9-hydroxyellipticine and derivatives as chemotherapy agents

The hydroxy group in 9-hydroxyellipticines increases the apparent affinity for DNA, stabilisation of toposiomerase II-DNA cleavable complex, oxidation to reactive quinone-imine intermediates, phosphorylation of p53 suppressor proteins and cytotoxicity relative to the parent ellipticines. Recent studies have focused on the mechanism of inhibition of phosphorylation of the mutant type of p53 protein, structural characterisation of the drug-DNA complex, the synthesis of carbohydrate derivatives and calculations of physical parameters, including dipole moments, as potential screens to allow identification of new active derivatives. Derivatisation at the 2- and 9-positions has lead to significant improvements in the in vivo activity of the 9-hydroxyellipticine derivatives and has provided important insights into the mechanism of action of these compounds.     

Determination of 9-hydroxyellipticine by redox colorimetry.

The chemical reactions involved in the decomposition of 9-hydroxyellipticine (9-OH-E), an anticancer agent, in polar solvents is explained. The reactions, which involve the formation of 9-oxo-ellipticine and the addition of a nucleophilic acid on the C10 site of the heterocyclic system, have been used to measure 9-OH-E quantitatively by colorimetry in solution and by reflection on paper surfaces. A method for the stabilization of 9-OH-E in polar solvents is proposed.     

隐丹参酮及其衍生物抗肿瘤活性研究进展

隐丹参酮是中药丹参的有效成分之一,对多种肿瘤显示很好的活性。其抗肿瘤效应包括抑制细胞增殖、诱导肿瘤细胞凋亡、抑制细胞迁移和侵袭、调节机体免疫功能和逆转药物耐药性等。抗肿瘤直接靶点有信号转导和转录激活因子3(STAT3)、酪氨酸蛋白磷酸酶SHP2、DNA拓扑异构酶2(top2),其它的作用机制包括诱导活性氧（ROS）产生、调控雌、雄激素受体信号、抑制PI3K/AKT信号通路等。此外,近年来研究人员还设计合成了许多隐丹参酮衍生物,并对其抗肿瘤作用进行了研究。本文主要就隐丹参酮及其衍生物抗肿瘤活性研究进展进行综述,希望能够有助于隐丹参酮及其衍生物在抗肿瘤方面的药物研发。     

新型骨靶向抗肿瘤大黄酚衍生物的合成

目的: 利用大黄蒽醌类化合物的抗肿瘤作用与趋骨性,将大黄酚抗肿瘤药5-氟脲嘧啶及其衍生物连接,合成系列新型骨靶向抗肿瘤衍生物.方法: 合成大黄酚衍生物,MTT法测定其对肿瘤细胞增殖的抑制作用,用羟基磷灰石吸附试验评价该类药物的体外骨亲和性.结果: 合成了21个大黄酚衍生物均为新化合物.实验显示所有化合物均有不同程度的骨亲和性,大部分化合物的亲和性高于阳性对照药四环素.结论: 大黄酚衍生物具有良好的骨亲和性.     

D-氨基葡萄糖及其衍生物抗肿瘤活性的初步研究

目的观察氨基葡萄糖盐酸盐(GlcNH2.HCl)、氨基葡萄糖(GlcNH2)和N-乙酰氨基葡萄糖(NAG)体外抑制人肝癌细胞(SMMC-7721)生长的作用,对小鼠S180肉瘤的肿瘤抑制作用以及对免疫系统的影响并探讨其作用机制。方法采用MTT法检测不同浓度的单糖对SMMC-7721细胞生长的影响,倒置显微镜观察细胞形态,琼脂糖凝胶电泳进行DNA断裂分析,流式细胞仪检测对细胞周期的影响。采取灌胃给药的方式,观察GlcNH2.HCl对S180小鼠瘤重、胸腺重和脾重以及荷瘤小鼠淋巴细胞转化率的影响。结果GlcNH2.HCl和GlcNH2能明显抑制肝癌细胞SMMC-7721的生长,且存在剂量依赖性,在500μg.mL-1浓度下,Glc-NH2.HCl和GlcNH2的抑制率为50.24%和52.19%,在1000μg.mL-1浓度下的抑制率分别为82.21%和83.2%。GlcNH2.HCl对SMMC-7721细胞存在周期特异性,可以使细胞发生S期阻滞。NAG对肝癌细胞的生长没有明显抑制作用。GlcNH2.HCl在125~500mg.kg-1的剂量范围内,对小鼠S180肉瘤均有一定的抑制作用,平均抑瘤率在27.84%~34.02%之间,其中250 mg.kg-1剂量的抑制作用最强,在该剂量范围下,GlcNH2.HCl对荷瘤小鼠具有明显增加胸腺指数和脾指数的作用,同时促进荷瘤小鼠脾脏T淋巴细胞转化,无明显毒副作用。结论GlcNH2.HCl体外呈剂量依赖性抑制人肝癌细胞SMMC-7721的生长,体内可能是通过直接杀伤肿瘤细胞的细胞毒作用和提高S180肉瘤小鼠细胞免疫水平来发挥抑瘤作用。     

