以糖为手性源的新骨架天然物Dinemasones的合成及抗菌活性研究

After decades of excessive use, bacterial resistance to the available antibiotics has been becoming increasingly serious. Seeking novel antibacterial drugs has become one of the hotspots of antimicrobial research today, especially the discovery of new lead compounds and novel targets. Natural products Dinemasones B and C, with a new multihydroxyl substituted pyrano[4,3-b]pyran- 5(7H)-one structure, showed excellent broad-spectrum antibacterial activity. With the new structure skeleton, these compounds have the potential to be developed as novel antibacterial drugs. However, because of the complex stereochemistry, their syntheses are difficult, and there is no reported study of their structure-activity relationship. Based on the unique structure, substitutions and stereochemistry of Dinemasones B and C, along with our extensive research experiences in carbohydrate chemistry, we intend to synthesize Dinemasones B and C using the common monosaccharide as the chiral source. Their derivatives will also be prepared through multiple points of structural manipulation, chiral modification and derivatization. Through systematic antibacterial activity screening, we expect to establish the antibacterial spectrum of this kind of compounds and obtain valuable structure-activity relationship. Moreover, we expect to discover several lead compounds with good antibacterial activity, and eventually explore their antibacterial mechanism and target. Our work could set the foundation for the further search of new antibacterial agents.

经过多年的发展，随着细菌耐药性的日益严重，通过寻找新的先导结构、发现新的抗菌靶点，进而研究全新的抗菌药物已成为当今抗菌药物研发的热点之一。具有多羟基取代吡喃并吡喃酮结构的天然产物Dinemasones B和C显示出很好的抗菌活性，抗菌谱广、结构母核全新，极具发展为抗菌新先导结构的潜力。但由于此类结构立体化学较复杂，有一定的合成难度，深入的合成及构效关系研究尚未开展。根据Dinemasones B和C结构特点和取代基及立体化学状态，结合申请人糖化学研究经验，拟利用单糖骨架作为手性源完成天然产物Dinemasones B和C的全合成研究，并开展多位点、多手性的结构修饰及衍生化；通过系统的抗菌活性筛选，期望明确此类结构的抗菌谱、总结出有价值的构效关系，发现具有良好抗菌活性的先导化合物；探索抗菌机理和作用靶点，为进一步寻找新型抗菌先导结构及抗菌药物打下基础。

随着细菌耐药性日益严重，寻找新先导结构、发现新抗菌靶点，进而研发全新抗菌药物已成为当今新药研究热点之一。文献报道具有多羟基取代吡喃并吡喃酮结构的天然产物Dinemasones B和C显示出良好的抗菌活性，结构母核全新，极具发展为抗菌新先导结构的潜力。但此类结构立体化学复杂，有较大合成难度，深入的合成及构效关系研究尚未开展。.根据Dinemasones B和C结构和立体化学特点，利用单糖作为手性源，通过18步反应，以31%总收率完成了(‒)-Dinemasone B的全合成，并开展了多位点、多手性的结构修饰及衍生化，得到一系列Dinemasone B衍生物；分别尝试了Dinemasone B差向异构化、以Allose、Galactose和4, 6-脱氧Mannose为起始物等四条合成路线，均未实现(‒)-Dinemasone C的全合成，最终完成了4-deoxy-Dinemasone C的合成及相关衍生物制备。通过系统、较为深入的抗菌活性筛选，Dinemasone B及其异构体对常见致病菌均未表现出预期的抑制活性，初步确定此类结构抗菌效果不明显，难以发展成为广谱的抗菌药物。因此课题中期申请把研究重点调整到抗肿瘤等活性研究方面。.选取A549、MCF-7、HCT-116、Hela四种肿瘤细胞系进行活性测试，其中C-01和C-15表现出了较好的活性，在20μM的浓度下，抑制率可以达到90%以上；进一步的衍生化及活性测试表明，该系列其中两个衍生物抑制白血病和肺癌细胞的IC50值分别达到0.26和0.36μM；在此基础上设计、合成了系列吡喃二乙烯酮衍生物，活性测试表明化合物L1-12对HepG-2、MCF-7和116WT三种细胞株的抑制活性等同甚至优于多柔比星，显示出良好的研究价值。鉴于Dinemasones B和C与岩白菜素的结构相似性，设计合成了岩白菜素硫酸化的衍生物并进行了Selectin结合活性测定。.课题首次以单糖为手性源完成了天然产物(‒)-Dinemasone B和4-deoxy-Dinemasone C的全合成，实现了多取代吡喃并吡喃酮骨架的立体选择性构建，解决了Nazarov环合关键底物的合成问题；明确了该骨架化合物对致病菌无明显抑制效果；发现吡喃二乙烯酮类化合物具有良好的抗肿瘤活性，作为先导物具有成药性研究和机制探索的价值。