Cyclic peptides has become an attractive modality for drug development due to their excellent binding affinity, target selectivity and low toxicity, however significant activity difference between the synthetic and natural cyclic peptides such as Phakillestatins has puzzled chemists for years. In an effort to explore the bioactive secondary structures, three pairs of cyclic Phakellistatin 6 analogs with special constrained stereo-features were prepared by regioselectively controlled intramolecular photoinduced single electron transfer (SET) reactions in this paper. The spatial configurationally features were systematically investigated by ECD and NMR, together with detailed structural analysis based on theoretical calculations, which showed that conventional turns rather than irregular γ-/β-turn secondary structures played important roles for the antitumor activities. We also presented the in vitro bioactive assay, liposomal leakage assays and electron microscopy analyses, which indicated the prepared cyclopeptide analogs excellent antitumor activities, most showing greater growth inhibitory effects than that of the famous anticancer agent paclitaxel.

环状肽由于其优异的结合亲和力，靶标选择性和低毒性而已成为药物开发的一种有吸引力的方式，然而，合成和天然环状肽（例如Phakillestatins）之间的显着活性差异已困扰着化学家多年。为了探索生物活性的二级结构，本文通过区域选择性控制的分子内光诱导单电子转移（SET）反应制备了三对具有特殊约束立体特征的环状Phakellistatin 6类似物。通过ECD和NMR系统研究了空间构型特征，并根据理论计算进行了详细的结构分析，这表明常规的转弯而不是不规则的γ-/β转弯二级结构在抗肿瘤活性中起着重要作用。我们还介绍了体外生物活性测定，脂质体渗漏测定和电子显微镜分析表明，所制备的环肽类似物具有优异的抗肿瘤活性，大多数显示出比著名的抗癌药紫杉醇更大的生长抑制作用。