA ladder更明显,激光共聚焦显微镜下可见形态不规则的碎片状或梅花状等典型的细胞凋亡形态;细胞的S期细胞增多,并出现明显的凋亡峰.结论:shRNA表达载体pSilencer 3.1-H1 neo-MDR1能够稳定、持久地抑制MDR1基因,并有效增强三尖杉酯碱诱导的HT9细胞凋亡.

摘要： 目的：探讨Rab7b在HHT诱导K562细胞凋亡中的作用及细胞自噬与凋亡的关系.方法：用MTF法检测HHT对K562细胞增殖抑制作用,用Annexin V/PI双染法检测K562细胞凋亡,并用Western blot检测自噬体的标志物LC3的表达,用自噬抑制剂3-Methyladenine(3-MA)抑制K562细胞自噬后检测HHT诱导的K562细胞凋亡变化,并用West-ena blot检测caspase3、9的蛋白表达及ERK1/2、Akt、Beclin 1的变化,同时,我们构建了Rab7b、Rab7b的持续活化型突变(Rab7b-Q67L)、Rab7b的失活型突变(Rab7b-ACC)和Rab7b干扰(Rab7b-RNAi)质粒,转染到K562细胞,用Annexin V/PI双染法检测表达不同突变型的Rab7b对K562细胞凋亡的影响,并用Western blot检测caspase3、9及ERK1/2、Akt通路蛋白的表达.

摘要： 本发明公开了高三尖杉酯碱和三尖杉酯碱在抑制血管生成中的新用途，研究表明，高三尖杉酯碱和三尖杉酯碱具有抑制血管生成的作用。其技术方案是：式I化合物在制备抑制血管生成的治疗和/或预防药物中的应用，其有效剂量范围，高三尖杉酯碱为0.03～0.1mg/Kg体重/天；三尖杉酯碱为0.05～0.1mg/Kg体重/天。本发明巧妙地以血管生成做为治疗疾病的靶点，具有以下优点：1.治疗针对已经启动的新生血管进行，具有特异性；2.由于血管内皮细胞暴露于血流中，药物直接发挥作用，故剂量小，疗效高，副作用小；3.由于内皮细胞基因表达相对稳定，故不易产生耐药性。

摘要： 本发明提供了一种能简化生产工艺，合理使用珍稀树种资源，减少废物排放，并能有效提高制剂产量的方法。本发明采用了含量较低的可再生的三尖杉小枝叶为原料，经过：打粉并用10%稀氨水碱化→超临界CO2流体萃取→分离回收三尖杉总生物碱→吸附树脂连续柱层析→回收三尖杉混合酯碱→制备高速逆流色谱并经紫外检测得到三尖杉酯碱与高三尖杉酯碱单体和少量的二者混合物→分别重结晶纯化得到供制剂用的纯品。

摘要： 本发明公开了三尖杉酯碱或其类似物的应用与所制得的制剂，其中，三尖杉酯碱或其类似物可制备预防或治疗由肠道病毒71型所引起的手足口病的药物，其药物制剂可为口服剂、注射剂或者外用剂，三尖杉酯碱或其类似物对肠道病毒71型具有明显的抑制作用。

摘要： 本发明涉及蕨类植物用于提取三尖杉酯碱或高三尖杉酯碱的应用，即蕨类植物中的华南鳞盖蕨植物用于提取三尖杉酯碱或高三尖杉酯碱的应用。从华南鳞盖蕨植物中发现、提取三尖杉酯碱或高三尖杉酯碱等同、替代珍稀树种三尖杉中的三尖杉酯碱或高三尖杉酯碱；华南鳞盖蕨植物为蕨类植物，生长迅速，采集量大，这是乔本三尖杉属树种所不能比拟的，由此可大大增加了抗癌药物所需的三尖杉酯碱和高三尖杉酯碱的原料来源，从而降低了成本。

摘要： 本发明公开了高三尖杉酯碱和三尖杉酯碱在抑制血管生成中的新用途，研究表明，高三尖杉酯碱和三尖杉酯碱具有抑制血管生成的作用。其技术方案是：式I化合物在制备抑制血管生成的治疗和/或预防药物中的应用，其有效剂量范围，高三尖杉酯碱为0.03～0.1mg/Kg体重/天；三尖杉酯碱为0.05～0.1mg/Kg体重/天。本发明巧妙地以血管生成做为治疗疾病的靶点，具有以下优点：1.治疗针对已经启动的新生血管进行，具有特异性；2.由于血管内皮细胞暴露于血流中，药物直接发挥作用，故剂量小，疗效高，副作用小；3.由于内皮细胞基因表达相对稳定，故不易产生耐药性。

摘要： 本发明提供了一种能简化生产工艺，合理使用珍稀树种资源，减少废物排放，并能有效提高制剂产量的方法。本发明采用了含量较低的可再生的三尖杉小枝叶为原料，经过：打粉并用10％稀氨水碱化→超临界CO2流体萃取→分离回收三尖杉总生物碱→吸附树脂连续柱层析→回收三尖杉混合酯碱→制备高速逆流色谱并经紫外检测得到三尖杉酯碱与高三尖杉酯碱单体和少量的二者混合物→分别重结晶纯化得到供制剂用的纯品。

摘要： 本发明公开了一种利用悬浮培养细胞生产抗肿瘤脱氧三尖杉酯碱的方法包括以下步骤：利用前体饲喂（三尖杉碱、L‑高亮氨酸）+诱导（刺激剂）的方式在海南粗榧叶腋细胞悬浮培养生产抗肿瘤脱氧三尖杉酯类生物碱的方法，该方法通过建立一种生长速度快的细胞系，解决生物量少的问题，该方法的核心内容是通过细胞这个生物反应器，将三尖杉碱转化为脱氧三尖杉酯碱，具有生产周期短而稳定、不占用耕地、产量稳定、有效成分含量高、不破坏自然资源的特点，具有极大的开发利用价值。

摘要： 本发明公开三尖杉酯碱用于制备抗新型冠状病毒药物的应用，属于抗病毒药物制备技术领域，药物通过SARS‑CoV‑2‑Sh/CMC模型及TMPRSS2h/CMC模型分析，确定了三尖杉酯碱与SARS‑CoV‑2的S蛋白和细胞TMPRSS2酶的结合特异性；利用SARS‑CoV‑2假病毒侵染ACE2高表达细胞和ACE2/TMPRSS2共同高表达细胞，证实药物具有双靶标的特性；利用SARS‑CoV‑2原始株及Delta 630突变株感染Vero E6细胞，证实药物具有显著抗SARS‑CoV‑2效果，且对Delta 630突变株的抑制作用更为敏感。

摘要： 本发明提供了新的抗人CD79b的单克隆抗体以及其与高三尖杉酯碱的缀合物在抗癌或肿瘤方面的应用。

摘要： 本发明公开了一种人参皂苷高三尖杉酯碱脂质体、其制备方法和应用。本发明的脂质体的原料包括如下重量份计的组分：10‑20份磷脂、0.5‑3.0份人参皂苷和1份高三尖杉酯碱；所述的脂质体不含有胆固醇、大豆油或油酸钠。该脂质体具有良好的制剂学特征、靶向性和药效，具有良好的成药前景。