Tobramycin与16S rRNA A位点复合物的分子动力学模拟

采用分子动力学方法(Molecular dynamics, MD)对托普霉素(Tobramycin)与16S rRNA的A位点复合物的特异性识别机制进行了理论模拟研究, 模拟时间为3.6 ns. 结果表明, A位点中波动最大的部位是两个环外碱基A1492和A1493; tobramycin的环Ⅰ和环Ⅱ是其最保守的结构单元, 可能参与了Tobramycin与16S rRNA的A位点之间的特异性识别. 另外, 发现一个残存时间为3.6 ns的“结构化”水分子, 它桥接了Tobramycin环Ⅱ的N3与环Ⅰ的N6'之间的氢键, 稳定了Tobramycin的结构; Tobramycin周围水合密度较高的位点出现在环Ⅰ和环Ⅱ附近, 这也正是晶体结构中形成较多水媒介氢键及动力学模拟中结构化水分子出现的位置. 动力学模拟证实Tobramycin与16S rRNA间的结合是大量氢键及水分子相互作用的结果, 这有助于设计和开发以Tobramycin为基础, 具有高亲和力及特异性的16S rRNA抑制剂.     

人T细胞中核酸结合亲环素(hCyP33)与 poly(A)+RNA(mRNA)特异性结合

人亲环素33(human cyclophilin 33, hCyP 33)是1996年发现的一个蛋白质. 它由1个N-端的RNA结合团块、1个C-端的亲环素团块和两者之间的连接部分组成. RNA结合蛋白(RNA-binding protein, RBP)是参与真核生物RNA转录后剪接(splicing)、修饰(modification)和输送(transport)等功能的一类蛋白质. 亲环素具有肽脯氨酰顺反异构酶活性, 在蛋白质折叠、输送和相互作用过程中起着关键作用. 器官移植时使用的免疫抑制剂环胞菌素A (cyclosporin A, CsA)能与亲环素类蛋白质结合, 并抑制它们的酶活性. 但是同时具有这两种不同功能的亲环素33在细胞生理过程中到底起了什么作用, 至今尚不清楚. 用离子交换色谱法和亲和吸附的方法研究了人亲环素33与各种细胞RNA的结合特异性, 证实了人亲环素33只同具有poly(A)尾序列结构的mRNA, 即poly(A)⁺ RNA发生特异性结合.     

活性维生素D3类似物的合成及构效关系研究

1α,25-二羟基维生素D₃(1α,25-(OH)₂-D₃,125D)是维生素D中最具生理活性的代谢产物,但因高钙血症副反应而限制其临床应用。从对构效关系的研究出发,迄今已合成三千多种类似物。本文综述了近年来对某些A环修饰(C2位修饰、C3位修饰、芳香A环类似物、A环开环类似物)、侧链修饰、CD环修饰、seco-B环修饰和非开环甾体的活性维生素 D₃ 类似物的设计、合成以及构效关系的研究,旨在为新型较佳活性维生素D₃类似物的合成及临床开发提供参考。     

18β-甘草次酸A环开环衍生物的合成及抗肿瘤活性

采用化学方法在18β-甘草次酸A环上进行结构修饰,合成了一系列新颖的A环具有不同官能团的开环衍生物.初步研究了它们对人体肝癌细胞HepG-2的体外细胞毒活性,结果表明,羟基的数目和位置对抑制HepG-2细胞增殖起着重要的作用.     

Nannocystin A的全合成

正Angew.Chem.Int.Ed.2016,55,13263~13266Nannocystin A是由赛诺菲制药公司及诺华生物医药研究所同时从myxobacterial genus,Nannocystis sp.中分离得到的大环脂肽,该分子作用于翻译延长因子-1α(EF-1α),针对EF-1α的候选药物Plitidepsin处于临床三期,nannocys-     

