链阳性菌素衍生物的半合成及构效关系

目的:介绍链阳性菌素半合成修饰的研究进展。方法:总结链阳性菌素衍生物的半合成及构效关系。结果和结论:原始霉素两主组分的半合成修饰产生了新的水溶性原始霉素衍生物,这些衍生物具有与天然产物相同的所有生物学特性,并能通过静脉给药。新的水溶性复合剂RP5950 0具有治疗由革兰氏阳性菌引起的严重感染所需的特性。     

盐酸克林霉素注射液不良反应观察

盐酸克林霉素（ｈｙｄｒｏｃｈｌｏｒｉｃｃｌｉｎｄａｍｙｃｉｎ）为一种新的半合成水溶性抗菌素。其作用机理是抑制细菌的蛋白质合成,对大多数革兰氏阳性菌和某些厌氧菌有良好的抗菌作用。Ⅱ期临床试验结果表明,盐酸克林霉素注射液的临床总有效率为９３．２％;细菌清...     

台勾霉素及其类似物的作用机制与生物合成研究进展

介绍近年上市用于治疗耐药性艰难梭菌的抗菌药物台勾霉素及其衍生物的开发现状、作用机制及生物合成途径,展望台勾霉素及衍生物的研究前景。台勾霉素具有不同于万古霉素的作用机制,通过阻碍RNA链合成的起始和转录来抑制核酸合成。台勾霉素的生物合成涉及台勾霉素内酯环的形成、2,4-二羟基-3,5-二氯-6-乙基苯甲酸及脱氧甘露糖侧链、以及后修饰等步骤;结合台勾霉素生物合成途径,采用组合生物合成与代谢工程改造,可快速获得高产菌株应用于工业化生产。     

克拉霉素制剂研究应用进展

克拉霉素为半合成大环内酯类抗生素,是红霉素的衍生物,具有稳定性好,杀菌能力强,低pH 条件下易溶解,口服吸收好,不良反应少,患者耐受性高等优点。对多种革兰阳性或革兰阴性,需氧或厌氧菌均具很高的抗菌效果。由于克拉霉素具有水溶性差,味极苦的特性,使其临床应用受到限制,本文对克拉霉素制剂的研究现状进行了综述,以期为克拉霉素制剂的进一步研究提供参考。     

硫酸丁胺卡那霉素的血浓度和胆浓度

硫酸丁胺卡那霉素是一种水溶性的、对其它氨基糖苷类抗生素如托普霉素和艮他霉素耐药的革兰氏阴性菌有效的半合成卡那霉素衍生物。本文用10名男性胆外科病人测定     

注射用链阳性菌素衍生物RP59500的特性及应用前景

链阳性菌素(streptogramin)代表一类特殊的抗生素,这一类抗生素中每个品种均由2个结构上完全无关的分子组成:A组链阳性菌素(macrolactones)和B组链阳性菌素(cydlic hexadepsipeptideS).A组和B组链阳性菌素均能在核糖体水平上抑制蛋白质的合成.它们的联合应用可出现协同作用,对大部分革兰阳性及部分革兰阴性细菌有效;同时可以减少耐药菌株的产生.A、B组链阳性菌素在血中的药代动力学参数十分相似,并可穿透,积聚在巨噬细胞及实验性心内膜炎的赘生物中.天然的链阳性菌素多不溶于水,不能静脉应用,因此在临床上不能用于严重感染.RP59500是水溶性的A、B组链阳性菌素的衍生物,是一种可注射的半合成链阳性菌素.由 quinupristin/dalfopristin以30:70混合而成.     

水溶性五环三萜酸衍生物的制备及研究进展

综述几种常见水溶性五环三萜酸衍生物的研究进展。五环三萜酸类化合物多具有广泛的生物活性,但因水溶性差、生物利用度低使其临床应用受到限制。以五环三萜酸为先导化合物,经结构修饰合成水溶性衍生物,并从中寻找出有生物活性和临床应用价值的化合物是当前天然药物化学研究的热点之一。     

聚乙二醇缀合熊果酸衍生物的合成及体外抗癌活性

目的:合成具有一定水溶性的聚乙二醇(PEG)缀合熊果酸衍生物并考察其体外抗癌活性。方法:以熊果酸(ursolic acid,UA)作为母核,采用PEG、琥珀酸对其C28位进行接合修饰,合成一系列PEG缀合熊果酸衍生物并考察其水溶性和抗癌活性;采用流式细胞术探讨其抗癌机制。结果:所合成系列PEG缀合熊果酸衍生物的水溶性较熊果酸有明显改善,同时具有更显著的体外抗癌活性;化合物8c对5株受试肿瘤细胞的IC50(48 h)均小于10μmol.L-1,将AGS细胞阻滞于G2/M期并具有诱导凋亡作用(凋亡率高于70%)。结论:将熊果酸C28位进行PEG修饰是保持和提高其抗癌活性的有效途径之一。     

利福平在非葡萄球菌和非分枝杆菌感染中的应用

利福平是地中海链霉菌产生的大环内酯族抗生素——利福霉素B的一种具有代表性的半合成衍生物.该族化合物是在1957年首次被分离到的,并于1971年用于治疗肺结核病及根治脑膜炎奈瑟球菌的无症状带菌者.     

喜树碱及其衍生物最新研究进展

喜树碱具有抗肿瘤活性,但毒副作用和水溶性差限制了它的使用,有必要对其进行结构上的修饰。该文总结了近年来喜树碱及其衍生物的合成与活性研究方面的最新进展。     

Semisynthetic bicyclomycin derivatives: preparation and antibacterial evaluation

A number of semisynthetic bicyclomycin derivatives have been prepared by modifications at various sites of the molecule. The preparation, characterization and antimicrobial evaluation of the new compounds is described. In contrast to bicyclomycin itself, the new derivatives 48 and 58 are also active against Proteus species. Otherwise, the antibacterial potency of the bicyclomycin molecule was found to be very sensitive to structural changes.     

