汉防己甲素全合成研究进展

汉防己甲素是防己科千金藤属植物粉防己中分离提取的双苄基异喹啉类生物碱,已作为临床药物用于抗风湿及阵痛、抗肺癌、抗矽肺。基于粉防己产量的限制及汉防己甲素的需求量增加,深入开展汉防己甲素的全合成研究势在必行。本文按照合成策略,对汉防己甲素的全合成方法进行了综述。      

粉防己碱拮抗α-石英细胞毒性的机理

借助于单细胞阳离子测定系统研究了α-石英诱发细胞毒性过程中,不同外钙浓度时粉防己碱作用后,细胞存活率与胞浆游离钙浓度的变化关系。研究发现粉防己碱可以通过阻断细胞离子通道,拮抗α-石英的细胞毒性。     

Pharmacophore modelling of structurally unusual diltiazem mimics at L-type calcium channels

The purpose of this theoretical study was to investigate the molecular features of some structurally unusual calcium antagonists with experimentally proved affinity to the diltiazem-binding site at L-type calcium channels. Therefore, sterical and electronic characteristics of cis-/trans-diclofurime, the verapamil-like derivatives McN-5691 and McN-6186 as well as the natural products papaverine, laudanosine, antioquine and tetrandrine were compared with the pharmacophoric requirements detected for classical diltiazem-like derivatives. This yielded a common pharmacophore model for all of these compounds. Based on this model, one single negative molecular electrostatic potential induced by the free electron pairs of the oxime oxygen of trans-diclofurime was detected that might be responsible for the stronger effects compared to the cis isomer. Furthermore, the dual diltiazem- and verapamil-like features of McN-5691 (and McN-6186) as well as the distinct pharmacophoric assignment of the laudanosine enantiomers may be interpreted on a molecular level. Finally, the crucial partial structure of the bis-benzylisoquinoline derivatives antioquine and tetrandrine being responsible for the calcium antagonistic effects could be revealed by superposition on the most active benzothiazepinone derivative 8-methoxydiltiazem. The results obtained for these unusual diltiazem mimics are discussed taking into consideration earlier findings for classical diltiazem-like derivatives.     

微量热法测定粉防己碱金属配合物的抑菌性

从中药粉防己中提取粉防己碱。 在无水乙醇中粉防己碱分别与M(NO3)2·3H2O(M=Cu,Zn,Co,Ni)反应,合成了4种新的金属配合物,其结构分别用FT-IR和UV等测试技术进行了表征。 应用微量量热仪分别测定了不同浓度的粉防己碱及4种粉防己碱的金属配合物、M(NO3)2·3H2O(M=Cu,Zn,Co,Ni)对大肠杆菌代谢作用的热功率-时间曲线,运用Logistic方程计算出细菌的生长速率常数,建立了生长速率常数与药物浓度间的关系,进而确定了最佳抑菌浓度。 结果表明,4种金属配合物的抑菌作用均比M(NO3)2·3H2O和粉防己碱强。     

Design,Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC₅₀ value of 0.57 μM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies.     

Pharmacokinetics of 10‐hydroxycamptothecin–tetrandrine liposome complexes in rat by a simple and sensitive ultra‐high performance liquid chromatography with tandem mass spectrometry

10‐Hydroxycamptothecin is a drug to cure various cancers. However, the 10‐hydroxycamptothecin cannot be widely applied in clinics due to fast elimination and resistance of various cancers to the drug. Nevertheless, co‐treatment with tetrandine is known to reverse the resistance of multi‐drug resistant cancers, and may present an effective strategy to improve the efficacy of 10‐hydroxycamptothecin. In order to improve the bioavailability and prolong the treatment time of the 10‐hydroxycamptothecin in vivo, we prepared 10‐hydroxycamptothecin‐tetrandrine liposome complexes with 10‐hydroxycamptothecin as the basic anticancer drug, tetrandrine and liposomes as carriers. In this article, an ultra‐high performance liquid chromatography tandem mass spectrometry method for the analysis of 10‐hydroxycamptothecin and tetrandrine in plasma has been developed, validated, and utilized to compare the pharmacokinetics of both drugs in the original dosage form and administered as liposome complexes. According to the pharmacokinetic parameters of mean residence time, half‐life period and clearance rate, the 10‐hydroxycamptothecin‐tetrandrine liposome complexes prolongs the retention and circulation time of 10‐hydroxycamptothecin in vivo, achieving a good sustained release effect. To the best of our current knowledge, the pharmacokinetic properties of 10‐hydroxycamptothecin‐tetrandrine liposome complexes in rats have not been reported yet. Our study can provide a helpful reference for further related study.     

汉防己甲素衍生物的合成及其生物活性

为寻找更为有效的抗肿瘤药物,改善汉防己甲素的抗肿瘤活性,本文以汉防己甲素为原料,经过Suzuki反应设计并合成了6个新的双苄基异喹啉类衍生物。新化合物经过质谱(MS)、核磁共振氢谱(~1H NMR)、核磁共振碳谱(~(13)C NMR)等技术手段进行了结构确证。采用细胞计数试剂盒(CCK-8)法初步评价了6个新化合物对人肺癌细胞(A549)和小鼠白血病细胞(P388)的抗肿瘤活性。结果表明,化合物均有不同程度的抗肿瘤活性,其中化合物H1、H4、H6对A549细胞的抗肿瘤活性(IC5010μmol/L)明显优于阳性对照汉防己甲素。     

粉防己碱在玻碳电极上的电化学行为及其与DNA的相互作用

应用循环伏安法、差分脉冲伏安法、控制电位电解法等电化学方法和紫外光谱法研究了粉防己碱在玻碳电极上的电化学行为及其与DNA的相互作用,并对相关电化学动力学参数进行考察。结果表明,粉防己碱在玻碳电极上发生了受扩散控制的不可逆氧化反应,其在玻碳电极上的电子转移数为2、质子转移数为2、电荷转移系数为0.62。粉防己碱的峰电流随着DNA的加入而降低,且峰电位发生正移,表明粉防己碱与DNA通过嵌插方式相互作用生成复合物,同时计算了两者反应的结合数以及结合常数,结果显示粉防己碱和DNA以1∶1结合形成粉防己碱-DNA复合物,结合常数为4.27×103。