选择性HDAC6抑制剂4-（（2,4-二氧基-3-苯乙基-3,4-二氢喹唑啉-1（2H）-基）-甲基）-N-羟基苯甲酰胺的合成

以靛红酸酐（2）为起始原料,经氮上烷基化、开环、关环以及酯的氨解生成异羟肟酸等多步简单反应合成了目标化合物选择性HDAC6抑制剂4-（（2,4-二氧基-3-苯乙基-3,4-二氢喹唑啉-1（2H）-基）-甲基）-N-羟基苯甲酰胺(1)。产物结构经¹H NMR、 ¹³C NMR 以及MS 确证。新的合成路线具有反应条件温和、后处理简单等优点，总收率83.8%。      

盐酸黄连素的汇聚式合成研究

报道了以1,2-亚甲二氧基苯为起始原料合成盐酸黄连素的汇聚式路线,该路线包括格氏试剂亲核开环、脱保护、环合等5步反应,总收率为33%.该路线反应条件温和、操作简单,且所有中间体及产物都经过~1H NMR、~(13)C NMR、MS鉴定.     

SB-590885的合成工艺研究

SB-590885是一种新型的三芳基咪唑类B-Raf激酶抑制剂,已报道的合成方法收率较低且操作繁琐,不适合工业化生产。本文设计了一条新的合成路线,以4-溴吡啶盐酸盐为起始原料,经偶联、脱保护、加成、氧化、环合、水解等反应得到目标化合物,产物结构经~1H NMR,~(13)C NMR和MS确证,总收率为9.53%,该方法原料便宜易得、反应条件温和、操作简单且总收率较高,是一条适合工业化生产的合成路线。     

异乳糖的合成研究

异乳糖是一种还原性双糖,在细菌的代谢过程中有着非常重要的生物学作用.以D-葡萄糖、D-半乳糖为起始原料,探索了异乳糖的多羟基区域选择性偶联与非选择性偶联两条合成路线,其中非选择性偶联路线经五锅反应,总收率高达44%,中间体及目标产物易于分离纯化,适宜于异乳糖的大量制备.中间体及最终产物的结构均通过NMR,HRMS进行表征.     

改进的锂卤交换法合成N-Boc-6-氨甲基烟醛

含酰胺基团的芳卤化合物锂卤交换制备芳醛化合物往往会失败或收率极低,本文采用改进的锂卤交换法成功地合成了单胺氧化酶抑制剂的关键中间体N-Boc-6-氨甲基烟醛。以5-溴-2-氰基吡啶为原料,通过"一锅法"直接将氰基还原成氨基的同时接上Boc保护基,随后在正丁基锂和异丙基氯化镁的作用下发生金属卤素交换反应,再与DMF反应,最终成功合成目标化合物N-Boc-6-氨甲基烟醛,总收率为70.5%。产物经~1H-NMR、~(13)C-NMR分析确证为目标产物。与文献报道的路线相比,该合成路线大大缩短。     

NMDA受体2A选择性抑制剂NVP-AAM077 的高效合成

本文报道一条以2,3-二氨基甲苯为原料，经过8步反应合成NMDA受体2A选择性抑制剂NVP-AAM077的高效率路线，其总收率为54%。合成中使用的关键反应包括NaIO₄/DMF介导的氧化芳苄溴到芳醛的反应以及亚膦酸酯对亚胺的加成反应等。     

Wallichanol类天然产物ABC环系合成研究

Wallichanol是一类具有独特桥环结构的二萜天然产物.以2-甲基-1,3-环己二酮作为起始原料,通过高立体选择性的Diels-Alder反应和金催化的炔烃碳环化反应构建Wallichanol的ABC三环核心骨架,共七步路线,总收率为42%.该合成工作为Wallichanol类天然产物全合成奠定了研究基础.     

