抗肿瘤药物DNA小沟区结合剂的研究进展

多靶点是抗肿瘤药物引起不良反应的主要原因之一,开发单一靶点药物是提高药物专属性的一种有效方法.以DNA小沟区为靶点的抗肿瘤药物是近年来研究的热点,它们主要是一些小分子化合物.目前已有多种小沟区结合剂处于基础和临床研究阶段,对近年来DNA小沟区结合剂的研究情况进行简要阐述.     

具有抗肿瘤活性的海洋生物研究进展

海洋环境与陆地环境有着显著的差异,其具有高盐、高压、低温、寡氧的特点,自身含有生物活性物质的海洋生物在极端的环境下经过长年的生长和代谢,积累了大量的抗菌、抗病毒、抗肿瘤活性物质等,其抗肿瘤作用已经成为目前研究的热点之一。海洋抗肿瘤药物主要来源于海洋动物、植物和微生物,通过现代科学方法和技术,从海洋生物中寻找具有抗肿瘤活性的化合物开发出具有抗肿瘤作用的海洋药物具有广阔前景。从而积极研究并深入探讨海洋生物的抗肿瘤活性,对治疗人类重大疾病具有现实意义。     

海洋微生物来源的抗肿瘤活性物质研究新进展

海洋微生物因其具有产生新型生物活性产物的巨大潜力,已受到全世界海洋研究人员的重视;近年来,从海洋微生物中已分离到许多结构新颖的抗肿瘤活性物质.综述来自海洋放线菌、海洋真菌、海洋细菌及海洋蓝细菌中的抗肿瘤活性物质的最新研究文献资料,对其研究进展作了分析,并展望了其发展前景.     

具有抗菌活性的海洋真菌天然产物研究新进展

近年来,病原微生物的耐药性已严重威胁到人类健康,从海洋微生物中寻找对耐药菌敏感的化合物成为研究的热点,其中海洋真菌因其能够产生大量结构新颖、活性显著的代谢产物而受到广泛关注。本文按照海洋真菌的来源进行分类,从海洋动物来源真菌、红树林来源真菌、海藻来源真菌、海水来源真菌等4个方面,综述了2014年来发表的具有抗菌活性的海洋真菌来源的新的天然产物,主要介绍天然产物的化学结构和生物活性,化合物结构式曾有文献报道的未包括在内,为具有抗菌活性的海洋真菌天然产物的进一步研究开发提供了参考。     

氧化阿朴菲生物碱衍生物与DNA的相互作用及抗肿瘤活性研究

目的研究氧化阿朴菲生物碱衍生物4位胺烷基甲酰胺取代的7 H-二苯并[de,g]喹啉-7-酮与小牛胸腺DNA的相互作用以及抗肿瘤活性。方法用紫外吸收光谱、荧光光谱和诱导CD光谱研究衍生物与小牛胸腺DNA的相互作用;用MTT法评价衍生物对NCI-H460,GLC-82和MCF 3种细胞株的细胞毒性。结果光谱研究结果表明,衍生物能与小牛胸腺DNA发生嵌入结合作用;细胞毒性测试表明,衍生物具有中等强度的抗肿瘤活性。结论衍生物的抗肿瘤活性很可能是因为衍生物能与DNA作用而产生的。     

抗肿瘤DNA疫苗的研究近况

DNA疫苗技术在近十年来取得了显著的进步,而它在肿瘤预防和治疗领域的优势,使得抗肿瘤的DNA疫苗成为当前医药界的一个研究热点。文章主要介绍了一些作为DNA疫苗免疫靶点的肿瘤抗原,包括已经鉴定并进入临床试验研究和潜在的.可作为治疗靶点的肿瘤抗原,并着重介绍了如何解决由于肿瘤抗原作为一种自身抗原而导致的抗肿瘤DNA疫苗所面临的免疫原性较弱和抗肿瘤效果不理想这两个主要的问题.包括: 加入分子佐剂.主要是一些细胞因子而有效提高抗肿瘤DNA疫苗的免疫原性;通过使用与肿瘤抗原基因种属不同,但具有一定同源性的基因而打破肿瘤抗原的外周免疫耐受。最后主要从肿瘤疫苗免疫的靶点入手.介绍了能够有效增强DNA疫苗抗肿瘤作用的几种新的策略。     

