Ullah Saif, Pelletier Julie, Sévigny Jean, Iqbal Jamshed
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad22060, Pakistan.
Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Abbottabad22060, Pakistan.
ACS Omega. 2022 Jul 19;7(30):26905-26918. doi: 10.1021/acsomega.2c03473. eCollection 2022 Aug 2.
Aberrant level of ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 is linked with numerous disorders, for instance, diabetes, cancer, osteoarthritis, chondrocalcinosis, and allergic reactions. These disorders may be cured or minimized by blocking the activity of ENPP1 and ENPP3 isozymes. In this study, arylamide sulphonates were synthesized, characterized, and evaluated for their capability to affect the activity of isozymes ENPP1 and ENPP3. Among the selective inhibitors of ENPP1, compounds and exhibited sub-micromolar IC values of 0.28 ± 0.08 and 0.37 ± 0.03 μM, respectively, followed by , with IC equal to 0.81 ± 0.05 μM, whereas out of the selective inhibitors of isozyme ENPP3, and preferably lessened the activity to half of the maximal inhibitory concentration of 0.15 ± 0.04 and 0.16 ± 0.01 μM alternatively. In addition, many structures including , , , , , , , , , , and inhibited the activity of both isozymes to a significant level. Enzyme kinetic study of compound revealed an uncompetitive mode of inhibition of ENPP1 isozyme, while competitively blocked the activity of ENPP3. Cell viability analysis revealed the compound as a cytotoxic agent against MCF7 (human breast cancer cell line) with a percentage inhibition of 63.2 ± 2.51%, whereas compounds , , , and decreased the HeLa cell viability (human cervical cancer cell line) to more than 50%. The tested compounds were non-cytotoxic against HEK293 (a human embryonic kidney cell line). Molecular docking analysis of selected inhibitors of both isozymes produced optimistic interactions with the influential amino acids, such as Leu290, Lys295, Tyr340, Asp376, His380, and Pro323 of ENPP1, whereas residues Asn226, His329, Leu239, Tyr289, Pro272, Tyr320, and Ala205 of ENPP3 crystallographic structure formed interactions with the potent inhibitors.
胞外核苷酸焦磷酸酶/磷酸二酯酶-1和-3水平异常与多种疾病相关，例如糖尿病、癌症、骨关节炎、软骨钙质沉着症和过敏反应。通过阻断ENPP1和ENPP3同工酶的活性，这些疾病可能得到治愈或病情减轻。在本研究中，合成并表征了芳酰胺磺酸盐，并评估了它们影响ENPP1和ENPP3同工酶活性的能力。在ENPP1的选择性抑制剂中，化合物 和 的半数抑制浓度（IC）值分别为亚微摩尔级，即0.28±0.08和0.37±0.03 μM，其次是 ，IC等于0.81±0.05 μM，而在ENPP3同工酶的选择性抑制剂中， 和 分别以0.15±0.04和0.16±0.01 μM的最大抑制浓度将活性降低至一半。此外，许多结构，包括 、 、 、 、 、 、 、 、 、 、 和 ，均在显著水平上抑制了两种同工酶的活性。化合物 的酶动力学研究表明其对ENPP1同工酶具有非竞争性抑制模式，而 竞争性地阻断了ENPP3的活性。细胞活力分析表明，化合物 作为一种针对MCF7（人乳腺癌细胞系）的细胞毒性剂，抑制率为63.2±2.51%，而化合物 、 、 和 将HeLa细胞（人宫颈癌细胞系）的活力降低至50%以上。所测试的化合物对HEK293（人胚肾细胞系）无细胞毒性。对两种同工酶的选定抑制剂进行的分子对接分析显示，它们与ENPP1的Leu290、Lys295、Tyr340、Asp376、His380和Pro323等有影响的氨基酸产生了积极的相互作用，而ENPP3晶体结构的Asn226、His329、Leu239、Tyr289、Pro272、Tyr320和Ala205残基与强效抑制剂形成了相互作用。
