Hussein Waleed M, Feder Daniel, Schenk Gerhard, Guddat Luke W, McGeary Ross P
The University of Queensland , School of Chemistry and Molecular Biosciences , Brisbane , QLD 4072 , Australia . Email:
Helwan University , Pharmaceutical Organic Chemistry Department , Faculty of Pharmacy , Ein Helwan , Helwan , Egypt.
Medchemcomm. 2018 Nov 13;10(1):61-71. doi: 10.1039/c8md00491a. eCollection 2019 Jan 1.
Transgenic studies in animals have demonstrated a direct association between the level of expression of purple acid phosphatase (PAP; also known as tartrate-resistant acid phosphatase) and the progression of osteoporosis. Consequently, PAP has emerged as a promising target for the development of novel therapeutic agents to treat this debilitating disorder. PAPs are binuclear hydrolases that catalyse the hydrolysis of phosphorylated substrates under acidic to neutral conditions. A series of phenyltriazole carboxylic acids, prepared by the reactions of azide derivatives with propiolic acid through copper(i)-catalysed azide-alkyne cycloaddition click reactions, has been assessed for their inhibitory effect on the catalytic activity of pig and red kidney bean PAPs. The binding mode of most of these compounds is purely uncompetitive with values as low as ∼23 μM for the mammalian enzyme. Molecular modelling has been used to examine the binding modes of these triazole compounds in the presence of a substrate in the active site of the enzyme in order to rationalise their activities and to design more potent and specific derivatives.
动物转基因研究表明，紫色酸性磷酸酶（PAP；也称为抗酒石酸酸性磷酸酶）的表达水平与骨质疏松症的进展之间存在直接关联。因此，PAP已成为开发新型治疗药物以治疗这种使人衰弱的疾病的一个有前景的靶点。PAP是双核水解酶，可在酸性至中性条件下催化磷酸化底物的水解。通过叠氮化物衍生物与丙炔酸通过铜（I）催化的叠氮化物-炔烃环加成点击反应制备了一系列苯基三唑羧酸，并评估了它们对猪和红芸豆PAP催化活性的抑制作用。这些化合物中的大多数的结合模式是纯粹非竞争性的，对哺乳动物酶的抑制常数低至约23μM。为了合理化它们的活性并设计更有效和特异的衍生物，已使用分子建模来研究这些三唑化合物在酶活性位点存在底物的情况下的结合模式。
