OSMAC策略在微生物次级代谢产物研究中的应用

目的 对单菌多次级代谢产物(One strain many compounds, OSMAC)策略在微生物次级代谢产物研究中的应用进展进行综述。方法 查阅近年来的相关文献,对微生物次级代谢产物研究中所应用的OSMAC策略进行分类和归纳总结。结果 近年来所应用的OSMAC策略主要包括改变培养基、改变培养条件或培养状态、混合培养、化学表观遗传修饰、添加酶抑制剂或其他物质等。结论 OSMAC策略在激活微生物沉默基因、增加次级代谢产物多样性方面发挥了重要作用,随着现代科学技术的发展,OSMAC策略与新技术结合必然会成为发现新药和先导化合物的一条重要途径。     

有机合成化学扩大了天然产物作为药物先导化合物的可能性

工业和学术界许多项目都是基于天然产物,或者是被设计成类似于天然产物的化合物.人们通过3种方法超越天然产物：一是通过组合化学技术,围绕天然产物骨架构建化合物;二是通过定向多样性合成路线,合成天然产物类似物;三是根据各种可用于既定目标分子合成的途径,创造天然产物新衍生物.     

糖类对先导化合物的化学修饰及其在药学中的应用

概述了国内外有关糖类对先导化合物化学修饰的研究,从单糖,二糖和寡糖,多糖三个层面,分别对糖及其省生物与先导化合物的键合方式,经过结构修饰的先导化合物的生物活性变化作了综述,结果表明,修饰过的先导化合物能有效地降低毒副作用,增强药效,所以,利用糖类对先导化合物进行化学饰是很有前途的研究领域。     

先导化合物结构优化策略(八)——药物转运体及其相关药物设计策略

转运体会对药物在人体中的转移和分布产生极大的影响.一方面可溶性载体转运体可以将药物转运进入组织器官,从而提升药物生物利用度以及改变药物的组织分布;另一方面,细胞上的ATP结合盒转运体会将某些药物排出细胞,从而降低细胞内药物浓度,产生耐药性.本文总结了人体中几种重要的药物转运体的底物特征以及针对药物转运体进行药物设计的策...     

天然产物在新药发现中的地位与机会（Ⅲ）有机合成化学扩大了天然产物作为药物先导化合物的可能性

工业和学术界许多项目都是基于天然产物，或者是被设计成类似于天然产物的化合物。人们通过３种方法超越天然产物：１是通过组合化学技术，围绕天然产物骨架构建化合物；２是通过定向多样性合成路线，合成天然产物类似物；３是根据各种可用于即定目标分子合成的途径，创造天然产物新衍生物。     

糖类对先导化合物的化学修饰及其在药学中的应用

1996年 ,孙昌俊等[1 6] 用相转移催化法 ,使木糖和葡萄糖的衍生物与含呋喃环的化合物反应得到有抗肿瘤活性的糖酯化合物( 1 1 )。此类化合物经 HL- 6 0细胞的体外癌细胞杀伤实验 ,表明部分化合物具有较高的抑瘤活性。(11)果糖糖酯化合物的合成。糖酯类化合物具有广泛的抗菌、抗肿瘤等的生理活性 ,而糖基磷酸酯还有抗病毒的活性。陈茹玉等 [1 7]对果糖与磷酰胺合成糖酯做了研究。磷酰胺是临床上广泛应用的抗癌药物—环磷酰胺的开环类似物 ,在体内具有选择性细胞毒作用。作者以 2 ,3,4 ,5-二 - O-亚异丙基果糖的 1位羟基与三氯氧磷经一系列…     

小单孢菌及其产生的次级生物活性代谢产物

原核微生物小单孢菌产生了740多个生物活性物质，化学结构类型多样，生物活性各异，主要为抗生素和一些人体酶抑制剂。小单孢菌不但能产生链霉菌产生的抗生素化学类型而且还有其独到之处。最受人重视的抗生素是庆大霉素、最主要的特征是产生氨基糖苷类抗生素和大环内酯类抗生素。福建省微生物研究所自20世纪60年代成功研发庆大霉素之后不问断地从我国各地水生环境中分离到多种抗生素、几种酶抑制剂和其他生物活性物质。本文还阐述近年来国外在小单孢菌中发现的一些有实用价值和有前途的微生物新药物，特别是烯二炔类抗肿瘤抗生素。     

内生菌在天然药物研究中的研究进展

内生菌具有丰富的生物多样性,是潜力巨大的微生物新资源。内生菌的研究对于保护野生与濒危药用植物、拓展药用资源、新药研发等均有一定意义。本文对近年来报道的内生菌的活性代谢产物、内生菌与药用植物的相互影响、内生菌对中药材道地性的影响等进行综述,为内生菌的进一步研究提供参考。     

