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α-氨基双膦酸三唑类化合物可作为 GGDPS 抑制剂。

α-Amino bisphosphonate triazoles serve as GGDPS inhibitors.

机构信息

Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, US.

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, US.

出版信息

Bioorg Med Chem Lett. 2024 Apr 1;102:129659. doi: 10.1016/j.bmcl.2024.129659. Epub 2024 Feb 17.

Abstract

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 in vivo 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.

摘要

通过抑制法尼基二磷酸合酶(GGDPS)来耗尽细胞内法尼基二磷酸的水平是一种通过限制调节细胞内运输的 Rab 蛋白的法尼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)产生了兴趣。我们之前的工作已经探索了一系列异戊烯三唑双膦酸盐基 GGDPS 抑制剂的结构-功能关系,这些修饰对酶、细胞和体内活性都有影响。我们已经合成了一系列新的α-氨基双膦酸盐,以了解修饰α位与可能与其他药物连接的部分的影响。评估这些化合物酶和细胞活性的生物测定表明,α-氨基的掺入使具有 GGDPS 抑制活性的化合物具有不同的活性,这种活性受异戊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了结构-功能关系的复杂性,并将为未来专注于肿瘤特异性药物输送的努力提供信息。

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ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors.
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Unraveling the Prenylation-Cancer Paradox in Multiple Myeloma with Novel Geranylgeranyl Pyrophosphate Synthase (GGPPS) Inhibitors.
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α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.
Bioorg Med Chem. 2018 Jan 15;26(2):376-385. doi: 10.1016/j.bmc.2017.10.023. Epub 2017 Oct 19.
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