第三代大环内酯类抗生素的结构改造及合成方法

酮内酯类抗生素是具有大环内酯结构的红霉素衍生物。大量耐药病原菌的迅速出现使红霉素类半合成抗生素临床应用出现了挑战,也促使了针对耐药菌的第三代酮内酯类药物的研发并取得了丰硕的研究成果,其代表药物为泰利霉素和喹红霉素。本文综述了近年来对酮内酯类抗生素C-6位、C-5位糖环、三环类、C-11,12位及C-12位等处结构修饰方面的新进展,重点介绍了第三代酮内酯半合成抗生素合成的方法研究。     

酮内酯类抗生素的结构修饰研究进展

近年来,发现了一类新的大环内酯类抗生素-酮内酯,它的结构特征为在C-3位酮基取代,C-11和C-12位形成环状碳酸酯,并在环状碳酸酯的氮原子上连接杂环.本文综述了近年来酮内酯类的半合成改造研究进展.     

新一代大环内酯类抗生素——酮内酯类简介

大量耐药病原菌的迅速出现加速了寻找新抗生素的步伐,近年来研制出一种经结构修饰的大环内酯类衍生物,即酮内酯。酮内酯是把14元大环内酯C-3上的红霉糖基替换为羰基而得到的新一类抗生素。现综述大环内酯的获得性耐药机制,进而阐明以大环内酯为基础经结构改造而来的酮内酯类抗生素的构效关系,并介绍其代表性药物泰利霉素和喹红霉素(ABT-773)的临床特性。     

异雷公藤内酯四醇的半合成研究（Ⅰ）

以雷公藤内酯酮为原料,经烯丙位烃基氧化、亲核酰化和还原反应,合成了异雷公藤内酯四醇,其结构经红外光谱、核磁共振光谱、质谱确证。     

三个甾体螺内酯-3-酮肟化合物的合成

目的 合成三个甾体螺内酯-3-酮肟化合物.方法 将在合成Drospirenone时得到的2个含螺内酯的中间体与产物的3位酮基进行成肟的修饰.结果 和结论目标产物经IR、1HNMR、MS确定.     

穿心莲内酯衍生物体外抗肿瘤作用及构效关系研究

目的:研究穿心莲内酯(AD)及其3,19-缩醛(酮)衍生物(3~15)、14-脱氧-11,12-二脱氢穿心莲内酯(ADD)C-15取代(16~28)及其复合8,17环氧化(31~34)等衍生物的体外抗肿瘤活性,用于指导抗肿瘤候选药物的合成。方法:以人食管癌Ec9706、人肺腺癌A549为模型,采用MTT法评价衍生物的活性,并进行初步的构效关系研究。结果:化合物3~15对2株肿瘤细胞的细胞毒活性较AD显著提高,其中化合物6对Ec9706的IC50为4.7μmol.L-1,而AD的IC50为81.7μmol.L-1。ADD的肿瘤细胞毒活性低于AD。不同的C-15取代基导致化合物16~28和31~34活性差异很大。AD的羟基乙酰化产物(35~37)活性比AD高,ADD的羟基乙酰化产物(38,39)活性比ADD低。结论:对AD的C-3,C-14,C-19羟基进行修饰、ADDC-15取代或C-15取代复合C-8,17双键环氧化可获得一系列体外抗肿瘤活性显著提高的衍生物。     

四环素类的化学改造

作者在寻求四环素类新的衍生物时,选择了在酸中稳定而又易得的强力霉素(DOXY)和甲烯土霉素(MTC)为母体,对其C-5、C-6及C-2位进行了一系列的化学结构改造工作。在C-5位上的化学结构改造工作,是将DOXY和MTC与二甲亚砜和醋酐一起进行反应,主要得到它们的具有5-酮基结构的衍生物,这些衍生物都没有生物活性。在C-6位上的化学结构改造工作,是     

酮内酯的抗耐药菌机制及结构修饰的研究进展

细菌对大环内酯耐药的机制主要为靶点的修饰、核蛋白的变异和主动外排作用。酮内酯有两个作用靶点：23S rRNA V区的A2058和Ⅱ区的A752，酮内酯通过与第二靶点A752结合，发挥其抗耐药茵活性。在此基础上对酮内酯进行结构修饰，合成出一系列具有抗耐药茵活性的化合物，本文简要综述了近年来酮内酯在这方面的研究进展。     

大环内酯类抗生素研究的新进展

对大环内酯类抗生素抗菌以外的作用和新大环内酯的品种进行了综述.大环内酯类抗生素对心血管疾病、闭塞性支气管炎、大泡性肺气肿、腹部手术、慢性便秘、免疫炎症等有一定的防治作用,还可利用其对细胞的穿透作用增强其他药物的作用.新大环内酯的品种有酮内酯、酰内酯、氨基甲酸酯和脱水内酯四类.     

