Iqbal Jamshed, El-Gamal Mohammed I, Ejaz Syeda Abida, Lecka Joanna, Sévigny Jean, Oh Chang-Hyun
a Centre for Advanced Drug Research , COMSATS Institute of Information Technology , Abbottabad , Pakistan.
b Department of Medicinal Chemistry, College of Pharmacy , University of Sharjah , Sharjah , United Arab Emirates.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):479-484. doi: 10.1080/14756366.2018.1428193.
Tissue-nonspecific alkaline phosphatase (TNAP) is an important isozyme of alkaline phosphatases, which plays different pivotal roles within the human body. Most importantly, it is responsible for maintaining the balanced ratio of phosphate and inorganic pyrophosphate, thus regulates the extracellular matrix calcification during bone formation and growth. The elevated level of TNAP has been linked to vascular calcification and end-stage renal diseases. Consequently, there is a need to search for highly potent and selective inhibitors of alkaline phosphatases (APs) for treatment of disorders associated with the over-expression of APs. Herein, a series of tricyclic coumarin sulphonate 1a-za with known antiproliferative activity, was evaluated for AP inhibition against human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). The methylbenzenesulphonate derivative 1f (IC = 0.38 ± 0.01 μM) was found to be the most active h-TNAP inhibitor. Another 4-fluorobenzenesulphonate derivative 1i (IC = 0.45 ± 0.02 μM) was found as the strongest inhibitor of h-IAP. Some of the derivatives were also identified as highly selective inhibitors of APs. Detailed structure-activity relationship (SAR) was investigated to identify the functional groups responsible for the effective inhibition of AP isozymes. The study was also supported by the docking studies to rationalise the most possible binding site interactions of the identified inhibitors with the targeted enzymes.
组织非特异性碱性磷酸酶（TNAP）是碱性磷酸酶的一种重要同工酶，在人体内发挥着不同的关键作用。最重要的是，它负责维持磷酸盐和无机焦磷酸盐的平衡比例，从而在骨骼形成和生长过程中调节细胞外基质钙化。TNAP水平升高与血管钙化和终末期肾病有关。因此，需要寻找高效、选择性的碱性磷酸酶（APs）抑制剂来治疗与APs过度表达相关的疾病。在此，评估了一系列具有已知抗增殖活性的三环香豆素磺酸盐1a - za对人组织非特异性碱性磷酸酶（h - TNAP）和人肠碱性磷酸酶（h - IAP）的AP抑制作用。发现甲基苯磺酸盐衍生物1f（IC = 0.38 ± 0.01 μM）是活性最强的h - TNAP抑制剂。另一种4 - 氟苯磺酸盐衍生物1i（IC = 0.45 ± 0.02 μM）被发现是h - IAP的最强抑制剂。一些衍生物还被鉴定为APs的高选择性抑制剂。研究了详细的构效关系（SAR），以确定对AP同工酶有效抑制起作用的官能团。对接研究也支持了该研究，以合理化所鉴定抑制剂与靶酶最可能的结合位点相互作用。
