青藤碱抗肿瘤作用研究进展

青藤碱（Sinomenine,SIN）是从中药青风藤分离出的一种生物碱单体,分子式为C19H23NO4,结构类似于吗啡,具有镇痛镇静、镇咳局麻、降血压、抗炎等作用,为植物中很强的组织胺释放剂。青藤碱除具有镇静抗炎作用外,对肿瘤细胞增殖也有较强的抑制作用,能够抑制多种恶性肿瘤细胞的生长[1]。现将青藤碱抗肿瘤作用研究进展作一综述。1青藤碱抗宫颈癌作用1.1青藤碱抑制宫颈癌细胞增殖张瑜等[2]探讨了青藤碱对宫颈癌Hela细胞的抑制作用。结果表明0.12.5 mmol·L-1青藤碱均能抑制宫颈癌Hela细胞增殖,并呈时间、剂量依赖性;青藤碱作用后,     

青藤碱衍生物的合成及其抗炎镇痛活性青藤碱衍生物的合成及其抗炎镇痛活性

目的为定向设计合成高效低毒的新一代青藤碱类药物提供线索。方法以青藤碱为先导物,对C环进行结构改造。结果共合成7个衍生物,进行了抗炎镇痛活性的筛选,结果表明,化合物2和5具有较好的抗炎镇痛作用。结论C环结构修饰值得进一步研究。     

1位芳基取代的青藤碱衍生物的合成和抗炎活性研究

目的 进行1位取代芳基的青藤碱衍生物的合成及体外抗炎活性研究。方法 以青藤碱为先导化合物,首先1位溴取代反应,然后通过Suzuki偶联反应对A环1位进行修饰,制得一系列取代芳基的青藤碱衍生物,所有化合物均经¹H-NMR、¹³C-NMR、MS结构确认;采用报告基因法研究青藤碱衍生物对NF-κB转录活性的影响。结果 Suzuki偶联反应得到的一系列化合物活性均优于对照药青藤碱。结论 筛选到的4f和4g可作为候选药物进行深入研究,对研发治疗风湿性关节炎药物具有重要意义。     

青藤碱-硝酸酯偶联物的合成及体外抗肿瘤活性筛选

目的:为寻找青藤碱有效的结构修饰方法以挖掘其抗肿瘤作用。方法:基于对母体结构特点的剖析设计合成了一系列青藤碱-硝酸酯偶联物,所合成偶联物的结构经IR光谱、¹H-NMR、¹³C-NMR和高分辨质谱确证。运用四甲基偶氮唑蓝(MTT)法筛选偶联物对人源5种肿瘤细胞(宫颈癌Hela细胞、肺癌A549细胞、肝癌HepG2细胞、乳腺癌MCF-7细胞和结肠癌HT-29细胞)体外抗肿瘤活性。结果:共设计合成了9个青藤碱-硝酸酯偶联物。相比其他系列的偶联物,6-苯腙基青藤碱-硝酸酯偶联物体外抗肿瘤作用更为突出,其中衍生物10d对Hela, MCF-7及HT-29细胞株的抑制作用均优于阳性对照药顺铂,IC₅₀分别为(9.72±0.53),(15.46±8.16),(8.19±1.05)μmol·L^-1。结论:衍生物10d对多种待测肿瘤细胞有良好的体外抗肿瘤活性,可作为抗肿瘤的前体药物分子,值得继续开展进一步的研究。     

青藤碱微乳与凝胶的皮肤渗透性比较

目的比较青藤碱微乳和凝胶对离体大鼠皮肤的透皮能力。方法以油酸-聚山梨酯-80-无水乙醇-水作为微乳的组成,采用改进的Franz扩散池研究青藤碱微乳和凝胶的透皮行为,用高效液相色谱法测定青藤碱浓度。结果青藤碱微乳的透皮速率大于青藤碱凝胶(P<0.01),青藤碱微乳平均透皮速率为116.44μg.cm-2.h-1,青藤碱凝胶为89.93μg.cm-2.h-1。结论青藤碱微乳有很强的透皮能力,有望成为青藤碱的新型透皮给药制剂。     

