Syntheses of pretubulysin derivatives for targeted tumor therapies

粘细菌产生大量具有生物活性的天然产物，如微管蛋白结合线性四肽微管溶素及其生物合成前体微管溶素。将合成具有在tubuvaline氮上的官能化侧链的pretubulysin的新衍生物，从而允许连接例如靶向捕捞、生物成像和肿瘤靶向所需的宽范围的官能团。对于肿瘤靶向递送，pretubulysin将与含有PEG和靶向配体的序列限定的寡氨基酰胺缀合。这些前药将显示三重响应性（pH不稳定键的裂解、内体中载体胺的质子化导致内体溶解性质，以及靶细胞胞质溶胶中二硫化物的裂解，这是前微管溶素的有效胞质递送和胞内释放所必需的。将在人肝细胞癌和乳腺癌异种移植模型中评价体内生物分布（NIR生物成像）和治疗疗效。

Myxobacteria produce a wealth of bioactive natural products such as the tubulin-binding linear tetra peptides tubulysins and their biosynthetic precursors, the pretubulysins. New derivatives of pretubulysin will be synthesized with functionalized side chains on the tubuvaline nitrogen, allowing the connection of a wide range of functionalities required e.g. for target fishing, bioimaging and tumor targeting. For tumor-targeted delivery pretubulysin will be conjugated to sequence-defined oligoaminoamides containing PEG and targeting ligands. These prodrugs will display triple responsiveness (cleavage of pH-labile bonds, protonation of carrier amines in endosomes resulting in endosomolytic property, and cleavage of disulfides in the cytosol of the target cell, necessary for efficient cytosolic delivery and intracellular release of pretubulysin. Biodistribution in vivo (NIR bioimaging) and therapeutic efficacy will be evaluated in human hepatocellular carcinoma and breast cancer xenograft models.