高价碘试剂为媒介的新型二氢卟吩光敏剂的选择性合成及其光动力活性研究

There is increasing interest in photodynamic therapy (PDT), as an anti-cancer strategy for the treatment of shallow small localized tumors. Among the different photosensitizers currently available, the several chlorins have received approval for clinic. Various chlorin-based structures have been developed in order to increase the photoefficiency. However, the functionalization of chlorins for developing new structures was limited because of their hard synthesis and inferior stability. As reported, hypervalent iodine-mediated oxidative coupling and nucleophilic substitution reaction was developed for synthesis of directly linked porphyrin dimer and meso-amino or meso-arylsulfanyl-substituted porphyrins. The mechanism for porphyrin to carry out those reactions was widely considered as involving single eletron transfer (SET) oxidation. The porphyrin radical cation, producing via SET oxidation, couples itself to form dimer or reacts with nucleophilic reagents to achieve meso-functionalization. Comprising with porphyrin, chlorin has the similar conjugate and redox properties but with one reduced pyrrole (i.e., pyrroline) ring. Therefore, we infer that similar oxidative coupling and nucleophilic substitution reaction of chlorin can be carried out if the oxidation of pyrroline ring could be avoided. The deduction and feasibility of this project was confirmed by our previous results. We found that the coupling reaction of Zn(II) chlorin can work smoothly with PIFA (yield 70%), and show high region-selectivity at the 20-position near the hydrogenated pyrrole ring. This chlorin dimer exhibits strong longwavelength absorption in the near-IR region, which suggests these compounds could be useful in treating tumors that are deeply seated. In this project, we will develop facile and efficient hypervalent iodine-mediated oxidative coupling and nucleophilic substitution reaction for synthesis of directly linked chlorins and new kinds of substituted chlorins. Based on those methods, some novel chlorin with hydrophilic groups will be preparated. The studies on the photodynamic activities of those novel photosensitizers also will be pushed forward. Our work will establish a further research foundation for finding new efficient photosensitizers.

二氢卟吩类光敏剂在光动力治疗（PDT）癌症上具有肿瘤选择性好、活性高等优点。合成结构新颖的二氢卟吩衍生物是进一步提高光动力学治疗效果、开发新型高效光敏剂的有效途径。据文献报道，金属卟啉在高价碘试剂作用下形成自由基阳离子中间体，再发生区域选择性的偶联或取代反应，能简便高效的合成不同功能化卟啉衍生物。二氢卟吩具有与卟啉相似的共轭特点、氧化还原性质，有望通过此类反应拓展其结构类型。前期研究证实，高价碘试剂与二氢卟吩锌配合物反应能够以70%的收率选择性的合成20-20'直接键连二氢卟吩，其光物理学性质符合理想光敏剂对作用光谱的要求。本项目拟研究二氢卟吩金属络合物在高价碘试剂媒介下的选择性偶联及取代反应，合成各种功能化的新型二氢卟吩衍生物。基于以上合成方法，制备适用于光动力学治疗的新型二氢卟吩衍生物，通过体外癌细胞培养及光敏剂活性测试，结合其光谱性质研究构效关系，为发现新型高效的光敏剂奠定基础。

二氢卟吩类光敏剂在光动力治疗（PDT）癌症上具有肿瘤选择性好，活性高等优点。由于其结构较复杂、稳定性较差或合成较困难等特点，二氢卟吩的结构和功能拓展受到了一定的局限。本项目以高价碘试剂为媒介，合成各种直接键连二氢卟吩、不同功能团取代的二氢卟吩衍生物，实现二氢卟吩光敏剂的结构丰富和高效合成。基于以上合成方法，制备适用于光动力学治疗的新型二氢卟吩衍生物，通过体外癌细胞培养及光敏剂活性测试，研究其构效关系，为发现新型高效的光敏剂奠定基础。.主要的研究结果与论点包括：.1）首次发现了新型的meso-meso直接键联双二氢卟吩的合成方法，该方法均有较好的区域选择性，偶联位点为二氢卟吩的20位。.2）首次发现二氢卟吩的meso胺基衍生化的方法，该方法均有较强的氧化剂依赖性，不同的氧化剂得到的产物不同。.3）通过DFT理论计算，发现二氢卟吩20位和10位的电荷密度不同，这可能是导致反应选择性的原因。.4）二氢卟吩化合物的meso位引入给电子基团能够有效的促使630 nm左右的吸收峰发生红移，并且能够提高荧光量子收率，是具有开发前景的一类光敏剂。.5）在探索新一代光敏剂的研究中，设计了CB2选择性配体与二氢卟啉连接，得到新型的光敏剂分子。设计合成了新型的大麻素受体拮抗剂，并将其连接到二氢卟啉分子上。