青藤碱对神经肌肉传递的作用

青藤碱对大鼠离体膈神经隔肌标本能可逆性阻滞神经肌肉的传递,呈浓度依赖性抑制作用;对神经干的兴奋性和传导性无明显影响。高Ca~(2+)溶液可拮抗青藤碱对神经肌肉传递的阻滞作用。在小鸡颈二腹肌实验,青藤碱可降低肌肉对ACh的敏感性。青藤碱与琥珀胆碱相似,均使蟾蜍腹直肌标本产生收缩反应。新斯的明不能桔抗青藤碱对神经肌肉传递的阻滞作用,且有加强作用。提示青藤碱具有去极化型肌松药的某些作用特点。     

两种方法测定盐酸青藤碱纯度及不确定度评定

目的：采用两种方法测定盐酸青藤碱纯度,并建立其不确定度评定方法。方法采用高效液相色谱法（ HPLC）对盐酸青藤碱纯度进行测定,并依据标准物质技术规范及相关计量技术规范要求,对HPLC法测定过程的不确定度进行了系统分析,并采用酸碱非水滴定法对盐酸青藤碱纯度值进行验证。结果采用HPLC法测定盐酸青藤碱纯度的标准值及其不确定度为99．87％±0．41％（k＝2,P＝0．95）。酸碱非水滴定法测定纯度值为99．88％,在不确定度范围之内。结论采用HPLC与酸碱非水滴定法联合测定盐酸青藤碱纯度及不确定度评定结果准确可靠,避免了采用一种技术带来的分析方法缺陷,有利于提高盐酸青藤碱的质量评价与控制水平,同时对盐酸青藤碱纯度标准物质的研制提供了科学依据。     

青藤碱的药理作用 Ⅶ.对胃肠道活动的影响及其机制

本文报告青藤碱对麻醉犬和免在位肠管的影响.静脉注射青藤碱引起小肠暂时兴奋,这种兴奋作用可被笨海拉明、六烃季胺完全阻断,阿托品完全或部分阻断,但切断两侧迷走神经不能阻断.给犬静脉注射青藤碱,可使胃分泌和酸度增加,胃蛋白酶活性无明显改变.青藤碱在兴奋肠管同时使血浆组织胺含量和淋巴形成增加,皮肤组织胺含量下降.以上结果表明青藤碱引起胃肠道兴奋的主要原因,系青藤碱释放组织胺的结果.     

青藤碱的药理作用Ⅶ.对胃肠道活动的影响及其机制

本文报告青藤碱对麻醉犬和免在位肠管的影响.静脉注射青藤碱引起小肠暂时兴奋,这种兴奋作用可被笨海拉明、六烃季胺完全阻断,阿托品完全或部分阻断,但切断两侧迷走神经不能阻断.给犬静脉注射青藤碱,可使胃分泌和酸度增加,胃蛋白酶活性无明显改变.青藤碱在兴奋肠管同时使血浆组织胺含量和淋巴形成增加,皮肤组织胺含量下降.以上结果表明青藤碱引起胃肠道兴奋的主要原因,系青藤碱释放组织胺的结果.     

盐酸青藤碱红外光谱分析

目的建立盐酸青藤碱的红外光谱分析方法.方法采用红外光谱法测定不同纯度盐酸青藤碱晶形的IR谱图并比较差异.结果与青藤碱标准品IR谱图比较,盐酸青藤碱对照品的羟基进行了缔合,在3 500～3 200 cm 峰形变宽;纯白色样品与对照品峰形一致;灰白色样品与淡黄色样品在2 400～2 300cm1有一∞=N吸收峰,且淡黄色样品的吸收峰较灰白色样品峰强.结论盐酸青藤碱IR谱图与其晶形纯度有关,运用红外光谱法进行分析,快速、简便、专属性强,为盐酸青藤碱质量控制提供参考.     

Shikonin and its derivatives: a patent review

Introduction: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects.

Areas covered: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed.

Expert opinion: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.     

Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution

1.?We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases.

2.?Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives.

3.?We identified the C2-position as the oxidation site by LC-MS and ¹H-NMR and showed that C2-substituted derivatives are no longer AO substrates.

4.?In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.     

