Pull-Down of Metalloproteins in Their Native States by Using Desthiobiotin-Based Probes

One-third of all proteins are estimated to require metals for structural stability and/or catalytic activity. Desthiobiotin probes containing metal binding groups can be used to capture metalloproteins with exposed active-site metals under mild conditions so as to prevent changes in metallation state. The proof-of-concept was demonstrated with carbonic anhydrase (CA), an open active site, Zn²⁺-containing protein. CA was targeted by using sulfonamide derivatives. Linkers of various lengths and structures were screened to determine the optimal structure for capture of the native protein. The optimized probes could selectively pull down CA from red blood cell lysate and other protein mixtures. Pull-down of differently metallated CAs was also investigated.     

Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes—first-line treatments—turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.     

N-杂环异海松酰基磺酰胺的制备及其抗肿瘤活性

为了寻求以天然资源为原料的抗肿瘤药物,以异海松酸为原料,设计并合成了6个N-[4-(异海松酰胺基)苯基]-杂环磺酰胺类化合物(Ⅴa～Ⅴf),采用FTIR、1HNMR、13CNMR和MS对其结构进行了表征.生物活性测试结果表明,部分化合物对人体宫颈癌细胞(Hela)、乳腺癌细胞(MDA-MB-231)、前列腺癌细胞(PC-3)和肝癌细胞(Hep G-2)具有良好的抑制活性.在浓度为100μmol/L时,N-[4-(异海松酰胺基)苯基]-2-氯-5-吡啶磺酰胺(Ⅴd)和N-[4-(异海松酰胺基)苯基]-3-溴-2-氯吡啶-5-磺酰胺(Ⅴe)对4种人体肿瘤细胞都具有良好的抑制活性,对上述人体肿瘤细胞的增殖抑制率均大于95％和94％;N-[4-(异海松酰胺基)苯基]-3-氯喹啉磺酰胺(Ⅴc)对上述肿瘤细胞的增殖具有较好的抑制活性.化合物Ⅴd和Ⅴe对4种肿瘤细胞的半抑制浓度(IC50)均低于临床上应用较广的抗癌剂5-氟尿嘧啶(5-FU),其抑制活性优于阳性对照,且对人体正常细胞——人脐静脉内皮细胞(HUVEC)的毒性低于对肿瘤细胞的毒性,有一定的临床应用前景.     

格列喹酮合成工艺研究

以4-[(4,4-二甲基-7-甲氧基-1,3-二氧代-异喹啉基)乙基]苯磺酰胺和环己异氰酸酯为原料经一步反应合成目标产物格列喹酮,通过单因素和正交试验分别研究了反应中各个影响因素的较佳反应条件,最终确定了一条合成格列喹酮的较佳工艺路线,反应的总收率平均为85.52%.     

N-芳基-5,7-二甲氧基-1,2,4-三唑并嘧啶磺酰胺的合成

以N-(2-氯苯基)-5-氨基-1，2，4-三唑-3-磺酰胺和N-(2，6-二氯苯基)-5-氨基-1，2，4-三唑-3-磺酰胺为原料，与丙二酰氯(由丙二酸与三氯氧磷反应得到)进行环合，分别制得N-(2-氯苯基)-5，7-二氯-1，2，4-三唑[1，5-a]嘧啶-3-磺酰胺和N-(2，6-二氯苯基)-5，7-二氯-1，2，4-三唑[1，5-a]嘧啶-3-磺酰胺。然后，用甲氧基取代嘧啶环上的氯原子得到78．7％N-(2-氯苯基)-5，7-二甲氧基-1，2，4-三唑[1，5-a]嘧啶-3-磺酰胺和70．8％N-(2，6-二氯苯基)-5，7-二甲氧基-1，2，4-三唑[1，5-a]嘧啶-3-磺酰胺；产品结构经元素分析，IR和^1HNMR谱确定。     

Convenient synthesis of sulfonamides from amines and p‐toluene sulfonyl chloride mediated by crosslinked poly(4‐vinylpyridine)

A general, mild, and convenient method has been developed for the synthesis of various N‐substituted and N, N‐disubstituted sulfonamides, as a class of sulfa drugs, from the corresponding amines and p‐toluene sulfonyl chloride in the presence of readily available crosslinked poly(4‐vinylpyridine) as a catalyst, base or polymeric substrates. The use of polymeric catalyst simplifies routine sulfonylation of amines because it eliminates the traditional purification. The polymer can be removed quantitatively and it can be regenerated and reused for several cycles without losing its activity. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

邻甲酸甲酯苯磺酰胺合成工艺的优化

对邻甲酸甲酯苯磺酰氯进行纯化,以邻甲酸甲酯苯磺酰氯为原料合成邻甲酸甲酯苯磺酰胺,并与以糖精为原料合成邻甲酸甲酯苯磺酰胺的方法对比,找出了合成邻甲酸甲酯苯磺酰胺的最佳合成工艺路线,为进一步合成磺酰脲类除草剂提供了一个经济、合理的中间体合成路线.     

胺交联的磺化聚芳醚砜酮荷电膜的制备及微观结构

采用乙二胺(EDA),己二胺(HDA)和对苯二胺(PPD)为交联剂,与磺化杂萘联苯聚芳醚砜酮(SPPESK)反应生成磺酰胺交联键,制备胺交联的磺化杂萘联苯聚芳醚砜酮荷电膜.通过元素分析确定交联程度.采用示差扫描量热,扫描电镜以及应力-应变测试等方法研究交联膜的微观结构.实验结果表明,交联剂的种类、用量以及SPPESK的初始磺化度显著影响体系的相容性,交联剂用量过高会导致交联膜发生微观相分离,影响交联膜的性能.胺交联法制备荷电膜时交联度不宜过高.     

手性磺酰胺醇催化苯乙酮的不对称还原反应

由天然氨基酸合成了6个手性磺酰胺醇,并对其在NaBH4/BF3.Et2O还原苯乙酮中的不对称催化性能进行了研究。这些磺酰胺醇催化苯乙酮的还原反应获得了很高的化学产率和较低的对映体过量。     

液相安培法检测鳗鱼中的磺胺类药物

本文建立了液相色谱安培检测鳗鱼中常用8种磺胺检测方法,采用甲醇:磷酸盐缓冲液(pH=3)梯度淋洗,反相C18分离.样品采用乙腈提取后,正己烷脱脂,用Oasis MCX、MAX小柱净化后,采用玻碳电极直流安培1.3V检测.线性范围为0.05-100μg/mL,分别做3个浓度的添加回收,方法回收率在52.8～102.0%之间,方法精密度在0.8～4.6%之间,方法定量限为0.5-4μg/kg.