黄酮及其衍生物的高效合成和抗肿瘤活性

目的设计合成一系列黄酮衍生物,并考察其抗肿瘤活性,并发现1种高效合成黄酮的新方法。方法以2,46,-三羟基苯乙酮为原料,选择性甲基化、酯化、Baker-Venkataraman重排成β-二酮,进而三氟甲磺酸三甲基硅酯催化β-二酮环合合成5个黄酮;以白杨素为母体,经烷基化反应、Man-nich反应合成了一系列白杨素衍生物。采用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-lium bromide]法测试部分目标化合物对脑胶质瘤细胞(C6)和人肝癌细胞(HepG2)的抑制活性。结果与结论合成了17个化合物,其中3个为新化合物。其结构经过核磁共振氢谱、质谱确认;4个目标化合物的体外抗肿瘤活性明显强于白杨素。     

Purity determinations in the bulk drug of the novel indoloquinone antitumor agent EO9

Summary The pharmaceutical development of the investigational cytotoxic drug EO9 included the structural characterization of the bulk drug by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and infrared (IR) spectroscopy, and analytical characterization by high-performance liquid chromatography and ultraviolet/visible spectrophotometry. The presence of impurities in the bulk drug was investigated. The intermediates in the synthesis of EO9 were structurally characterized by NMR spectroscopy and MS, and analytically characterized by HPLC analysis with photodiode array (PDA) detection. All of the intermediates were below their limits of detection in EO9 bulk drug. The amounts of residual organic solvents were determined by gas chromatography. Methanol and ethanol were detected, but the amounts present did not exceed the limits as set in the United States Pharmacopeia XXII.     

海洋抗肿瘤候选药物普那布林(Plinabulin)及类似物的研究进展孙天文1,2,丁忠鹏1, 王世潇2, 赵建春1,2, 管华诗1,2,

【】 微管蛋白是细胞骨架的重要组成部分,在维持形态、信号传导及有丝分裂等过程中起着重要的作用。普那布林(Plinabulin)是在从海洋焦曲霉菌中分离得到的天然产物 Phenylahistin 结构基础上,经构效关系研究,合成出的二酮哌嗪类微管蛋白抑制剂。普那布林作为抗肿瘤候选药物,目前已进入临床二期研究。近年来,为了获得高效、低毒和生物利用度更高的普那布林衍生物,本领域研究人员进行了大量的优化研究,获得了一些具有更好活性的衍生物。本文就普那布林及其类似物优化的研究进展进行综述。     

Synthesis and antitumor activity of new derivatives of xanthen-9-one-4-acetic acid

Xanthen-9-one-4-acetic acid (XAA) analogues in which the substituents in positions 5 and 6 are included in cyclic structures are described. Direct in vitro toxicity of the synthesized compounds against four tumor cell lines was evaluated, and their ability to stimulate mouse peritoneal macrophages and human monocytes in culture to become tumoricidal (indirect toxicity) was also studied. Despite low direct toxicity, almost all the compounds proved to be able to significantly enhance the lytic properties of both murine macrophages and human monocytes as well as the parent compound XAA and its most active derivative DMXAA taken as reference. In particular, compounds 4a, 5a, 7a, 13a,b, and 16a,b showed higher activity than the lead compound on human monocytes, compound 7a being 2.5 times more active than DMXAA, which is the most potent compound synthesized so far. Moreover, compounds 4a, 5a, 7a, 13a, 16a, and 16b proved to be able to induce TNF production in human immune cells.     

