Synthesis and kinetic evaluation of cyclophostin and cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases.
Synthesis and kinetic evaluation of cyclophostin and cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases.
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DOI：
10.1021/jm301216x
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发表时间：
2012-11-26
影响因子：
7.3
通讯作者：
Cavalier, Jean Francois
中科院分区：
文献类型：
--
作者：
Point, Vanessa;Malla, Raj K.;Diomande, Sadia;Martin, Benjamin P.;Delorme, Vincent;Carriere, Frederic;Canaan, Stephane;Rath, Nigam P.;Spilling, Christopher D.;Cavalier, Jean Francois
合成了一系列可定制的顺式和反式单环烯醇膦酸酯类化合物。研究了它们对属于不同脂肪酶家族的6种代表性脂肪分解酶的抑制作用及其机制。对于哺乳动物的胃和胰腺脂肪酶，测试的任何化合物都没有抑制作用。相反，来自结核分枝杆菌(Rv0183和Lipy)的茄病镰刀菌切削酶和脂肪酶都被完全灭活。最好的抑制剂呈顺式构象(H和OME)，对相同的酶表现出比脂肪酶抑制剂奥利司他更高的抑制活性。我们的结果表明，膦酸环的γ-碳上的化学基团对抑制效率有很大的影响，导致对目标脂肪酶的选择性显著提高。对微生物(真菌和分枝杆菌)脂肪酶的有效和选择性抑制表明，这些7元单环烯醇膦酸酯应该为开发新型和高选择性的抗菌剂提供有用的线索。
New series of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. Best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat towards same enzymes. Our results have revealed that chemical group at the γ-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these 7-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents.
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影响因子：
3.6
作者：
He, AY;Yan, BL;Rath, NP
通讯作者：
Rath, NP
DOI：
10.1016/j.bbalip.2009.05.002
发表时间：
2009-10-01
影响因子：
4.8
作者：
Amara, Sawsan;Lafont, Dominique;De Caro, Alain
通讯作者：
De Caro, Alain
DOI：
10.1016/j.bbapap.2004.06.005
发表时间：
2004-09-01
影响因子：
3.2
作者：
De Caro, J;Sias, B;De Caro, A
通讯作者：
De Caro, A
影响因子：
4.7
作者：
Du, Jing;Wang, Zhao
通讯作者：
Wang, Zhao
影响因子：
3.5
作者：
Carriere, F;Rogalska, E;Verger, R
通讯作者：
Verger, R