大环内酯类抗生素研究的新进展

对大环内酯类抗生素抗菌以外的作用和新大环内酯的品种进行了综述.大环内酯类抗生素对心血管疾病、闭塞性支气管炎、大泡性肺气肿、腹部手术、慢性便秘、免疫炎症等有一定的防治作用,还可利用其对细胞的穿透作用增强其他药物的作用.新大环内酯的品种有酮内酯、酰内酯、氨基甲酸酯和脱水内酯四类.     

C-19393 S2 and H2, new carbapenem antibiotics. I. Taxonomy of the producing strain, fermentation and antibacterial properties

C-19393 S2 and H2 are new carbapenem antibiotics produced by a streptomycete. The producing strain was taxonomically studied and named Streptomyces griseus subsp. cryophilus. Cobaltous compounds were necessary for production of the antibiotics. C-19393 S2 and H2 showed a broad spectrum of antibacterial activities with C-19393 H2 being 8 approximately 120 times more active than C-19393 S2. They also exhibited beta-lactamase-inhibiting activities and acted synergistically with ampicillin and cefotiam against clinical isolates resistant to beta-lactam antibiotics.     

Metabolism of (2S)-pterosin A: identification of the phase I and phase II metabolites in rat urine

The metabolic profile of the potent hypoglycemic agent, (2S)-pterosin A (1), in rat urine via intragastrical oral administration was investigated. In total, 19 metabolites (M1-M19) were identified. Among these, 16 metabolites were characterized by high-performance liquid chromatography solid-phase extraction-tube transfer-NMR, and seven metabolites were further isolated from the treated urine to enable further structural determination. Twelve of these are new compounds. The phase I metabolites of 1 were formed via various oxidations at positions C-3, C-10, C-12, C-13, or C-1 followed by decarboxylation of C-10 or C-14, and lactonization at C-12/C-14 or C-14/C-12. The phase II metabolites were glucuronide conjugates from the parent compound or phase I metabolites. The major metabolites were found to be (2S)-14-O-glucuronylpterosin A (M9), (2S)-2-hydroxymethylpterosin E (M14), and (±)-pterosin B (M19). Quantitative HPLC analysis of metabolites, based on similar UV absorption and use of the regression equation of 1, indicated that ～71% 1 was excreted as metabolites in rat urine.     

A 20S combined with a 22R configuration markedly increases both in vivo and in vitro biological activity of 1α,25-dihydroxy-22-methyl-2-methylene-19-norvitamin D3

Six new analogues of 1α,25-dihydroxy-19-norvitamin D(3) (3a-4b, 5, and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues 5 and 6) generates the compounds that are slightly more potent than 1α,25-(OH)(2)D(3) in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the S configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the respective (20R,22R)-, (20R,22S)-, (20S,22R)-, and (20S,22S)-diols, were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols 21a, 21b, and 22a as well as analogues 3a, 5, and 6 were confirmed by the X-ray crystallography.     

Studies on macrocyclic lactone antibiotics. VIII. Absolute structures of rhizoxin and a related compound

The absolute structure of rhizoxin, a potent antifungal and antitumor antibiotic, was determined by interrelation with compound 2 whose structure was established by X-ray analysis. Since a 18OH group was introduced at C-3 on a hydrolytic cleavage of C-2, C-3 epoxy group with alkaline H2(18)O, the original epoxy oxygen should be retained at C-2. The stereo-chemistry at C-2 and C-3 positions in rhizoxin was, therefore, determined as 2R,3S.     

Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine

The C-9 and C-7 monoesters and C-7, C-9 diesters of heliotridine with (S)-(+) and (R)-(-)-2-hydroxy-2-phenylbutyric acid were prepared, converted into their N-oxides, and compared with the corresponding C-9 monoesters of retronecine in the in vivo P388 lymphocytic leukemia screen. Relative in vitro cytotoxicities of some of the free bases and their corresponding N-oxides were also measured against the A204 rhabdomyosarcoma cell line by using the soft agar colony forming assay. Stereochemistry at C-7 of the necine and at C-2' of the necine acid appears to have a significant effect on the antitumor activity in this system. In the heliotridine series, the configuration of the necic acid has a pronounced effect on the site selectivity (C-7 vs C-9) in esterification with carbodiimidazole. An explanation for this site selectivity is offered.     