3-甲基-1H-吡咯合成工艺研究

以二乙胺盐酸盐和甘氨酸乙酯盐酸盐为起始原料,经Mannich反应、磺酰胺化反应、吡咯啉成环反应、脱水烯化、脱氢芳构化、水解和脱羧反应合成3-甲基-1H-吡咯,最优反应条件下公斤级七步反应总收率达到24.4%,中间体及产物结构经~1H NMR、~(13)C NMR和MS(ESI)确证。该工艺路线原料经济易得,反应条件温和,操作简便,适合于工业化生产。     

同源模建和分子对接研究HDAC1/HDAC8的选择性

组蛋白去乙酰化酶(HDACs)是近年来治疗肿瘤的重要靶标之一.由于HDACs包含多种亚型,且各亚型的生理功能存在一定的差异,其选择性抑制剂的开发已成为当前的研发热点.我们通过同源模建的HDAC1结构,与已有的HDAC8晶体结构的活性位点进行比较分析,探讨了对两者选择性有重要影响的残基,为基于受体的选择性抑制剂研究提供重要信息.同时选择了52个HDAC抑制剂,分别建立了HDAC1、HDAC8的活性值与对接打分值的线性回归模型.所建的HDAC1和HDAC8的线性构效关系模型的非交叉验证系数R2分别为0.82和0.80,表明具有一定的统计学意义.利用所建模型对已设计合成的化合物进行了预测,预测结果对HDAC1、HDAC8选择性抑制剂的优化改造提供了一定的指导意义.     

美托洛尔的合成工艺研究

本文以价廉易得的对羟基苯乙酸甲酯为原料,通过酚羟基苄基保护、酯键还原、甲基化、脱苄基得到关键中间体对甲氧基乙基苯酚5,再与环氧氯丙烷发生烷基化反应,最后与异丙胺反应开环得到美托洛尔。对于合成路线中的关键步骤进行了工艺优化,分步平均收率高达89.3%,6步反应总收率也高达48%。中间体及目标化合物均通过~1HNMR和~(13)CNMR确证了结构。该方法具有原料易得、合成步骤短、收率高以及易于工业化制备等优点。     

Synthesis of 2-amino-8-oxodecanoic acids (Aodas) present in natural hystone deacetylase inhibitors

[reaction: see text] Differently substituted 2-amino-8-oxodecanoic acids (Aodas), present in naturally occurring inhibitors of hystone deacetylase (HDAC), have been prepared using a convergent approach. The configuration in position 2 was derived from enantiomerically pure allylglycine or glutamic acid, whereas the stereochemistry of the substituent in position 9 derived from lactic acid or glyceraldehyde derivatives. Starting from allylglycine, (S)-Aodas, protected at the nitrogen as Boc or Fmoc, were obtained in four steps in about 30% overall yield. These products have been used to prepare a simplified analogue of a natural cyclic tetrapeptide HDAC inhibitor by SPPS.     

对甲苯磺酸催化合成马来酸二丁酯

以马来酸和正丁醇为原料,采用对甲苯磺酸化催化剂合成马来酸二丁酯。经实验确证了酯化的优化条件,获得９６．６７％的酯化率。     

叔丁基杯[6]芳烃的去叔丁基反应

报道了以对叔丁基杯[6]芳烃为原料,室温时,在三氯化铝催化下选择性脱去叔丁基的工艺.探讨了在合成去叔丁基杯[6]芳烃实验中催化剂用量对反应结果的影响,并对反应机理进行了讨论.结果表明,当n(AlCl3)∶n(p-tert-calix[6]arene)=8~9.5∶1时,分离得到了两种去叔丁基杯[6]芳烃:5-叔丁基-37,38,39,40,41,42-六羟基杯[6]芳烃和37,38,39,40,41,42-六羟基杯[6]芳烃,当n(AlCl3)∶n(p-tert-calix[6]arene)=10.5∶1时,得到37,38,39,40,41,42-六羟基杯[6]芳烃,产率90.8%.     

Synthesis,Biological Evaluation and Molecular Modeling of Cyclic Tetrapeptide Based Inhibitors HDAC

Histone deacetylases(HDACs) are considered to be among the most promising targets for the development of anti-cancer drugs, and HDAC inhibitors(HDACIs) have become a promising class of anti-cancer drugs. To explore whether thioacetyl group as the zinc binding group(ZBG) and a slight change in the hydrophobicity of the recognition domain of HDACIs could alter their activities, we synthesized a series of cyclo[-L-Am7(SAc)-Aib-L-Phe(n-Cl)-D-Pro-] and evaluated their HDAC-inhibitory and antiproliferative activities. The results show that these peptides could inhibit HDAC at 10^-9 mol/L level, and could selectively inhibit the proliferation of three human cancer cell lines with IC₅₀ at 10^-6 mol/L level. Docking study was conducted to examine the mechanisms by which these peptides interact with HDAC2. It appeared that a zinc ion in the active site of HDAC was coordinated by the carbonyl oxygen atom of the ZBG in the inhibitor. Both the ZBG domain of all the peptides and the surface recognition domain of cyclo[-L-Am7(SAc)-Aib-L-Phe(o-Cl)-D-Pro-] and that of cyclo[-L-Am7(SAc)-Aib-L-Phe(m-Cl)-D-Pro-] interacted with HDAC2 via hydrogen bonding. Hydrophobic interaction has been considered to provide favorable contributions to stabilizing the complexes, and the introduction of a chlorine atom at the aromatic ring on the L-Phe position of these peptides affected the interaction between each of these inhibitors and the enzyme, resulting in slight change in the structure of the surface recognition domain of the peptides.     

