新型尿苷肽类抗结核抗生素Sansanmycin的结构修饰与构效关系研究

项目名称： 新型尿苷肽类抗结核抗生素Sansanmycin的结构修饰与构效关系研究

项目编号： No.30801448

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 化学工业

项目作者： 解云英

作者单位： 中国医学科学院

项目金额： 18万元

中文摘要： Sansanmycin（SS）是我们发现的一组具有抗多药耐药结核杆菌活性的先导化合物，研究证明其属于新型尿苷肽类磷酸-N-乙酰胞壁酸-五肽转位酶（MraY转位酶）抑制剂，鉴于SS具有抗结核杆菌的活性、作用靶点新颖、与现用抗结核药物异烟肼和利福平无交叉耐药、毒性低的特点，为了提高其抗菌活性，特对其进行深入开发研究。1.根据构效关系，通过半合成方法合成了17个衍生物，得到一个活性比原药SSA高4倍的衍生物；2.通过小组分纯化鉴定，从发酵液复合物中分离到了14个结构特异的SSA类似物，其中5个活性优于SSA，一个活性比SSA提高了8倍；3.为进一步对SS进行深入结构修饰，通过定向生物合成的方法合成了结构中引入卤原子的衍生物。本项目共得到32个新型衍生物，其中多个活性优于原药；构效关系分析表明提高脂溶性有利于提高SS的抗菌活性，N-末端NH2是活性必需基团，酰化使其活性丢失，一定长度的烷基化可提高其活性；并且通过定向生物合成的方法合成了结构中引入卤原子的衍生物，为进一步对SS进行深入的结构修饰奠定了基础。本项目的实施为探索开发与现用药物作用机制不同的新型抗结核药物奠定了基础

中文关键词： 结核杆菌；磷酸-N-乙酰胞壁酸-五肽转位酶（MraY转位酶）；Sansanmycin;尿苷肽；构效关系

英文摘要： Sansanmycin were a group of leading compounds with activity against MRD-TB, which was first discovered by us.They belonged to Uridyl-peptide antibiotics which can inhibit MraY translocase. In addition, Sansanmycin had low toxicity. In view of the foregoing, it deserves further researching and developing. 1.According to the the SAR, 17 derivatives of SSA were semi-synthesized with the SSA as the lead. Among these analogs tested, 1d showed a 4-fold increase in activity against MRD-TB compared to SSA. 2.14 novel SSA analogs were identified from the SS complex. Amonst, five analogs afforded antimycobacterial activity greater than SSA. What's more, one analog show a 8-fold increase in antimycobacterial activity compared to SSA. 3. Halide-containing SSA derivatives were biosynthesized by precursors-directed method to further modify the structure of SSA. In conclusion, 32 novel compounds were obtained and many had antimycobacterial activity greater than that of SSA. Structure activity analysis showed that increase of lipophilicity can lead to an improvement of antimycobacterial activity of this kind of compounds. The protonated ammonium ion of N-terminal might play a key role. The acyl side-chain might be not beneficial for the activity, but some size of alkyl side-chain might be of benefit for the activity. In addition, halogenated Sansanmycin were biosynthesized, which based for further structural modification of SSA. The implement of this project might be conductive to R&D of novel mechinasm antimycobacterial drugs.

英文关键词： Mycobacterium Tuberculosis; Phospho-MurNAc-Pentapeptide Translocase(MraY tranlocase); Sansanmycin; Uridyl-peptide; Structure and activity relationship