新型稠杂环氮杂糖类HIV逆转录酶抑制剂的设计、合成及活性评价

AIDS caused by human immunodeficiency virus (HIV), has caused a serious damage to human health and social development due to its high mortality rate and the quick and wide spread of epidemic. In addition, the HIV virus mutates very easily and can develop resistance to current drug. Therefore, it is urgently necessary to develop novel anti-HIV drugs with high efficiency, low toxicity and effective treating methods. Considering the good anti-HIV activities of azasugars and the thiazinan-4-one pharmacopore with sulfur atom, and based on our preliminary research results, in this project, we plan to synthesize a series of novel fused heterocyclazasugar derivatives targeting to the key enzyme of HIV reverse transcriptase (HIV-RT). The compounds were designed based on the detail SAR analysis of nonnucleoside reverse transcriptase inhibitors (NNRTIs). Such fused heterocyclazasugars have the structural features of the multiple position of hydrogen bonding, hydrophobic interaction, which would result the multimode synergetic interaction and the improvement of the specific recognition and binding affinity between the molecule and enzyme. As a result, the compound would be expected to be of higher HIV-RT inhibitory activity. Furthermore, the compounds will be evaluated for their anti-HIV-RT activity in vitro for discovering efficient and nontoxic anti-HIV drug. The relationship between structure and anti-HIV-RT activity of the compounds will be studied. The research might provide novel anti-HIV lead compounds containing sugar moiety and would have important scientific and practical significance in discovering novel anti-HIV drug. In addition, the project will also enrich glycochemistry and glycobiology, and increase the diversity of carbohydrate-based bioactive compounds.

艾滋病（AIDS）是由人类免疫缺陷病毒（HIV）感染所致，因其死亡率高、传播快、流行面广，以及病毒变异性大、易产生抗药性等，是目前最具威胁的重大疾病之一，亟待研究新的高效、低毒抗HIV药物及治疗方法。本课题以HIV复制周期中的关键酶-HIV逆转录酶（HIV-RT）为靶点，基于氮杂糖及含硫药效团噻嗪烷酮良好的抗病毒活性，结合非核苷类HIV逆转录酶抑制剂（NNRTI）构效关系，在申请者初步研究结果的基础上，拟设计合成新型稠杂环（噻嗪烷酮并多环）氮杂糖衍生物，实现化合物分子与酶之间多位点氢键、疏水与π-π堆积、蝶型构象匹配等多方式协同作用，增强化合物与HIV-RT的识别作用和结合力，提高其逆转录酶抑制活性，发现高活性HIV逆转录酶抑制剂，建立构效关系。为进一步研发新型高效低毒抗HIV药物提供先导化合物和重要理论依据，丰富糖化学与糖生物学的研究内容及化合物多样性。

艾滋病（AIDS）是由人类免疫缺陷病毒（HIV）感染所致，因其死亡率高、传播快、流行面广，以及病毒变异性大、易产生抗药性等，是目前最具威胁的重大疾病之一，亟待研究新的高效、低毒抗HIV药物及治疗方法。本课题以HIV复制周期中的关键酶—HIV逆转录酶（HIV-RT）为靶点，基于氮杂糖及含硫药效团噻嗪（唑）烷酮良好的抗病毒活性，结合非核苷类HIV逆转录酶抑制剂（NNRTI）构效关系，设计、合成新型稠杂环（噻嗪烷酮并多环）氮杂糖衍生物，以发现高活性HIV逆转录酶抑制剂。以天然五、六碳单糖等为起始原料，经官能团保护、取代、脱保护等多步反应，得到含叠氮基的关键糖中间体，利用串联Staudinger/Aza-Wittig/环合反应，合成了系列新型含噻唑（嗪）烷酮或苯并噻嗪烷酮的稠杂二环、三环和四环氮杂糖；并在三环基础上，引入叠氮和炔基，构建双官能化中间体，进而利用分子内“click”反应，合成具类蝶形限制构象的稠杂五环氮杂糖。此外，利用（氮杂）糖醛、氨基酸酯和巯基酸的三组分一锅法反应，得到含噻唑烷酮或苯并噻嗪烷酮基的类核苷衍生物，后者经分子内酰胺关环，合成得到新型含苯并噻嗪烷酮的稠杂四环氮杂糖。微波辐射可以显著提高上述稠杂氮杂糖的合成效率。化合物结构及构型经1H、13C和2D NMR、HR-ESI-MS及X-Ray等波谱分析表征确证。测试了所合成稠杂氮杂糖的抗HIV逆转录酶（HIV-RT）活性。结果表明：所合成新型稠杂氮杂糖大多具有显著的HIV-RT抑制活性，部分三、四、五环稠杂氮杂糖的活性达到IC50 < 1 μM。构效分析表明糖环上羟基构型及保护基对HIV-RT抑制活性有显著的影响；在具类蝶形限制构象的稠杂四、五环氮杂糖中，提高分子整体的疏水性将有利于化合物的的酶抑制活性。其它相关工作，新合成的二芳基噻唑烷酮衍生物具有中等的HIV-RT抑制活性（IC50 最小为 3.53 μM）；含噻唑烷酮基的类核苷衍生物具有一定的免疫增强活性；三唑连接的双硼酸蒽荧光探针可选择性识别Lewis Y（Ley）寡糖，并选择性标记HEP3B细胞。本项目研究为进一步设计合成稠杂氮杂糖类抗病毒药物奠定了基础，丰富了糖化学药物的研究内容及结构多样性。

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