Rat hormone sensitive lipase inhibition by cyclipostins and their analogs.
Rat hormone sensitive lipase inhibition by cyclipostins and their analogs.
复制标题
DOI：
10.1016/j.bmc.2015.01.028
复制
发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Dupureur CM
中科院分区：
文献类型：
--
作者：
Vasilieva E;Dutta S;Malla RK;Martin BP;Spilling CD;Dupureur CM
环柱蛋白是双环亲脂性磷酸盐天然产物。我们在这里报道了合成的环柱蛋白P和R的个体非对映体对激素敏感脂肪酶（HSL）具有纳摩尔的ic50。这些化合物的较弱的非对映体的ic50值弱10倍。cyclipostin P的单环磷酸盐类似物几乎与双环天然产物一样有效。两种环柱蛋白的双环膦酸盐类似物的ic50值与较弱的非对映体磷酸盐相似（约400 nM）。cyclopostin P的单环膦酸盐类似物具有类似的效力。一系列单环膦酸盐类似物的疏水尾部从环的内酯侧延伸，是相当差的抑制剂，ic50约为50 μM。最后，乙酰胆碱酯酶（AChE）的天然产物环磷素（cyclophostin）缺乏环磷素的碳氢化合物尾部，对HSL没有活性。这些结果表明了这些化合物的关键SAR，疏水尾部。较小的内酯环对活性并不重要，与环磷素和乙酰胆碱有相似之处。对环波斯特蛋白P反式非对映体的HSL抑制动力学进行了详细的研究。该反应为不可逆反应，KI为40 nM，失活速率常数为0.2 min−1。这些结果与环磷酰胺和乙酰胆碱的观察结果相似。
Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC50s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC50s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC50s similar to those of the weaker diastereomer phosphates (about 400 nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC50s around 50 μM. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a KI of 40 nM and a rate constant for inactivation of 0.2 min−1. These results are similar to those observed for cyclophostin and AChE.
登录
查看更多内容
影响因子：
3.5
作者：
Dutta, Supratik;Malla, Raj K.;Bandyopadhyay, Saibal;Spilling, Christopher D.;Dupureur, Cynthia M.
通讯作者：
Dupureur, Cynthia M.
影响因子：
2.7
作者：
de Jong, JC;Sorensen, LG;Jacobsen, P
通讯作者：
Jacobsen, P
影响因子：
3.5
作者：
Ebdrup, S;Jacobsen, P;Vedso, P
通讯作者：
Vedso, P
DOI：
10.1111/j.1432-1033.1994.tb18878.x
发表时间：
1994-06-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
LOOKENE, A;SKOTTOVA, N;OLIVECRONA, G
通讯作者：
OLIVECRONA, G
影响因子：
--
作者：
Ottosson, J;Hult, K
通讯作者：
Hult, K