Boron‐Containing Peptidomimetics – A Novel Class of Selective Anti‐tubercular Drugs

Medical treatment for tuberculosis is complicated nowadays by the appearance of new multiresistant strains, and therefore, new antibiotics are in great need. Here, we report the synthesis and in vitro testing of a new class of highly selective antimicrobial boron‐containing peptidomimetics with compounds exhibiting activity against Mycobacterium tuberculosis at ≤5 μg/mL. The new approach developed makes it possible to synthesize variously substituted β‐aminoboronic acids and their derivatives with a high level of diastereoselectivity.     

中药大黄的综合研究 Ⅰ.大黄中蒽醌衍生物抗菌效价的研究

中药大黄在祖国医学經驗中不但用以緩下、健胃及利胆,并且亦作为清毒消炎之用。关于大黄水煎剂抗菌作用的实驗研究,文献已有报告;但关于其抗菌作用有效成分的研究报告很少。据文献,Costa Rica地方民間曾用Cassia reticulata叶的浸出物口服以治疗淋病。1947年,Robbias,Kavanagh和Thayer等曾从此叶分离出一种Cassicacid,发現其对金黄色葡萄球菌、枯草杆菌、草分枝杆菌、淋病双球菌、蕈状菌及包皮垢菌等有显著抑制作用,其抑菌最低浓度为4—32微克/毫升;但对大腸杆菌、肺炎杆菌及綠脓     

Insulin aspart (AspB28 human insulin) derivatives formed in pharmaceutical solutions

Purpose. To isolate and identify the main insulin aspart (Asp^B28 human insulin) derivatives formed in pharmaceuticals (pH 7.4 at 5°C), to estimate rates of formation, and to determine their biologic potencies. Methods. Insulin aspart derivatives have been isolated by reversed-phase high-performance liquid chromatography (RP-HPLC), and identified by RP-HPLC, peptide mapping, amino acid analysis, mass spectrometry, and N-terminal amino acid sequence analysis. Results. The main derivatives formed were isoAsp^B28, isoAsp^B3, Asp^B3, and desPhe^B1-N-oxalyl-Val^B2 insulin aspart. At 5°C, the rate constants were 0.00028/month for isoAsp^B28 and isoAsp^B3, 0.00024/month for Asp^B3, and 0.00013/month for desPhe^B1-N-oxalyl-Val^B2 derivatives of insulin aspart. Unexpectedly, the rate of isomerization of B28 was high compared to the rate of B3 deamidation at both 5°C and 45°C. The N-terminal and especially the C-terminal of the B-chain are highly flexible, which may explain the high rate of isoAsp^B28 formation and that deamidation of Asn^B3 occurs. All the derivatives had full in vivo biologic potencies. Conclusion. Except for isoAsp^B28 insulin aspart, the main derivatives formed in pharmaceuticals of insulin aspart and human insulin at pH 7.4 are similar. They are all fully active in vivo. In proteins, flexibility of the polypeptide chain seems more important than sequence in the formation of succinimides.     

New substituted benzimidazole derivatives: a patent review (2013 – 2014)

Introduction: The benzimidazole nucleus is found in a variety of naturally occurring compounds and is of significant importance in medicinal chemistry. Owing to its conspicuous pharmacological properties, benzimidazoles have become an important pharmacophore and sub-structure in drug design and have been screened for a wide range of biological activities.

Areas covered: Areas covered in this paper include a review of the biological effects, mechanisms and synthesis of benzimidazole derivatives in the past 2 years based on patents. The patent databases Scifinder and esp@cenet were used to locate patent applications that were published between 2013 to present. Information from articles published is also included.

Expert opinion: Benzimidazole derivatives are remarkably effective compounds to many diseases and may have the potential to be the first effective therapy against Ebola virus. Therefore, it is of great importance to develop specific design software and sustainable industrial synthetic routes for the development of effective and clinically relevant benzimidazole compounds.     