Glycopeptide antibiotics and their novel semi-synthetic derivatives

Glycopeptide antibiotics, vancomycin and teicoplanin, inhibit cell wall synthesis in Gram-positive bacteria by interacting with peptidoglycan D-Ala-D-Ala peptide stem termini of the pentapeptide side chains of the peptidoglycan precursors. In glycopeptide-resistant bacteria, multiresistance poses major therapeutic problems. New potent antibacterial agents are needed to combat these resistance problems, resulting in the explosion of novel glycopeptides in recent years. The glycosylation patterns of glycopeptides and the chemical modifications of the glycosyl moieties greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. Considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. This review provides an overview of the chemistry, the antimicrobial activity, the pharmacokinetics and the toxicology of teicoplanin and other glycopeptide antibiotic derivatives.     

Semisynthesis,Cytotoxic Activity,and Oral Availability of New Lipophilic 9-Substituted Camptothecin Derivatives

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Recent progress in the development of tubulin inhibitors as antimitotic antitumor agents

Tubulin protein is a major target of drug molecules, and consequently, tubulin inhibitors have attracted great attention as antimitotic antitumor agents for chemotherapeutic use. Hundreds of synthetic or semisynthetic tubulin inhibitors have been discovered and developed recently that are related to the natural products colchicine, vinblastine, and taxol. Representatives include allothiocolchicinoids, vinorelbine, and taxotere. This review will describe the recent progress being made in the development of novel antimitotic antitumor tubulin inhibitors. The emphasis has been placed on related research in the author's laboratory, including development of colchicine derivatives and other colchicine binding site drugs, such as flavonoids and quinolone derivatives. Syntheses and modifications of novel compounds, biological activity evaluation, and structural activity relationships will be discussed as well. Further research will undoubtedly lead to the discovery of additional tubulin inhibitors that have potential for use as anticancer drugs.     

The antihypertensive and positive inotropic diterpene forskolin: effects of structural modifications on its activity

Four naturally occurring analogues of forskolin were isolated. Forty-nine semisynthetic derivatives were prepared, incorporating structural alterations at the 1-, 6-, 7-, 9-, 11-, and 14/15-positions. Blood pressure lowering properties of 53 compounds were assessed in anesthetized normotensive cats and of 31 compounds in conscious spontaneously hypertensive (SH) rats. The positive inotropic properties of 25 compounds were investigated in an isolated guinea pig atrial preparation. Forskolin was unique among the compounds in its hypotensive activity in cats and in its positive inotropic properties. Although several derivatives displayed oral antihypertensive activity in the SH rats, none was significantly more potent than forskolin. The optimal structural requirements for activity are apparent, since they are found in forskolin itself.     

A review of natural and modified betulinic,ursolic and echinocystic acid derivatives as potential antitumor and anti-HIV agents

The aim of this review is to update current knowledge on the betulinic, ursolic and echinocystic acids and their natural and semisynthetic analogs, focussing on their cytotoxic and anti-HIV activities. Then, the last results of the authors' team on unusual semisynthetic derivatives of these triterpenoids will be presented in order to establish structure/activity relationships.     

Selectivity of pyripyropene derivatives in inhibition toward acyl-CoA:cholesterol acyltransferase 2 isozyme

Selectivity of 96 semisynthetic derivatives prepared from fungal pyripyropene A, originally isolated as a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), toward ACAT1 and ACAT2 isozymes was investigated in the cell-based assay using ACAT1- and ACAT2-expressing CHO cells. Eighteen derivatives including PR-71 (7-O-isocaproyl derivative) showed much more potent ACAT2 inhibition (IC50: 6.0 to 62 nM) than pyripyropene A (IC50: 70 nM). Among them, however, natural pyripyropene A showed the highest selectivity toward ACAT2 with a selectivity index (SI) of >1000, followed by PR-71 (SI, 667).     

Antitumor properties of podophyllotoxin and related compounds

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.     

Influence of silymarin and some flavonoids on lipid peroxidation in human platelets

Sixteen natural phenolics and semisynthetic derivatives thereof, including silymarin, flavonoids, catechines and phenolic acids, together with 6 standard drug substances with anti-inflammatory, antioxidant and peroxide radical scavenging properties have been tested in an in vitro model using human platelets for their inhibitory action against N-ethyl maleimide-induced lipid peroxidation. The malondialdehyde formed during the reaction was estimated by means of the thiobarbituric acid method. In all compounds tested, the inhibitory action was clearly dose-dependent; IC50 values were calculated from the dose-activity curves. The IC50 found ranged from between 1.47 nM and approximately 900 mM.     

New trends in extraction, identification and quantification of artemisinin and its derivatives.

Artemisinin, a sesquiterpene lactone endoperoxide, and a number of its precursors, metabolites and semisynthetic derivatives have shown to possess antimalarial properties. Several methods have been reported for the measurement of artemisinin and its main derivatives in plant material and biological fluids. However, most of them are either not sufficiently sensitive and do not offer reliable results, or are difficult to apply in routine analyses. Therefore, new methods for the determination of these compounds, such as supercritical fluid extraction and chromatography, pressurized solvent extraction, microwave-assisted extraction, high-performance liquid chromatography coupled to mass spectrometry or evaporative light scattering detection, will be presented. Applications to plant material, pharmaceutical formulations and biological fluids will also be reviewed.