Use of the quorum sensing inhibitor furanone C-30 to interfere with biofilm formation by Streptococcus mutans and its luxS mutant strain

Streptococcus mutans is recognised as a major aetiological agent of dental caries. One of its important virulence factors is its ability to form biofilms on tooth surfaces. The aim of this study was to evaluate the effects of the quorum sensing inhibitor furanone C-30 on biofilm formation by S. mutans and its luxS mutant strain. The effects of furanone C-30 on biofilms of both strains formed on 96-well microtitre plates at 37 °C were determined by a colorimetric technique (MTT assay). Different concentrations of furanone C-30 (0.0, 2.0 and 4.0 μg/mL) and different time points of biofilm formation (4, 14 and 24 h) were investigated. The structures and thickness of the biofilms were observed by confocal laser scanning microscopy (CLSM). Quorum sensing-related gene expression (ftf, smu630, brpA, gbpB, gtfB, vicR, comDE and relA) was investigated by real-time polymerase chain reaction (RT-PCR). The results showed that synthetic furanone C-30 can inhibit biofilm formation by S. mutans and its luxS mutant strain, although it does not affect the bacterial growth rate itself. The quantities of biofilm formed by both strains significantly decreased (P<0.05) and the biofilms became thinner and looser as revealed by CLSM with increasing concentrations of furanone C-30. Expression of the genes tested was downregulated in the biofilms by the addition of furanone C-30. These results revealed that synthetic furanone C-30 can effectively inhibit biofilm formation by S. mutans and its luxS mutant strain.     

Chemoenzymatic preparation of silybin beta-glucuronides and their biological evaluation.

Chemoenzymatic glucuronidation of the optically pure silybin A (1) using ovine liver glucuronyl transferase afforded three beta-glucuronides of silybin, substituted at phenolic OH groups at the positions C-20 (2), C-7 (3), and C-5 (4) formed in the yields 27, 62.5, and 2.5%, respectively. Using these standards, it was shown that the main silybin conjugate in humans is its 20-beta-D-glucuronate (2), while the C-7 regioisomer (3) was formed in lower proportion. The rate of conjugation of (natural) silybin diastereomers 10S, 11S and 10R, 11R, and therefore also their metabolism in humans is rather different. The radical scavenging activity of 2 is considerably lower than that of its aglycone (1); however, the activity of 3 is higher than in the silybin. These findings corroborate the hypothesis that, at physiological pH, the exclusive target for one-electron oxidation of the silybin molecule is the o-methoxy-phenolic structure at C-19, C-20. This is first pharmacological study using optically pure silybin.     

Metabolic products of microorganisms. 245. Colabomycins, new antibiotics of the manumycin group from Streptomyces griseoflavus. II. Structure of colabomycin A

The structure of colabomycin A (1) was elucidated by a detailed spectroscopic analysis. Two-dimensional NMR spectroscopy experiments provided assignments of the proton and carbon resonances of the tetraene carboxamide chains occurring in 1. The configurations of eight out of nine double bonds were determined by analysis of their coupling constants. The absolute configurations of C-4 (4S), C-5 (5R) and C-6 (6S) were established from the CD spectra of the parent compound and of 2-(6-oxo-2,4-hexadienoylamino)-5,6-epoxy-1,4-benzoquinone (2), which was obtained from 1 by mild chromic acid oxidation.     

Investigation of the hydrolysis of ginsenosides by high performance liquid chromatography-electrospray ionization mass spectrometry

The hydrolysis of ginsenoside standards and the crude extracts of ginseng has been investigated at different pH values (2.4-11.2) using high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI-MS). The experimental results indicated that the pH value of aqueous solutions is an important factor in changing the composition of ginsenosides. For (20 S)-protopanaxadiol ginsenosides, ginsenosides with a large mass hydrolyzed to form hydrolysates (20 S)-Rg3 and (20 R)-Rg3 at pH 4.3. There were more hydrolyzed products observed at pH 3.3: (20 S)-F2, C-25,26 hydrated ginsenoside "C-Y1" and "C-Y2" (MW=802 Da) accompanied with (20 S)-Rg3, (20 R)-Rg3. At pH 2.4, only (20 R)-Rg3, (20 S)-F2, a small quantity of (20 S)-Rg3 and three C-25,26 hydrated ginsenosides were obtained. For (20 S)-protopanaxatriol Re, no hydrolysates were observed at pH 4.3; it was hydrolyzed at pH 3.3 to form hydrolysates (20 S)-Rg2, (20 R)-Rg2 and hydrated C-25,26 (MW=802 Da) and at pH 2.4 only C-25,26 hydrated ginsenosides "C-Y1" and "C-Y2" (MW=802 Da) were left in the solution. Similar hydrolysis reactions could be also observed for the crude extracts of ginseng. It showed that HPLC/ESI-MS is a fast and convenient method to study the hydrolysis of ginseng.     

A novel carbapenem antibiotic, SM-7338 structure-activity relationships

A series of new carbapenem compounds, which have a pyrrolidin-3'-ylthio group substituted with various aminocarbonyl group at C-5' position as C-2 side chain, have been prepared. The antibacterial activity and the stability to renal dehydropeptidase-I of these compounds were investigated, and the structure-activity relationships were discussed. In this series, SM-7338; (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthi o]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (5a) was the most interesting compound.