加兰他敏重要中间体溴那维定的合成

以6-溴异香草醛和酪胺为原料,经一锅法进行连续的两步还原胺化制得N-甲基-N-(4-羟基苯乙基)-2-溴-5-羟基-4-甲氧基苯甲胺(4),收率85%。以5%聚乙二醇为相转移催化剂,氯仿为溶剂,铁氰化钾为氧化剂,对4进行氧化偶联,合成了加兰他敏的重要中间体溴那维定,收率39%,其结构经1H NMR,IR和MS确证。     

骨靶向抗肿瘤药物中间体N-Boc-N’-3,3-双(二乙氧膦酰基)丙基甘氨酰胺的合成

采用缩合、Michael加成、氢化还原和偶联等多步应合成了骨靶向抗肿瘤药物的关键中间体——N-Boc-N’-3,3-双(二乙氧膦酰基)丙基甘氨酰胺,其结构经1H NMR,13C NMR,IR和MS确证。     

双嘧达莫的合成工艺改进

以乙酰乙酸乙酯为原料,与硫脲缩合成嘧啶环后,经硝化和氧化、硝基还原、与尿素缩合生成2,4,6,8-四羟基嘧啶[5,4-d]并嘧啶,再经氯代、亲核取代等反应合成了抗血栓药双嘧达莫,总收率25.2%,其结构经1H NMR和HR-MS确证。     

Inhibitors for the immuno- and constitutive proteasome: current and future trends in drug development

Proteolytic degradation is an essential cellular process which is primarily carried out by the 20S proteasome core particle (CP), a protease of 720 kDa and 28 individual subunits. As a result of its central functional role, the proteasome represents an attractive drug target that has been extensively investigated during the last decade and validated by the approval of bortezomib by the US Food and Drug Administration (FDA). Currently, several optimized second‐generation proteasome inhibitors are being explored as anticancer drugs in clinical trials, and most of them target both constitutive proteasomes (cCPs) and immunoproteasomes (iCPs). However, selective inhibition of the iCPs, a distinct class of proteasomes predominantly expressed in immune cells, appears to be a promising therapeutic rationale for the treatment of autoimmune disorders. Although a few selective agents have already been identified, the recently determined crystal structure of the iCP will further promote the development and optimization of iCP‐selective compounds.     

Peptide-mediated blood-brain barrier transport of polymersomes

A polymeric nanocarrier: Polymersomes tagged with a dodecamer peptide that recognizes gangliosides GM1 and GT1b are shown to cross the blood-brain barrier, both in an in?vitro model and in?vivo. The combination of polymeric vesicles with a small GM1-binding peptide and GM1/GT1b gangliosides as targeting sites for blood-brain barrier transport is unprecedented.     

Lead-oriented synthesis: a new opportunity for synthetic chemistry

The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.