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α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors.
Bioorganic & Medicinal Chemistry ( IF 3.5 ) Pub Date : 2017-10-19 , DOI: 10.1016/j.bmc.2017.10.023
Robert A Matthiesen 1 , Michelle L Varney 2 , Pauline C Xu 3 , Alex S Rier 1 , David F Wiemer 4 , Sarah A Holstein 2
Affiliation  

Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.



中文翻译:

α-甲基化增强了类异戊二烯三唑二膦酸盐作为香叶基香叶基二磷酸合酶抑制剂的效力。

通过抑制香叶基香叶基二磷酸合酶(GGDPS)来破坏蛋白质香叶基香叶基化代表了一种针对多种恶性肿瘤的新治疗策略,特别是那些以蛋白质过度分泌为特征的恶性肿瘤,例如多发性骨髓瘤。我们的工作表明,一些类异戊二烯三唑二膦酸盐是 GGDPS 的有效且选择性抑制剂。在这里,我们介绍了通过在 α-碳上掺入甲基进行修饰的一系列新的类异戊二烯三唑的合成和生物学评价。这些研究表明,α-甲基取代基的引入增强了这些化合物作为 GGDPS 抑制剂的效力,并且在高香叶基/高香基系列的情况下,消除了烯烃立体化学对抑制活性的影响。甲基的掺入允许制备 POM 前药,与相应的盐相比,其细胞活性增加了 10 倍。这些研究为未来研究这些新型 α-甲基三唑二膦酸盐的抗骨髓瘤活性的临床前研究奠定了基础。

更新日期:2017-10-19
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