来源于微生物代谢产物的溶栓药物研究进展

血栓性疾病是威胁人类健康的重要疾病,而溶栓酶是治疗血栓性疾病最有效的药物,但其不良反应限制了临床应用。寻找高效低毒的溶栓药物是目前研究的热点问题,来源于微生物代谢产物的溶栓酶是一种重要的溶栓酶,1989-2008年间各国研究人员相继报道了很多能够产生溶栓酶的微生物,主要有β-溶血链球菌、金黄色葡萄球菌、链霉菌、假单胞菌属、杆菌、海洋绿藻类、真菌类等。文中全面介绍了这几类微生物产生的溶栓酶,并着重阐述了其化学结构特点和溶栓机制,说明微生物代谢产物是溶栓药物的重要来源。     

药物代谢产物安全性评价策略

药物代谢产物存在质和／或量的种属差异，现综述药物代谢产物安全性评价的重要性及评价策略和评价项目。当发现代谢产物是人特有或人体主要代谢产物高于给药剂量或全身暴露量（二者中的较低者）的10％，特别是这些物质比毒性试验动物体内水平高时更应关注其安全性，必须及早确证这些代谢产物，并进行一般毒性试验、遗传毒性试验、胚胎一胎仔发育试验和致癌试验等。     

基于OSMAC策略对深海来源真菌Acrostalagmus luteoalbus SCSIO F457化学多样性的初步研究

摘要：目的 采用单菌多次级代谢产物（OSMAC）策略对1株采自南海深海2 801 m沉积环境的白黄笋顶孢霉属真菌Acrostalagmus luteoalbus SCSIO F457进行化学多样性的初步研究。方法 通过在不同培养基、不同pH与不同盐度条件下对菌株进行培养调控并筛选2种适宜发酵条件进行小规模发酵。采用硅胶柱层析、葡聚糖凝胶层析、半制备高效液相等色谱学方法对发酵产物进行化学分离,利用NMR、MS等波谱学技术并结合文献鉴定化合物结构,并对化合物进行初步抗氧化和抗菌活性测试。结果 从菌株SCSIO F457的发酵产物中共新增分离鉴定11个单体化合物,包括paulownin（1）、cyclo(L-Phe-L-Pro)（2）、cyclo(L-Tyr-L-Pro)（3）、cyclo(L-Val-L-Pro)（4）、cyclo(D-Ile-L-Pro)（5）、cyclo(D-Leu-L-Pro)（6）、1-methyoxy-4-(2-hydroxy)ethylbenzene（7）、2-(4-hydroxyphenyl)-ethanol（8）、1-phenylbutane-2,3-diol（9）、3-methoxy-2-methyl-4H-pyran-4-one（10）及3-(hydroxy-acetyl)-1H-indole（11）,化合物7表现出较弱的1,1-二苯基-2-苦基肼（1,1-Diphenyl-2-picryl-hydrazyl, DPPH）自由基清除活性。     

Structure-based design,optimization of lead,synthesis, and biological evaluation of compounds active against Trypanosoma cruzi

Chagas' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease–Trypanosoma cruzi–has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4-amino-5-carbonitrile-pyrimidine analogues were proposed, synthesized ( 5a-f and 7g-h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC₅₀ = 2.79 ± 0.00 μM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain.     

新结构类型抗真菌先导化合物的研究进展

近年来深部真菌感染率不断升高，而目前临床上现有的抗真菌药物均存在较大缺陷，难以满足治疗所需，因此寻找全新结构类型和全新作用机制抗真菌先导化合物对研发新一代抗真菌药物具有重要意义。本文综述了近年来新报道的抗真菌先导化合物，详细讨论了它们的化学结构、抗真菌活性和构效关系，并评述了它们的现有问题和未来发展方向。     

水中四乙基铅氢化原子吸收测定法探究

四乙基铅是一种有毒的物质,国际上对四乙基铅的测定工作也从未停止。对水中四乙基铅氢化原子的吸收测定有着非常重要的意义,它可以为水质检测工作提供具有实际参考价值的理论依据。     

Hearing loss,lead (Pb) exposure,and noise: a sound approach to ototoxicity exploration

To determine the state of the research on ototoxic properties of Pb, evaluate possible synergistic effects with concurrent noise exposure, and identify opportunities to improve future research, we performed a review of the peer-reviewed literature to identify studies examining auditory damage due to Pb over the past 50 years. Thirty-eight studies (14 animal and 24 human) were reviewed. Of these, 24 suggested potential ototoxicity due to Pb exposure, while 14 found no evidence of ototoxicity. More animal studies are needed, especially those investigating Pb exposure levels that are occupationally and environmentally relevant to humans. Further investigations into potential interactions of Pb in the auditory system with other hazards and compounds that elicit ototoxicity are also needed in animal models. To better assess the effects of Pb exposure on the human auditory system and the possibility of a synergism with noise, future epidemiological studies need to carefully consider and address four main areas of uncertainty: (1) hearing examination and quantification of hearing loss, (2) Pb exposure evaluation, (3) noise exposure evaluation, and (4) the personal characteristics of those exposed. Two potentially confounding factors, protective factors and mixtures of ototoxicants, also warrant further exploration.     