Cardioprotective effects of 9-hydroxyellipticine on ischemia and reperfusion in isolated rat heart

We determined the effect of 9-hydroxyellipticine (9HE) on ryanodine receptor (RyR) and cardiac function after global ischemia in isolated rat hearts. The binding of [3H]-ryanodine in rabbit cardiac sarcoplasmic reticulum was displaced by 9HE in a biphasic manner corresponding to the two sites model with IC50 values of 6.1 microM and 55 mM. The increase of the intracellular Ca2+ concentration induced by caffeine in CHO cells expressing cardiac-type RyR was suppressed by 9HE in a concentration-dependent manner. Pretreatment of the heart with 9HE decreased the total duration of reperfusion-induced ventricular fibrillation (VF) and delayed the onset of VF. There was also a significant recovery of contractile force of ischemic hearts following 9HE. Unlike nifedipine, an L-type Ca2+-channel blocker, 9HE did not suppress the contraction of rat papillary muscles. Thus, 9HE exerts the cardioprotective effects against ischemia /reperfusion injury without changing hemodynamic indices.     

Recent advances in artemisinin and its derivatives as antimalarial and antitumor agents

Artemisinin, the first and last naturally occurring 1, 2, 4-trioxane originated from Artemisia annua, L. and its derivatives are a potent class of antimalarial drugs. The clinical efficacy of these drugs is characterized by an almost immediate onset and rapid reduction of parasitemia, and it is high in such areas as well where multidrug-resistance is rampant. Furthermore, artemisinin and many of its analog possess not only antiparasitic effect against Plasmodium falciparum, Schistosoma japonicum and Clonorchis sinensi but also immuno-modulation effects, and antitumor activities. This review covers the chemistry of artemisinin including synthesis of acetal-, non acetal-type C-12 analogs, C-11- and C-13 derivatives from artemisitene, ring-contracted derivatives, dimers, and trimers. Modes of biological action of artemisinin - derived analogs are also reviewed. The main objective of this article is to review the literatures of recent progress taken place in chemistry, mode of biological actions of artemisinin, and its derivatives as antimalarial and antitumor agents during the last three years (1999-2001).     

青蒿素类药物抗肿瘤作用的基础与临床研究

青蒿素类(Art)抗疟药具有多种药理活性,近年来对其抗肿瘤作用的基础研究较多,相关的临床研究也逐渐开展。大量体外和动物体内实验结果显示:Art可抑制或杀伤肿瘤细胞;诱导肿瘤细胞凋亡:阻滞细胞周期;抑制血管生成;延缓或逆转肿瘤细胞的多药耐药性;与铁制剂合用或与转铁蛋白结合可提高对肿增细胞的选择性杀伤作用。临床探索提示Art对肿瘤具有治疗或辅助治疗作用。Art对人体毒性低,与传统化学治疗药物有协同增效作用且无交叉耐药性。应加强Art抗肿瘤的临床研究以明确其抗肿瘤性质、范围、剂量、疗程及不良反应。     

Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives

Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their primary amine and the C-10 position of the ellipticine ring and (ii) that a double bond was present between the nitrogen and the alpha-carbon of the amino acid moiety. All amino acid-NMHE adducts exhibit a higher lipophilic property than the parent compound (NMHE) directly correlated with the length of the aliphatic chain of the amino acids. The adducts interact with DNA through an intercalating process with apparent binding constant ranging from 2 X 10(5) to 5 X 10(5) M-1 at pH 7.40. The presence of the amino acid moiety linked to NMHE results (i) in a slight decrease of the cytotoxicity on L1210 cells in vitro (ID50 ranged from 0.20 to 0.50 microM) as compared to NMHE (ID50 = 0.05 microM), (ii) in a decrease of the antitumor efficiency in vivo against L1210 leukemia for leucine-NMHE and valine-NMHE (ILS at LD0/2 = 35% and 31%, respectively), (iii) in a suppression of the antitumor activity for alanine-NMHE and glycine-NMHE (ILS less than 25%), (iv) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacteriostatic effect is directly correlated with the lipophilic property of the drugs. These findings are discussed in terms of a structure-activity relationship.     