源于海洋微生物抗肿瘤活性物质的研究

海洋微生物是抗肿瘤活性物质的重要来源。近十几年来,已从不同的海洋微生物中分离鉴定了许多结构新颖的抗肿瘤活性物质,显示出诱人的研究开发前景。文章就目前国内外海洋微生物抗肿瘤活性物质的研究作一综述,并展望其发展前景。     

Santamarin的抗肿瘤活性及对DNA拓扑异构酶的影响

目的研究Santamarin的体内外抗肿瘤活性及对DNA拓扑异构酶(TOPO)活性的影响。方法以7株人肿瘤细胞株为模型,采用改良MTT法检测Santamarin对肿瘤细胞增殖的影响;以小鼠移植性肉瘤S180和小鼠移植性肝癌H22为模型,检测Santamarin对在体肿瘤生长的影响;以pBR322 DNA为底物,采用琼脂糖凝胶电泳检测Santamarin对TOPO介导的pBR322 DNA解旋反应的影响,以及对pBR322 DNA是否具有直接断裂作用。结果Santamarin对7株人肿瘤细胞株的半数抑制浓度(IC50)在0.99~3.61mg·L-1之间;Santamarin30、90和270mg·kg-1剂量对S180生长的抑制率分别为51.44%、63.60%和56.37%;对H22生长的抑制率分别为40.77%、39.47%和46.73%。Santamarin在2g·L-1时完全抑制TOPOI、Ⅱ的活性,但对DNA无直接断裂作用。结论Santamarin具有较为明显的体内外抗肿瘤活性,对DNA TOPO活性的抑制可能是其作用机制之一。     

Mirabijalone-B的抗肿瘤效应及对DNA拓扑异构酶的影响

目的研究化合物Mirabijalone-B(MB)的抗肿瘤活性及对DNA拓扑异构酶(TOPO)活性的影响。方法以5株人肿瘤细胞株为模型,采用改良MTT法检测化合物MB的体外抗肿瘤活性;以质粒pBR322超螺旋DNA为底物,采用凝胶电泳分别检测MB对TOPOⅠ、Ⅱ介导的pBR322DNA解旋反应的影响。结果化合物MB对5株人肿瘤细胞株K562、HL-60、A549、Bel-7402和SGC-7901生长增殖的半数抑制浓度(IC50)分别为8.73、1.26、4.44、1.93和3.55mg.L-1;MB在80和16mg·mL-1浓度时,分别完全抑制TOPOⅠ、Ⅱ介导的pBR322超螺旋DNA的解旋反应;但在无TO-PO存在的条件下,MB对pBR322超螺旋DNA的解旋反应无直接影响。结论化合物MB体外明显抑制人肿瘤细胞的生长增殖,对DNATOPO尤其是TOPOⅡ活性的抑制可能是其抗肿瘤作用的机制之一。     

Design and development of sequence selective lexitropsin DNA minor groove binders

The concept of lexitropsins, or information-reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The chemical, physical, and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility, and charge. For longer ligands, such as are required to target unique sequences in biological systems (14–16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin-DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral, and antiretroviral properties, and in the inhibition of critical cellular enzymes including topoisomerases, is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological response they invoke is also described. © 1995 Wiley-Liss, Inc.     

Tanshinone IIA triggers p53 responses and apoptosis by RNA polymerase II upon DNA minor groove binding