Novel camptothecin derivatives as topoisomerase I inhibitors

Background: Camptothecin (CPT), a pentacyclic alkaloid isolated by Wall et al. in 1958 from the Chinese tree Camptotheca acuminata, was reported to possess an interesting antitumor activity. Late in 1985, it was reported by Liu et al. that the cytotoxic activity of CPT was attributed to a novel mechanism of action involving the nuclear enzyme classified as type I DNA topoisomerase. Since the explanation of the unique mechanism of action, many derivatives have been synthesized and some of them are in various stages of preclinical and clinical development. Among them, two derivatives, topotecan and irinotecan, have successfully entered into the market and are used as topoisomerase I poisons in clinical practice. Objective: The main focus of the present review is to describe the development of CPT derivatives over the years dividing them by decades according to the date of discovery and focusing attention on molecules that were published in patents. Results/conclusion: To summarize, > 150 patents have been deposited over the past 30 years. Structure–activity relationship studies suggest that substitutions at the 7-, 9- or 10-positions of most CPT derivatives enhance their antitumor activity, but at the 11- or 5-position usually lead to activity decrease.     

Identification of novel HIV-1 integrase inhibitors using shape-based screening, QSAR, and docking approach

The objective of this study is to identify novel HIV‐1 integrase (IN) inhibitors. Here, shape‐based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV‐1 IN, and in silico validation is performed by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using genetic function approximation (GFA) method with good internal (cross‐validated r² = 0.852) and external prediction (). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as a template for shape‐based screening of ZINC database. Toxicity prediction was also performed using Deductive Estimation of Risk from Existing Knowledge (DEREK) program to filter non‐toxic molecules. Inhibitory activities of screened non‐toxic molecules were predicted using derived QSAR models. Active, non‐toxic screened molecules were also docked into the active site of HIV‐1 IN using Auto Dock and dock program. Some molecules docked similarly as highly active molecule of the benzodithiazine derivatives. These molecules also followed the same docking interactions in both the programs. Finally, four benzodithiazine derivatives were identified as novel HIV‐1 integrase inhibitors based on QSAR predictions and docking interactions. ADME properties of these molecules were also computed using Discovery Studio.     

Preferred conformation of the benzyloxycarbonyl-amino group in peptides*

Structural parameters, derived from X-ray crystallographic data, have been compiled for 35 derivatives of amino acids, peptides, and related compounds, which contain the N-terminal benzyloxycarbonyl (Z) group. The geometry of the urethane moiety of this end group is closely similar to that of the tert-butoxycarbonyl (Boc) group, except for a relaxation of some bond angles because the Z group is sterically less crowded than the Boc group. For the same reason, the Z group has greater conformational flexibility. As a result, packing forces in the crystal may cause greater deformations of bond angles, resulting in larger variations of observed bond lengths and bond angles than in Boc-peptide crystals. The aromatic rings of the Z end groups tend to stack in crystals. Conformational energy calculations indicate that most conformations of Z-amino acid-N' -methylamides and of corresponding Boc derivatives have similar dihedral angles and relative energies, i.e. the nature of the N-terminal end group has little effect on the conformational preferences of the residue next to it. In particular, the computed fraction of molecules with a cis urethane (C-N) bond is similar for the two derivatives: 0.51 and 0.42 in Boc-Pro-NHCH₃ and Z-Pro-NHCH₃, respectively, and 0.02 in the two Ala derivatives. There exist several computed conformations of Z-Ala-NHCH₃ and Z-Pro-NHCH₃ in which the phenyl ring and the C-terminal methylamide group are close to each other. Because of favorable nonbonded interactions, such conformations are of low energy.     

The application of graphene oxide in drug delivery

Introduction: As a shining star in material science, graphene oxide (GO) and its derivatives possess potential applications in a variety of areas. Among them, the application of GO to drug delivery has attracted ever-increasing interest in the past few years.

Areas covered: In this article, the authors summarize the latest progress of utilizing GO in the field of drug delivery. In particular, the functionalization of GO, cytotoxicity of GO and its derivatives, in vitro and in vivo drug delivery and the comparison with carbon nanotube-based delivery systems are discussed. Future perspectives and possible challenges in this emerging field are briefly described.

Expert opinion: GO and its derivatives are highly attractive for the application to drug delivery due to their exceptional physiochemical properties and unique planar structure in spite of some existing challenges, such as the reproducibly smart functionalization of GO and the investigation of its long-term toxicology.