Syntheses of pretubulysin derivatives for targeted tumor therapies

粘细菌产生丰富的生物活性天然产物，如微管蛋白结合的线性四肽、微管蛋白及其生物合成前体微管蛋白。将在Tubuvaline氮上合成具有功能化侧链的新的管溶素前衍生物，使其能够连接靶标捕鱼、生物成像和肿瘤靶向等所需的广泛功能。对于肿瘤靶向递送，预管溶素将与含有聚乙二醇靶向配体的序列定义的寡氨酰胺偶联。这些前体药物将表现出三重反应(pH不稳定键的裂解，内体中载体胺的质子化导致内溶性质，以及靶细胞胞浆中二硫化物的裂解，这是有效的胞液输送和细胞内释放管溶前蛋白所必需的)。在人肝细胞癌和乳腺癌异种移植模型中，将评估体内的生物分布(近红外生物成像)和治疗效果。

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.