Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2
Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2
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化学酶法合成抗氧化转录因子Nrf2的新型激活剂(2R,3R,4R)-脱羟甲基环氧喹诺星(DHMEQ)
DOI：
10.1039/c1ob05205e
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
T. Sugai and K Umezawa
中科院分区：
文献类型：
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作者：
Y. Niitsu;M. Hakamata;Y. Goto;T. Higashi;M. Shoji;T. Sugai and K Umezawa
Dehydroxymethylepoxyquinomicin （DHMEQ, 1a）是一种特异性且有效的NF-κB抑制剂，目前正被开发为一种抗炎和抗癌药物。而以前只有（2S,3S,4S）形式是可用的外消旋物通过脂肪酶催化的对映选择性分离，在本研究中建立了一个新的途径，生产(2R,3R,4R)-形式使用化学酶的方法。（1R*,2R*,3R*）-2,3-环氧-5- n-[（2-羟基苯甲酰基）氨基]-4,4-二甲氧基环己基-5-烯-1-醇（2a）在二级羟基和酚羟基上均已己烷化，并被伯克霍尔德菌催化水解。反应以高度对映选择性的方式进行（E bbb500），得到对映纯态的(1S,2S,3S)-2a。酶反应产物经过几个化学步骤转化得到(2R,3R,4R)-DHMEQ (1a)，而立体化学纯度没有任何损失。此外，我们新发现(2R,3R,4R)-DHMEQ激活Nrf2， Nrf2是一种诱导多种抗氧化酶表达的转录因子。它在启动子报告子试验中激活Nrf2。它还增加了目标抗氧化蛋白的表达，并消除了ros诱导的神经细胞系细胞死亡。由此，本研究以脂肪酶为原料制备了(2R,3R,4R)-DHMEQ，有望成为新型抗炎药。
Dehydroxymethylepoxyquinomicin (DHMEQ, 1a) is a specific and potent inhibitor of NF-κB, and it is now being developed as an anti-inflammatory and anticancer agent. While previously only the (2S,3S,4S)-form had been available from the racemate by using lipase-catalyzed enantioselective resolution, in the present study a new route for production of the (2R,3R,4R)-form was established by use of a chemoenzymatic approach. (1R*,2R*,3R*)-2,3-Epoxy-5-N-[(2-hydroxybenzoyl)amino]-4,4-dimethoxycyclohex-5-en-1-ol (2a) was hexanoylated on both secondary and phenolic hydroxy groups, and subjected to Burkholderia cepacialipase-catalyzed hydrolysis. The reaction proceeded in a highly enantioselective manner (E >500) to give (1S,2S,3S)-2a in an enantiomerically pure state. Several chemical steps of transformation from the enzyme reaction product gave (2R,3R,4R)-DHMEQ (1a) without any loss of stereochemical purity. Moreover, we newly found that (2R,3R,4R)-DHMEQ activated Nrf2, which is a transcription factor that induces the expression of multiple antioxidant enzymes. It activated Nrf2 in a promoter reporter assay. It also increased the expression of target antioxidant proteins and cancelled ROS-induced cell death in a neuronal cell line. Thus, (2R,3R,4R)-DHMEQ was efficiently prepared by a newly designed route using lipase, and it may be useful as a new anti-inflammatory agent.