Multivalent benzene polyphosphate derivatives are non-Ca(2+)-mobilizing Ins(1,4,5)P(3) receptor antagonists.
Multivalent benzene polyphosphate derivatives are non-Ca(2+)-mobilizing Ins(1,4,5)P(3) receptor antagonists.
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DOI：
10.1166/msr.2012.1016
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发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Potter BV
中科院分区：
文献类型：
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作者：
Mills SJ;Luyten T;Erneux C;Parys JB;Potter BV
肌醇1，4，5-三磷酸[Ins（1，4，5）P3 1]通过Ins（1，4，5）P3受体[InsP 3R]动员细胞内Ca 2+。尽管在合成InsP 3R部分激动剂和拮抗剂的设计方面已经取得了一些进展，但是仍然存在一些有用的小分子竞争性拮抗剂的实例。一个“多价”的方法进行了探索和新的二聚多磷酸化的芳香族衍生物的设计，合成和生物学评价。已建立的弱InsP 3R配体苯1，2，4-三磷酸[Bz（1，2，4）P3 2]通过其5-位以两种不同的方式二聚，首先直接作为联苯衍生物联苯2，2 ′，4，4 ′，5，5 ′-六磷酸，[BiPh（2，2 ′，4，4 ′，5，5 ′）P6 8]和其区域异构体联苯3，3 ′，4，4 ′，5，5 ′-六磷酸[BiPh（3，3 ′，4，4 ′，5，5 ′）P6 11]。其次，在柔性乙烯桥连二聚体（9）及其相应的1，2-二磷酸二聚体（10）中引入连接基序，两者大致类似于非常弱的拮抗剂1，2-双（2-氨基苯氧基）乙烷-N，N，N '，N'-四乙酸（BAPTA 7）。在过表达1型InsP 3R的透化L15成纤维细胞中，BiPh（2，2 ′，4，4 ′，5，5 ′）P6（8）以明显竞争的方式抑制Ins（1，4，5）P3诱导的Ca 2+释放[IC 50 187 nM]，Bz（1，2，4）P3二聚体（9）仅略弱[IC 50 380 nM]。还针对I型Ins（1，4，5）P3 5-磷酸酶评价化合物。所有化合物均对去磷酸化具有抗性，其中BiPh（2，2 ′，4，4 ′，5，5 ′）P6（8）是迄今为止合成的任何联苯衍生物的最有效抑制剂[IC 50 480 nM]，而Bz（1，2，4）P3乙烯二聚体（9）较弱[IC 50 3.55 μM]。BiPh（3，3 ′，4，4 ′，5，5 ′）P6（11）也抑制5-磷酸酶[IC 50 730 nM]，并显示出意想不到的Ca 2+释放活性[EC 50 800 nM]。因此，从拮抗剂（8）的磷酸苯酯基团重新定位（11）中的单个镜像磷酸苯酯基团不会显著改变酶抑制活性，但会引起Ca 2+释放活性的显著转变。这些新试剂证明了多价方法的能力，并且可能有助于研究通过InsP 3R的信号传导的化学生物学，并作为进一步设计的模板。
Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3 1] mobilizes intracellular Ca2+ through the Ins(1,4,5)P3 receptor [InsP3R]. Although some progress has been made in the design of synthetic InsP3R partial agonists and antagonists, there are still few examples of useful small molecule competitive antagonists. A “multivalent” approach is explored and new dimeric polyphosphorylated aromatic derivatives were designed, synthesized and biologically evaluated. The established weak InsP3R ligand benzene 1,2,4-trisphosphate [Bz(1,2,4)P3 2] is dimerized through its 5-position in two different ways, first directly as the biphenyl derivative biphenyl 2,2′,4,4′,5,5′-hexakisphosphate, [BiPh(2,2′,4,4′,5,5′)P6 8] and with its regioisomeric biphenyl 3,3′,4,4′,5,5′-hexakisphosphate [BiPh(3,3′,4,4′,5,5′)P6 11]. Secondly, a linker motif is introduced in a flexible ethylene-bridged dimer (9) with its corresponding 1,2-bisphosphate dimer (10), both loosely analogous to the very weak antagonist 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA 7). In permeabilized L15 fibroblasts overexpressing type 1 InsP3R, BiPh(2,2′,4,4′,5,5′)P6 (8) inhibits Ins(1,4,5)P3-induced Ca2+ release in a apparently competitive fashion [IC50 187 nM] and the Bz(1,2,4)P3 dimer (9) is only slightly weaker [IC50 380 nM]. Compounds were also evaluated against type I Ins(1,4,5)P3 5-phosphatase. All compounds are resistant to dephosphorylation, with BiPh(2,2′,4,4′,5,5′)P6 (8), being the most effective inhibitor of any biphenyl derivative synthesized to date [IC50 480 nM] and the Bz(1,2,4)P3 ethylene dimer (9) weaker [IC50 3.55 μM]. BiPh(3,3′,4,4′,5,5′)P6 (11) also inhibits 5-phosphatase [IC50 730 nM] and exhibits unexpected Ca2+ releasing activity [EC50 800 nM]. Thus, relocation of only a single mirrored phenyl phosphate group in (11) from that of antagonist (8) does not markedly change enzyme inhibitory activity, but elicits a dramatic switch in Ca2+-releasing activity. Such new agents demonstrate the power of the multivalent approach and may be useful to investigate the chemical biology of signaling through InsP3R and as templates for further design.