Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid
Synthesis, Chiral High Performance Liquid Chromatographic Resolution and Enantiospecific Activity of a Potent New Geranylgeranyl Transferase Inhibitor, 2-Hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic Acid
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DOI：
10.1021/jm900232u
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发表时间：
2010-05-13
影响因子：
7.3
通讯作者：
Coxon, Fraser P.
中科院分区：
文献类型：
--
作者：
McKenna, Charles E.;Kashemirov, Boris A.;Coxon, Fraser P.
3-（3-吡啶基）-2-羟基-2-膦酰基丙酸（3-PEHPC，1）是2-（3-吡啶基）-1-羟基亚乙基双（膦酸）（利塞膦酸，2）的膦酰基羧酸（PC）类似物，利塞膦酸是一种骨质疏松症药物，通过抑制破骨细胞中的法尼基焦磷酸合酶（FPPS），阻止蛋白质异戊二烯化，从而降低骨吸收。1具有比2低的骨亲和力，并且弱抑制Rab香叶基香叶基转移酶（RGGT），选择性地阻止Rab GTP酶的异戊烯化。本文报道了米诺膦酸的PC类似物2-羟基-3-咪唑并[1，2-a]吡啶-3-基-2-膦酰基丙酸（3-IPEHPC，3）的合成及生物活性研究。Like 1，3选择性抑制J774细胞中Rab 11与Rap 1A的异戊二烯化，并降低细胞活力，但在这些测定中活性高33- 60倍。在通过手性HPLC拆分3（> 98%ee）后，我们发现在分离的ROOT抑制测定中（+）-3-E1比（-）-3-E2有效得多，在抑制J774细胞中Rab异戊二烯化方面类似于比（-）-3-E2有效17倍（LED 3 μ M），并且在细胞活力测定中活性高> 26倍。1的对映异构体在RGGT和异戊烯化抑制试验中表现出4倍或更小的效力差异。
3-(3-Pyridyl)-2-hydroxy-2-phosphonopropanoic acid (3-PEHPC, 1) is a phosphonocarboxylate (PC) analogue of 2-(3-pyridyl)-1-hydroxyethylidenebis(phosphonic acid) (risedronic acid, 2), an osteoporosis drug that decreases bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) in osteoclasts, preventing protein prenylation. 1 has lower bone affinity than 2 and weakly inhibits Rab geranylgeranyl transferase (RGGT), selectively preventing prenylation of Rab GTPases. We report here the synthesis and biological studies of 2-hydroxy-3-imidazo[1,2-a]pyridin-3-yl-2-phosphonopropionic acid (3-IPEHPC, 3), the PC analogue of minodronic acid 4. Like 1,3 selectively inhibited Rab11 vs. Rap 1A prenylation in J774 cells, and decreased cell viability, but was 33-60x more active in these assays. After resolving 3 by chiral H PLC (>98% ee), we found that (+)-3-E1 was much more potent than (-)-3-E2 in an isolated ROOT inhibition assay, similar to 17 x more potent (LED 3 mu M) than (-)-3-E2 in inhibiting Rab prenylation in J774 cells and >26x more active in the cell viability assay. The enantiomers of 1 exhibited a 4-fold or smaller potency difference in the RGGT and prenylation inhibition assays.