Cathepsin X is a cysteine carboxypeptidase that is involved in various physiological and pathological processes. In particular, highly elevated expression and activity of cathepsin X has been observed in cancers and neurodegenerative diseases. Previously, we identified compound Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) as a potent and specific reversible cathepsin X inhibitor. Here, we have explored the effects of chemical variations to Z9 of either benzodioxine or triazol moieties, and the importance of the central ketomethylenethio linker. The ketomethylenethio linker was crucial for cathepsin X inhibition, whereas changes of the triazole heterocycle did not alter the inhibitory potencies to a greater extent. Replacement of benzodioxine moiety with substituted benzenes reduced cathepsin X inhibition. Overall, several synthesized compounds showed similar or improved inhibitory potencies against cathepsin X compared to Z9, with IC₅₀ values of 7.1 μM–13.6 μM. Additionally, 25 inhibited prostate cancer cell migration by 21%, which is under the control of cathepsin X.

组织蛋白酶X是一种半胱氨酸羧肽酶，参与各种生理和病理过程。特别地，已经在癌症和神经退行性疾病中观察到组织蛋白酶X的高度表达和活性。以前，我们确定了化合物Z9（1-（2,3-二氢苯并[ b ] [1,4]二恶英-6-基）-2-（（4-异丙基-4 H -1,2,4-三唑-3 -yl）thio）ethan-1-one）作为有效的和特定的可逆组织蛋白酶X抑制剂。在这里，我们探讨了化学变化对Z9的影响苯并二恶英或三唑部分的结构以及中心酮亚甲硫基连接基的重要性。酮亚甲硫基连接子对组织蛋白酶X的抑制至关重要，而三唑杂环的变化并没有更大程度地抑制抑制力。用取代的苯取代苯并二恶英部分减少了组织蛋白酶X抑制。总体而言，与Z9相比，几种合成的化合物对组织蛋白酶X表现出相似或改善的抑制力，IC ₅₀值为7.1 μM–13.6μM。另外，在组织蛋白酶X的控制下，有25种抑制了21％的前列腺癌细胞迁移。