Reduced DNA topoisomerase II activity and drug-stimulated DNA cleavage in 9-hydroxyellipticine resistant cells

We have isolated a Chinese hamster lung cell line resistant to 9-hydroxyellipticine (DC-3F/9-OH-E) which is also cross-resistant to topoisomerase II inhibitors such as amsacrine and etoposide. In this work we have studied quantitatively both DNA topoisomerase II activity by decatenation of kinetoplast DNA and drug-stimulated DNA cleavage of pBR 322. DNA topoisomerase II activity of DC-3F/9-OH-E nuclear extract was reduced by 3.5-fold as compared to that from DC-3F (sensitive parent) nuclear extract. We also found that DC-3F/9-OH-E nuclear extracts have a reduced capacity to induce in vitro topoisomerase II-mediated DNA cleavage upon stimulation by etoposide and amsacrine (7- and 10-fold respectively). Besides, mixing nuclear extracts from both sensitive and resistant cells indicates that either the enzyme in resistant cells is modified or a modulating factor is associated to it. Our results suggest that the resistance of the DC-3F/9-OH-E cell line to topoisomerase II inhibitors might be due to both a reduced amount of the enzyme and its reduced ability to form the cleavable complex in the presence of drugs.     

抗肿瘤青蒿素衍生物的研究

目的:为抗肿瘤青蒿素衍生物的深入研究和开发提供参考.方法:查阅文献,对抗肿瘤青蒿素衍生物的研究新进展进行归纳总结.结果:高活性的抗肿瘤青蒿素衍生物多为C-10位取代物;青蒿素二聚体及三聚体的抗肿瘤活性可能优于单体衍生物.结论:青蒿素衍生物有望在不久的将来应用于肿瘤治疗.     

Renal toxicity of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate in the wistar rat

Celiptium (N2-methyl-9-hydroxy-ellipticinium) is an antitumoral agent used to treat bone metastases from breast carcinomas. This new drug appeared to be of great interest because of the absence of hepato-or myelotoxicity. Three different investigators recently mentioned cases of celiptium-induced renal failure. We therefore undertook a study of renal function and morphology in female Wistar rats. Two single i.v. doses (10 or 20 mg/kg) were administered and animals were sacrificed 4, 8, 15, 28 and 60 days after injection. One group of rats received multiple doses, 5 mg/kg/week for 8 weeks. No mortality was observed. With the 10 mg/kg single dose creatinine clearance (Ccr) and urinary enzymes did not change, and tubular lesions were rare. With the 20 mg/kg single dose CCr decreased on day 4 and returned to normal on day 28. Urinary enzyme excretion (AAP, NAG, GT) increased. Renal lesions were diffuse with tubular necrosis, luminal dilation and later (day 28) interstitial cellular infiltration. These lesions persisted on day 60 and appeared to be irreversible. Ultrastructural studies showed numerous large fat droplets in proximal tubular cells. Glycerol concentrations in renal cortex homogenates were increased while phospholipids are slightly decreased. With 5 mg/kg every week (multiple doses) Ccr decreased and tubular lesions similar to the observed with the 20 mg/kg single dose were seen. Thus celiptium induced dose-dependent nephrotoxicity in rats with prolonged tubular alterations. Since it has been shown that renal tubular cells metabolized celiptium in vitro into electrophilic intermediates, we suggest that free radicals and quinone derivatives may contribute to peroxidation of unsaturated fatty acids and play a role in the nephrotoxicity of the drug.     

Chitosan and its derivatives as vehicles for drug delivery

Abstract

Chitosan and its derivatives as vehicles for drug delivery can achieve the purpose of sustained release and controlled release for drugs, improve the stability of drugs, and reduce adverse drug reactions. So, the bioavailability of drugs can be enhanced. Therefore, chitosan and its derivatives have become a hotspot in the field of drug delivery. Their characteristics as drug delivery vectors were introduced, the types and applications were summarized. The development direction of chitosan and its derivatives in this field was also forecasted.