Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University, Kowakae, Higashiosaka-shi, Osaka 577-8502, Japan.
Bioorg Med Chem. 2010 Jan 1;18(1):455-9. doi: 10.1016/j.bmc.2009.10.004. Epub 2009 Oct 8.
Biotransformation studies conducted on the furanocoumarins isoimperatorin (1) and imperatorin (3) have revealed that 1 was metabolized by Glomerella cingulata to give the corresponding reduced acid, 6,7-furano-5-prenyloxy hydrocoumaric acid (2), and 3 was transformed by G. cingulata to give the dealkylated metabolite, xanthotoxol (4) in high yields (83% and 81%), respectively. The structures of the new compound 2 have been established on the basis of spectral data. The metabolites 2 and 4 were tested for the beta-secretase (BACE1) inhibitory activity in vitro, and metabolite 2 slightly inhibited the beta-secretase activity with an IC(50) value of 185.6+/-6.8 microM. The metabolite 4 was less potent activity than compounds 1-3. In addition, methyl ester (2Me), methyl ether (2a) and methyl ester and ether (2aMe) of 2 were synthesized, and investigated for the ability to inhibit beta-secretase. Compound 2aMe exhibited the best beta-secretase inhibitory activity at the IC(50) value 16.2+/-1.2 microM and found to be the 2aMe showed competitive mode of inhibition against beta-secretase with K(i) value 11.3+/-2.8 microM.
对呋喃香豆素异补骨脂素（1）和补骨脂素（3）进行的生物转化研究表明，1 被胶孢炭疽菌代谢生成相应的还原酸 6,7-呋喃-5-丙烯酰氧基羟香豆酸（2），3 被胶孢炭疽菌转化为脱烷基代谢物花椒毒素（4），产率分别为 83%和 81%。新化合物 2 的结构是基于光谱数据确定的。对代谢物 2 和 4 进行了体外β-分泌酶（BACE1）抑制活性测试，代谢物 2 对β-分泌酶活性有轻微抑制作用，IC50 值为 185.6+/-6.8 microM。代谢物 4 的活性比化合物 1-3 弱。此外，还合成了 2 的甲酯（2Me）、甲醚（2a）和甲酯和醚（2aMe），并对其抑制β-分泌酶的能力进行了研究。2aMe 表现出最好的β-分泌酶抑制活性，IC50 值为 16.2+/-1.2 microM，发现 2aMe 对β-分泌酶表现出竞争性抑制模式，K(i) 值为 11.3+/-2.8 microM。
