1-azafagomine: A hydroxyhexahydropyridazine that potently inhibits enzymatic glycoside cleavage
1-azafagomine: A hydroxyhexahydropyridazine that potently inhibits enzymatic glycoside cleavage
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DOI：
10.1002/chem.19970030616
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发表时间：
1997-06-01
影响因子：
4.3
通讯作者：
Thomsen, IB
中科院分区：
文献类型：
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作者：
Bols, M;Hazell, RG;Thomsen, IB
以2，4-双烯醇（22）和4-苯基三唑啉-3，5-二酮（18）为原料，经四步反应合成了（3，4-反式-4，5-反式）-4，5-二羟基-3-羟甲基六氢吡啶嗪（16），总收率32%。在第一步中，18和22之间的Diels-Alder反应以88%的产率得到（+/-）-2-羟甲基-8-苯基-1，6，8-三氮杂双环[4.3.0]壬-3-烯-7，9-二酮（23 c）。用原位生成的三氟甲基（甲基）二环氧乙烷环氧化23 c，得到反式环氧化物24 c，产率为62%。用高氯酸水解环氧化物，立体选择性地得到（2，3-反式-3，4-反式）-3，3-二羟基-3-羟甲基-8-苯基-1，6，8-三氮杂双环[4.3.0]壬烷-7，9-二酮（26），产率73%。在第四步也是最后一步中，肼解26 Save 16，产率为84%。哒嗪16被发现是一种有效的抑制剂，葡萄糖苷酶，异麦芽糖酶和糖原磷酸化酶，而半乳糖苷酶和α-甘露糖苷酶不受抑制。β-葡糖苷酶的抑制与pH无关，并且发现是由于未质子化的16。
(3,4-trans-4,5-trans)-4,5-dihydroxy-3-hydroxymethylhexahydropyrida- zine (16) was synthesized in four steps from 2,4-pentadienol (22) and 4-phenyltriazolin-3,5-dione (18) in an overall yield of 32%. In the first step a Diels-Alder reaction between 18 and 22 gave (+/-)-2-hydroxymethyl-8-phenyl- 1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62 % yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3-trans-3 ,4-trans)-3,3-dihydroxy-3-hydroxymethyl-8-phenyl-1 ,6,8-triazabicyclo[4.3.0]nonane-7,9-dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 Save 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of rand beta-glucosidase, isomaltase and glycogen phosphorylase, while galactosidases and alpha-mannosidase were not inhibited. The inhibition of beta-glucosidase is independent of pH, and was found to be due to unprotonated 16.