基于9-联烯嘌呤构建环状大小不同的手性碳环核苷

Carbocyclic nucleosides, as analogues of nucleosides, are more stable than nucleosides, which possess a promising application prospect in antiviral and anticancer activities. For the synthesis of carbocyclic nucleosides, the key point is the construction of chiral carbocyclic rings. However, the reports have many disadvantages including long steps, unavalability of chiral starting materials, poor selectivities, and low total yields. Therefore, it is of great importance to built more effective synthetic methods to construct chiral carbocyclic nucleosides. In recent years, the applicant is focus on the design and synthesis of nucleoside analogues and selective modification. With 9-allenyl-9H-purines as starting materials, a series of acyclic nucleoside analogues have been designed and synthesized successfully. And the reactivity and regioselectivity of 9-allenyl-9H-purines have been known and grasped well. In this project, with 9-allenyl-9H-purines as starting material, we will synthesize three-, four-, five-, and six-membered chiral carbocyclic nucleoside analogues via asymmetric [2+1], [2+2], [3+2], [4+2] cycloaddition reactions. To achieve this goal, we will search different catalytic systems to control the reaction sites of double bond in allene group. By further derivation, the corresponding chiral carbocyclic nucleotide analogues will be obtained. And the compound library of carbocyclic nucleoside and nucleotide analogues will also be built. Finally, we will summarize the synthetic methodology and carry out the preliminary biological activities studies.

碳环核苷作为核苷的类似物在结构上比核苷更具稳定性，在抗病毒、抗肿瘤活性等方面具有更广阔的应用前景。手性碳环的构筑是该类化合物合成的关键，但目前的合成方法存在反应步骤多、手性源不易得到、选择性差、总收率低等不足之处。因此，建立更加高效的手性碳环核苷的合成方法是一个非常有意义的研究课题。申请人近年来一直从事核苷类似物的设计合成及选择性结构修饰，并以9-联烯嘌呤为原料设计合成了系列非环核苷类化合物，对9-联烯嘌呤的反应活性及区域选择性有深入的了解。本项目拟以9-联烯嘌呤为原料，通过不对称[2+1]、[2+2]、[3+2]、[4+2]等环加成反应，选择不同催化体系，调控联烯双键的反应位点，构建三元、四元、五元和六元手性碳环核苷化合物，并进一步衍生得到系列手性碳环核苷酸类化合物，进而建立碳环核苷(核酸)类化合物库，总结合成的方法学，并对其药理活性进行初步研究。

本项目以环状大小不同的手性碳环核苷的构筑为研究主线，通过不对称[2+1]、 [3+2]、[3+3]等环加成反应，选择不同催化体系，进行了手性三元、五元和六元碳环核苷和9-烯基吡唑核苷类似物的设计合成研究，设计合成了四个系列共计189个手性核苷类化合物，发展了系列手性三元碳环、五元碳环和六元碳环和9-烯基吡唑核苷类似物的合成方法学，极大地丰富了核苷类化合物库，为新核苷类活性物质的发现提供了良好的物质基础；并且通过筛选部分碳环核苷体外抗肿瘤和抗病毒活性，获得了5个对HBV-DNA有较好抑制效果的碳环核苷，为深入研究生物活性提供了良好的研究基础。.共发表标注本项目编号（21472037）的论文11篇，均为SCI论文，影响因子都大于5.0；在国内外学术会议上交流论文25篇，做会议邀请报告（含口头报告）11次；邀请国内外知名专家讲学41人次；申请国家发明专利7项，获得发明专利授权5项，获河南省首届专利奖一等奖1项。在国家自然科学基金的促进下，科学研究、人才培养及其它工作均取得了很好的成绩，课题负责人郭海明教授入选：百千万人才工程国家级人选，国家有突出贡献中青年专家，享受国务院特殊津贴专家，国家中青年科技创新领军人才，国家“万人计划”领军人才，河南省二级教授，河南省杰出专业技术人才。培养研究生27名，其中2名获得博士学位，14名获得硕士学位，目前有3名在读博士，8名在读硕士。