Our previous work has shown that tanshinone IIA (Tan IIA) is a DNA minor groove binder instead of an intercalator as previously thought. In this study, we have further demonstrated that the molecular antitumor pharmacology of Tan IIA is dependent on its groove-binding capability. First, we investigated the structure damage to duplex DNA upon Tan IIA binding using circular dichroism spectra. Subsequently, we performed western blot, flow cytometry analysis, chromatin immunoprecipitation, and quantitative real-time PCR to illustrate the RNAPII degradation, phosphorylation, and distribution along the transcribed gene in H22 cells exposed to Tan IIA. In addition, p53 activation and apoptosis induction in both cultured H22 cells and in mice bearing the ascitic-type H22 were measured following Tan IIA treatment. It was revealed that Tan IIA decreases the level of RNAPII by altering DNA structure. At the low dose range (0.2-4 μM) of Tan IIA exposure, the DNA structure damage results in the inhibition of RNAPII binding to DNA and the initiation of RNAPII phosphorylation, while higher concentrations of Tan IIA (4-20 μM) cause complete phosphorylation and degradation of RNAPII followed by p53 activation and apoptosis. A similar apoptosis induction by RNAPII was observed in animals. Apoptosis of tumor cells from ascitic fluid was not detected until RNAPII levels were downregulated by Tan IIA, which requires 40 mg/kg body weight of Tan IIA. It was concluded that DNA-conformational-damage-dependent RNAPII response upon groove binding is the molecular basis of the antitumor property of Tan IIA, in vivo and in vitro.     

Development of distamycin-related DNA binding anticancer drugs

The relatively low therapeutic index of the clinically used alkylating agents is probably related to the fact that these compounds cause DNA damage in a relatively unspecific manner, mainly involving guanine-cytosine rich stretches of DNA present in virtually all genes, therefore inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. These considerations explain why in the last twenty years there has been an increasing interest in the identification of compounds which can target DNA with a much higher degree of sequence specificity than that of conventional alkylators. Minor groove binders (MGBs) are one of the most widely studied class of alkylating agents characterised by a high level of sequence specificity. The prototype of this class of drugs is distamycin A which is an antiviral compound able to interact, non-covalently, in the minor groove of DNA in A-T rich regions. It is not cytotoxic against tumour cells and thus has been used as a carrier for targeting cytotoxic alkylating moieties in the minor groove of DNA. The benzoyl mustard derivative of distamycin A, tallimustine, was found to be able to alkylate the N₃ of adenine in the minor groove of DNA only in the target hexamer 5’-TTTTGA or 5’-TTTTAA. Tallimustine was investigated in the clinic and was not successful because it causes severe bone marrow toxicity. The screening of other distamycin derivatives, which maintain antitumour activity and exhibit much lower toxicity against human bone marrow cells than tallimustine led to the identification of brostallicin (PNU-166196) which is currently under early clinical investigation. Although MGBs which bind DNA in A-T rich regions have not fulfilled the expectations, it is too early to draw definitive conclusions on this class of compounds. The peculiar bone-marrow toxicity observed in the clinic both with tallimustine or with CC-1065 derivatives is not necessarily a feature of all MGBs, as indicated by recent evidence obtained with brostallicin and other structurally unrelated MGBs (e.g., ET-743).     

The development of pyrrolobenzodiazepines as antitumour agents

Introduction: DNA interacting agents play a major role in cancer chemotherapy, either as single agents, in combination drug regimens, or as components of novel targeted therapies. The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues.

Areas covered: The development of the pyrrolobenzodiazepines (PBDs) from their discovery as natural products in the 1960s, through synthetic PBD monomers, PBD hybrids and conjugates, and PBD dimers is described. The latter molecules are capable of forming sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. In particular, the development of PBD dimer SJG-136 (SG2000), currently in Phase II clinical trials, is presented. Potential future cancer therapeutic applications of PBDs, including their use as components of targeting strategies, are also discussed.

Expert opinion: The culmination of over four decades of study on structure–activity relationships of PBDs has led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. The challenge for the next phase in the development of the PBDs is to harness this activity and potency in a new generation of cancer therapeutics.     

Brostallicin (PNU-166196), a new minor groove DNA binder: preclinical and clinical activity

Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided.     