Thyroid hormone changes in males exposed to lead in the buenos aires area (argentina)

The relationship between lead levels in blood (PbB) and hormones T3, T4, T4F and TSH were studied in 75 subjects exposed to lead at work. PbB levels in blood were determined by atomic absorption spectrophotometry and hormones by enzymoimmunoassay. Positive and significant correlations among thyroid hormones and TSH vs blood lead level in the ranges 8-50 and 26-50 micro g dl(-1)were found ('r' between 0.304 and 0.621 and 0.431 and 0.619, respectively). At PbB levels between 8 and 26 micro g dl(-1)significant correlation was only found for TSH (r= 0.731). In the range PbB 50-98 micro g dl(-1), 'r' was significant only for T3 (-0.746) and T4 (-0.514). Significant differences were observed in T4 and T4F levels between exposed and non-exposed groups. The results obtained indicate the need for monitoring thyroid hormones and TSH levels in workers exposed to lead.     

High levels of blood lead in griffon vultures (Gyps fulvus) from Cazorla Natural Park (southern Spain)

The blood lead of 23 griffon vultures (Gyps fulvus) trapped in 2003 was analyzed in order to evaluate exposure to lead in the vulture population of Cazorla Natural Park (in southern Spain). In 2001 the use of leaded gasoline in vehicles was banned in the European Union; however, lead ammunition is still used in Spain in big-game hunting for red deer, fallow deer, mouflon, and wild boar, which are ingested by vultures from September to March. The mean concentration of lead in blood was 43.07 +/- 31.96 microg/dL with a range of 17.39-144.80 microg/dL. Only two vultures had lead levels below 20 microg/dL, and two others had blood lead concentrations close to 150 microg/dL. In view of the results, we think the population of vultures from Cazorla Natural Park is suffering subclinical exposure to lead, with some individuals exposed to high toxicity risk. We concluded that ingestion of lead in the metallic form alone is sufficient to produce these blood lead concentrations, and we recommend the prohibition of lead ammunition for big-game hunting in order to preserve the vulture population.     

原子吸收分光光度法测定白花蛇舌草注射液中铅的含量

目的对白花蛇舌草注射液中铅含量进行考察,以便更加有效地控制其内在质量。方法采用微波消解法处理样品,以磷酸二氢铵和硝酸镁作为基体改进剂,用原子吸收分光光度石墨炉法对白花蛇舌草注射液中铅含量进行测定。结果铅在5-40μg.L^-1范围内线性关系良好（r=0.9992）,平均回收率为99.27%（RSD=0.73%）。结论该法简便、准确、专属性较好,可有效地控制白花蛇舌草注射液中铅的含量。     

Differences in the total body clearance of lead compounds in the rat and mouse: Impact on pharmacokinetic screening strategy

1. The in vivo clearance (CL) for 498 compounds representing more than 40 lead optimization programmes were compared in the rat and mouse.

2. A total of 278 of the compounds had similar CL values in rat and mouse and 41 compounds had a high CL in one rodent species and a low CL in the other (median seven-fold difference). For this latter subset, comparative in vitro plasma protein binding, liver microsomal or hepatocyte intrinsic CL provided plausible explanations for the observed in vivo differences in many cases.

3. A considerable proportion of compounds with substantially different CL in rodents, and those with a high CL in both rat and mouse, had a low-to-moderate CL in dog and/or monkey (43%). A larger proportion (71%) had promising pharmacokinetics in higher species when CL was low in both rat and mouse.

4. Drug-discovery scientists should consider the potential for there to be substantial differences in the disposition of leads in different rodent species and design screening cascades to explore this possibility.     

Toxic effects and depuration after the dietary lead(II) exposure on the bioaccumulation and hematological parameters in starry flounder (Platichthys stellatus)

Platichthys stellatus (mean length 20 ± 2 cm, mean weight 160.15 ± 15 g) were exposed to the different levels of dietary lead(II) at the concentrations of 0, 30, 60, 120, 240 mg/kg for 4 weeks. Depuration was conducted for 2 weeks after exposure. The lead exposure over 60 mg Pb/kg induced the significant bioaccumulation in tissues of P. stellatus (5–30 μg/g tissue), except for brain and muscle where the exposure to 240 mg Pb/kg caused the bioaccumulation (2–4 μg/g tissue). The hematological parameters such as red blood cell (RBC) counts, hematocrit (Ht) value and hemoglobin (Hb) concentration were substantially decreased over 60 mg Pb/kg, and lasted even after the depuration period. For plasma components, calcium and magnesium levels in plasma were generally decreased over 60 mg Pb/kg, and glucose level was also mainly increased over 60 mg Pb/kg. Total protein was significantly decreased over 120 mg Pb/kg after 4 weeks exposure. Glucose and total protein showed the restoration after the depuration period in groups of fish exposed previously to over 60 and 120 mg Pb/kg, respectively. However, other parameters that changed during the exposure over 60 mg Pb/kg did not recovered. For enzymatic components in plasma, glutamic oxalate transminase (GOT), glutamic pyruvate transminase (GPT) and alkaline phosphatase (ALP) were significantly increased over 120 mg Pb/kg, and there was only restoration observed after the depuration for ALP over 120 mg Pb/kg.