Moroy Gautier, Denhez Clément, El Mourabit Haquima, Toribio Alix, Dassonville Alexandra, Decarme Martine, Renault Jean-Hugues, Mirand Catherine, Bellon Georges, Sapi Janos, Alix Alain J P, Hornebeck William, Bourguet Erika
Laboratoire de Spectroscopies et Structures Biomoléculaires (LSSBM), Faculté des Sciences, IFR53 Biomolécules, Université de Reims-Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France.
Bioorg Med Chem. 2007 Jul 15;15(14):4753-66. doi: 10.1016/j.bmc.2007.05.001. Epub 2007 May 6.
Structural analogues of Ilomastat (Galardin), containing unsaturation(s) and chain extension carrying bulky phenyl group or alkyl moieties at P'1 were synthesized and purified by centrifugal partition chromatography. They were analyzed for their inhibitory capacity towards MMP-1, MMP-2, MMP-3, MMP-9 and MMP-14, main endopeptidases involved in tumour progression. Presence of unsaturation(s) decreased the inhibitory potency of compounds but, in turn increased their selectivity for gelatinases. 2b and 2d derivatives with a phenyl group inhibited preferentially MMP-9 with IC50 equal to 45 and 38 nM, respectively, but also display activity against MMP-2 (IC50 equal to 280 and 120 nM, respectively). Molecular docking computations confirmed affinity of these substances for both gelatinases. With aims to obtain a specific gelatinase A (MMP-2) inhibitor, P'1 of Ilomastat was modified to carry one unsaturation coupled to an alkyl chain with pentylidene group. Docking studies indicated that MMP-2, but not MMP-9, could accommodate such substitution; indeed 2a proved to inhibit MMP-2 (IC50=123 nM), while displaying no inhibitory capacity towards MMP-9.
合成了伊洛马司他（加拉迪恩）的结构类似物，其在P'1处含有不饱和键以及带有庞大苯基或烷基部分的链延长结构，并通过离心分配色谱法进行纯化。分析了它们对MMP-1、MMP-2、MMP-3、MMP-9和MMP-14的抑制能力，这些是参与肿瘤进展的主要内肽酶。不饱和键的存在降低了化合物的抑制效力，但反过来增加了它们对明胶酶的选择性。带有苯基的2b和2d衍生物优先抑制MMP-9，IC50分别等于4５和38 nM，但也对MMP-2显示活性（IC50分别等于280和120 nM）。分子对接计算证实了这些物质对两种明胶酶的亲和力。为了获得一种特异性的明胶酶A（MMP-2）抑制剂，对伊洛马司他的P'1进行修饰，使其带有一个与带有亚戊基的烷基链相连的不饱和键。对接研究表明，MMP-2能够容纳这种取代，而MMP-9则不能；事实上，2a被证明可以抑制MMP-2（IC50 = 123 nM），而对MMP-9没有抑制能力。