磺酰胺类抗肿瘤药物研究进展

磺酰胺类药物是药物中重要的一类,有着广泛的生物活性,特别是近年来大量具有抗肿瘤活性的磺酰胺类化合物被报道,其中一些化合物已进入临床试验阶段。尽管这些结构新颖的化合物有一个共同的结构特征,即为芳环或者杂芳环磺酰胺类化合物,但它们的作用机制却表现出多样性,如干扰微管蛋白聚合、阻滞细胞周期正常进行、抑制碳酸酐酶、叶酸依赖性酶、甲硫氨酰氨肽酶和组蛋白去乙酰酶、抑制血管内皮细胞生长因子等。文中根据磺酰胺类化合物的作用靶点,介绍了其在抗肿瘤药物研究中的最新进展。     

DNA minor groove alkylating agents structurally related to distamycin A

Analogues of naturally occurring antitumour agents, such us distamycin A, which bind in the minor groove of DNA, represent a new class of antineoplastic compounds currently under investigation. Distamycin Ahas attracted researchers’ attention not only for its biological activity, but also for its non-intercalative binding to the minor groove of double-stranded B-DNA, where it forms a strong reversible complex preferentially at the nucleotide sequences consisting of 4 - 5 adjacent AT base pairs. Distamycin has also been used as a DNA sequence-selective vehicle for the delivery of alkylating functions to DNA targets, leading to a sharp increase in cytotoxicity, in comparison to that of distamycin alone. In the last few years, several hybrid compounds, in which known antitumour derivatives or simple active moieties of known antitumour agents have been tethered to distamycin frames, have been designed, synthesised and tested. Several efforts have been made to modify the DNA sequence selectivity and stability of distamycin; structural modifications have been based on replacement of pyrrole by other heterocycles and/or benzoheterocycles resulting in a novel class of minor groove binding molecules called lexitropsins. The role of the amidino moiety has also been studied by substitution with various groups, including ionisable, acid or basic and non-ionisable groups. The synthesis of a hybrid derived from combining distamycin A and a naturally occurring alkylating agent structurally related to pyrrolo [2,1-c][1,4] benzodiazepine group, such as anthramycin and DC-81, has been also reported. Several classes of distamycin derivatives that have been reported in the published literature and in recent patent fillings have been described in this review article.     

Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug of a chloromethylbenzindoline DNA minor groove alkylator

Metabolic reduction can be used to activate prodrugs in hypoxic regions of tumours, but reduction by ionising radiation is also theoretically attractive. Previously, we showed that a cobalt(III) complex containing 8-hydroxyquinoline (8-HQ) and cyclen ligands releases 8-HQ efficiently on irradiation in hypoxic solutions [Ahn G-O, Ware DC, Denny WA, Wilson WR. Optimization of the auxiliary ligand shell of cobalt(III)(8-hydroxyquinoline) complexes as model hypoxia-selective radiation-activated prodrugs. Radiat Res 2004;162:315-25]. Here we investigate an analogous Co(III) complex containing the potent DNA minor groove alkylator azachloromethylbenzindoline (azaCBI, 1) to determine whether it releases 1 on radiolytic and/or enzymatic reduction under hypoxia. Monitoring by HPLC, the azaCBI ligand in the Co(III)(cyclen)(azaCBI) complex (2) slowly hydrolysed in aqueous solution, in contrast to the free ligand 1 which readily converted to its reactive cyclopropyl form. Irradiation of 2 (30-50 microM) in hypoxic solutions released 1 with yields of 0.57 micromol/J in formate buffer and 0.13 micromol/J in human plasma. Using bioassay methods, cytotoxic activation by irradiation of 2 at 1 microM in hypoxic plasma was readily detectable at clinically relevant doses (> or = 1 Gy), with a estimated yield of 1 of 0.075 micromol/J. Release of 1 from 2 was also observed in hypoxic HT29 cultures without radiation, with subsequent conversion of 1 to its O-glucuronide. Surprisingly, overexpression of human cytochrome P450 reductase in A549 cells did not increase the rate of metabolic reduction of 2, suggesting that other reductases and/or non-enzymatic reductants are responsible. Thus the cobalt(III) complex 2 is a promising prodrug capable of being activated to release a very potent cytotoxin when reduced by either ionising radiation or cells under hypoxic conditions.     

棘白霉素类抗真菌药的研究进展

棘白霉素类抗真菌药是一类新型抗真菌药，作用于真菌细胞壁，对于念珠菌属以及曲霉菌属均有效，而且安全性较高。目前开发的品种有卡泊芬净、米卡芬净、阿尼芬净，均已通过FDA认证上市。现从作用机制、抗菌活性、药动学、临床评价、药物相互作用和不良反应等几方面对其做一综述。