Synthesis, Kinetic Characterization and Metabolism of Diastereomeric 2-(1-(4-Phenoxyphenylsulfonyl)ethyl)thiiranes as Potent Gelatinase and MT1-MMP Inhibitors
Synthesis, Kinetic Characterization and Metabolism of Diastereomeric 2-(1-(4-Phenoxyphenylsulfonyl)ethyl)thiiranes as Potent Gelatinase and MT1-MMP Inhibitors
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DOI：
10.1111/j.1747-0285.2009.00898.x
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发表时间：
2009-12-01
影响因子：
3
通讯作者：
Chang, Mayland
中科院分区：
文献类型：
--
作者：
Gooyit, Major;Lee, Mijoon;Chang, Mayland
明胶酶（MMP-2和MMP-9）与许多病理状况有关，包括癌症和心血管疾病。因此，这些酶的小分子抑制剂被高度寻求用作潜在的治疗剂。2-（4-苯氧基苯磺酰基甲基）硫杂环丙烷（SB-3CT）先前已被证明是明胶酶的有效和选择性抑制剂，然而，由于苯氧基环的帕拉和磺酰基的α-位的氧化，它被快速代谢。SB-3CT的α-甲基变体被设想为改善代谢稳定性并作为机制探针。我们在此描述了这些结构变体作为明胶酶的有效抑制剂的合成和评价。发现四种合成立体异构体中的两种（化合物5 b和5d）表现出明胶酶和MMP-14（MT 1-MMP）的缓慢结合抑制，这是这类抑制剂的机制的标志。这些化合物抑制MMP-2、MMP-9和MMP-14的能力可以更有效地靶向癌组织。新合成的抑制剂的代谢表明，在α-位氧化为磺酰基和在末端苯环的对位氧化均被阻止。相反，硫杂环丙烷硫的氧化是这些明胶酶抑制剂观察到的唯一生物转化途径。
Gelatinases (MMP-2 and MMP-9) have been implicated in a number of pathological conditions, including cancer and cardiovascular disease. Hence, small molecule inhibitors of these enzymes are highly sought for use as potential therapeutic agents. 2-(4-Phenoxyphenylsulfonylmethyl)thiirane (SB-3CT) has previously been demonstrated to be a potent and selective inhibitor of gelatinases, however, it is rapidly metabolized because of oxidation at the para position of the phenoxy ring and at the alpha-position to the sulfonyl group. alpha-Methyl variants of SB-3CT were conceived to improve metabolic stability and as mechanistic probes. We describe herein the synthesis and evaluation of these structural variants as potent inhibitors of gelatinases. Two (compounds 5b and 5d) among the four synthetic stereoisomers were found to exhibit slow-binding inhibition of gelatinases and MMP-14 (MT1-MMP), which is a hallmark of the mechanism of this class of inhibitors. The ability of these compounds to inhibit MMP-2, MMP-9, and MMP-14 could target cancer tissues more effectively. Metabolism of the newly synthesized inhibitors showed that both oxidation at the alpha-position to the sulfonyl group and oxidation at the para position of the terminal phenyl ring were prevented. Instead oxidation on the thiirane sulfur is the only biotransformation pathway observed for these gelatinase inhibitors.