桥环化合物环数的计算方法

总结了 7种计算桥环化合物环数的方法。重点介绍了由A .Srikrishna提出的一种简便方法 ,并将此法应用于有机杂环化合物环数的确定 ,得到了满意结果     

色胺酮衍生物设计、合成及抗肿瘤活性构效关系研究

首先合成吲哚醌衍生4a~4f,氧化水解得到邻氨基苯甲酸衍生物5a~5d.以这两者为原料设计合成A和/或D环取代的色胺酮衍生物1a~1q.然后,以色胺酮6位酮羰基分别与水合肼、盐酸羟胺反应生成C环席夫碱结构.最后,以哌嗪结构取代B环嘧啶酮合成茚(1,2-b)喹喔啉-11-酮.共设计合成20个化合物,其中新化合物13个.对所合成化合物的结构经红外光谱、核磁氢谱、元素分析确证.测定所合成化合物对肿瘤细胞A549的体外抑制活性.结果表明化合物1b,1c,1i,1j,1p和1q表现出较强的肿瘤细胞抑制活性,IC50值分别为3.58,0.99,1.03,2.10,0.51和0.43μmol·L-1.构效关系研究表明:D环卤素取代提高抗肿瘤活性,而取代基团在A环时则减弱抗肿瘤活性;B环(嘧啶环)被哌嗪环取代后抗肿瘤活性消失(IC50100μmol·L-1);而C环酮羰基生成席夫碱结构抗肿瘤活性与色胺酮相当.     

齐墩果酸A环与C环内酯衍生物的设计合成

齐墩果酸是一个五环三萜类天然产物,具有多种生物活性和药理活性.以齐墩果酸为起始原料,采用间氯过氧苯甲酸以及过氧化脲等试剂进行其A环和C环内酯化修饰,以较高收率获得了系列齐墩果酸A/C环内酯化衍生物.所有产物均经~1H NMR、~(13)C NMR和高分辨质谱数据分析进行了结构确定,其中有12个化合物为新化合物.     

亮点介绍

复杂活性天然产物(±)-Pentalenolactone A Methyl Ester的首次全合成Angew.Chem.Int.Ed.2012,51,12072～12076 Pentalenolactone类天然产物是由原核有机物经过体内代谢而产生的一类倍半萜类化合物,包括Pentalenolacto-nes A,B,D,E,F,G H,O和P等.其结构特点是具有包含六元内酯环的稠合的[5,5,6]三环体系结构,而六元内酯环采用顺式构型,而且每个环系都具有不同的氧化态.Pentalenolactone类天然产物具有非常广谱的生物活性.例如Pentalenolactone具有广谱的抗生素活性,对革兰氏阳性菌和革兰氏阴性菌以及真菌等均有效.同时,它还具有非常强的抗肿瘤和抗病毒活性.最近,北京大学深圳研究生院杨震、李闯创等通过Co参与的Pauson-Khand反应、TMS     

兴国乌头碱及其氢溴酸盐的结构

研究了兴国乌头碱(C21H29NO3)及其氢溴酸盐的晶体.结构均采用全矩阵最小二乘法精修.运用反常散射法测定氢溴酸盐绝对构型,从而确定了兴国乌头碱的绝对构型.在两个结构中,A环与E环都成稳定的椅式构象,B环与C环则呈船型,分子间均存在较强的氢键,形成稳定的晶体.结构中有十个不对称碳原子.     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Synthesis of novel chiral bidentate hydroxyalkyl-N-heterocyclic carbene ligands and their application in palladium-catalyzed Mizoroki–Heck couplings and asymmetric addition of diethylzinc to benzaldehyde

A small library of new chiral bidentate hydroxyalkyl-imidazolium salts 1 is conveniently synthesized on multi-gram scale from inexpensive and commercially available chiral pool amino acids. The corresponding carbenes, generated by deprotonation of imidazolium salts 1, in combination with palladium(II) chloride were tested in the Mizoroki–Heck coupling reaction. The most significant results in terms of yields and reactivities were achieved with low catalyst loading. The catalytic activities of these imidazolium salts were also investigated in the asymmetric addition of diethylzinc to benzaldehyde. The use of MgO nanoparticles as an additive in conjunction with these ligands played a crucial role in increasing the efficiency of these reactions.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.     

Facile synthesis of bicyclic 1-arylpyrazol-5-ones

In this Letter, we described a facile method for constructing fused bicyclic 1-arylpyrazol-5-one ring system. We employed various methylene-containing carboxylic acids as the substrates and proved that the pyrazolone ring closure requires activated methylene group in intermediate II. Accordingly, a series of structurally diversified, fused bicyclic 1-arylpyrazol-5-ones was prepared in moderate to high yields using the requisite substrates.