Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and activities. We have synthesized a new series of α-amino bisphosphonates to understand the impact of modifying the alpha position with a moiety that is potentially linkable to other agents. Bioassays evaluating the enzymatic and cellular activities of these compounds demonstrate that incorporation of the α-amino group affords compounds with GGDPS inhibitory activity which is modulated by isoprenoid tail chain length and olefin stereochemistry. These studies provide further insight into the complexity of the structure-function relationship and will enable future efforts focused on tumor-specific drug delivery.

中文翻译：

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α-氨基二膦酸三唑作为 GGDPS 抑制剂

通过抑制香叶基香叶基二磷酸合酶 (GGDPS) 来消除细胞水平的香叶基香叶基二磷酸，是通过限制调节细胞内运输的 Rab 蛋白的香叶基香叶基化来破坏蛋白质运输的潜在策略。因此，人们对开发 GGDPS 抑制剂用于治疗以异常蛋白质产生为特征的恶性肿瘤（包括多发性骨髓瘤）感兴趣。我们之前的工作探索了一系列基于异戊二烯三唑双膦酸酯的 GGDPS 抑制剂的结构-功能关系，其修饰对酶、细胞和活性有影响。我们合成了一系列新的 α-氨基二膦酸盐，以了解用可能与其他药物连接的部分修饰 α 位置的影响。评估这些化合物的酶活性和细胞活性的生物测定表明，α-氨基的掺入提供了具有 GGDPS 抑制活性的化合物，该活性受类异戊二烯尾链长度和烯烃立体化学的调节。这些研究进一步深入了解结构与功能关系的复杂性，并将使未来的工作重点关注肿瘤特异性药物输送。