Structural biasing elements for in-cell histone deacetylase paralog selectivity

We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.     

Preparation of [3H]6-nitroquipazine, a potent and selective 5-hydroxytryptamine uptake inhibitor

The synthesis of 6-nitroquipazine, a very potent and selective 5-hydroxytryptamine (5-HT; serotonin) uptake inhibitor, labeled with tritium is described. High specific activity [3H]6-nitroquipazine could be prepared by the nitration of [3H]quipazine using a mixture of equal volumes of sulfuric acid and nitric acid. The radiochemical yield was approximately 50% based on [3H]quipazine. The radiochemical purity was more than 95% from high performance liquid chromatography(HPLC) and thin layer chromatography(TLC) determinations. [3H]6-Nitroquipazine would be a new suitable radioligand for studying 5-HT transporter complex in brain and platelets.     

The HDAC/HSP90 Inhibitor G570 Attenuated Blue Light-Induced Cell Migration in RPE Cells and Neovascularization in Mice through Decreased VEGF Production

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side effects associated with their use underscore the need to elucidate other mechanisms involved and identify additional molecular targets for the sake of therapy improvement. The previous literature provided us with a solid rationale to preliminarily explore the potential of selective HDAC6 and HSP90 inhibitors to treat wet AMD. Rather than furnishing single-target agents (either HDAC6 or HSP90 inhibitor), this study recruited scaffolds endowed with the ability to concomitantly modulate both targets (HDAC6 and HSP90) for exploration. This plan was anticipated to accomplish the important goal of extracting amplified benefits via dual inhibition (HDAC6/HSP90) in wet AMD. As a result, G570 (indoline-based hydroxamate), a dual selective HDAC6-HSP90 inhibitor exerting its effects at micromolar concentrations, was pinpointed in the present endeavor to attenuate blue light-induced cell migration and retinal neovascularization by inhibiting VEGF production. In addition to the identification of a potential chemical tool (G570), the outcome of this study validates the candidate HDAC6-HSP90 as a compelling target for the development of futuristic therapeutics for wet AMD.     

单萜吡啶生物碱Aucubinine A的合成

Aucubinine A是自aucubin在人类大肠杆菌存在时的代谢产物中分离得到的一种单萜生物碱.本课题组实现了起始于4-氢-5-羟基-3-亚甲基-5H-环戊二烯[2,1-c]吡啶(6)对aucubinine A的首次合成,总产率为30%.硼氢化以及随后的在碱性介质中的氧化将6转化为两个非对映异构的二醇7,然后经苄位选择性氧化生成aucubinine A.     

正十六烷基磺酰氯的合成

正十六烷醇经亚磺酰甩作用转换成1－氯代正十六烷,在相转移催化剂条件下,1－氯代正十六烷和硫脲进行亲核反应,合成正十六烷基异硫脲盐酸盐,并以此为中间体用氯气氧化法制备正十六烷基磺酰氯,纯度大于95％,总收率为67％。     

Selective hetero-trisfunctionalization of the large rim of a biomimetic calix[6]arene using host-guest chemistry as a synthetic tool

A calix[6]arene has been selectively functionalized by three different groups at the large rim. The strategy relies on the hostguest recognition chemistry of a biomimetic metal complex at the small rim (so-called "funnel complex") and the Huisgen cycloaddition. The intramolecular thermal reaction proceeds with a high efficiency, chemio- and regioselectivity, allowing the monofunctionalization of one aromatic unit among three. Thanks to the high yield and selectivity of the reaction, it can be applied successively twice on the same compound, which opens the route for inherently chiral calix[6]arenes. This methodology not only is of wide potential for obtaining and exploiting calix[6]arenes that are dissymmetrized at the large rim, but also stands as an exemplary strategy for the selective appending of a functional group on a host platform.