Department of Chemistry, Hazara University, Mansehra-21300, Khyber Pakhtunkhwa, Pakistan.
Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia.
Bioorg Chem. 2018 Aug;78:324-331. doi: 10.1016/j.bioorg.2018.03.026. Epub 2018 Mar 30.
Thymidine phosphorylase triggers the phosphorylation of pyrimidine base to thymine and 2-deoxyribose 1-phosphate which undergoes dephosphorylation to 2-deoxyribose. It plays a role in tumor angiogenesis which is referred to the development of blood vessels during tumor growth and therefore is an attractive drug target. Keeping in view the greater importance of its inhibition, here in this study we have synthesized piperazine analogs (1-18) and evaluated for thymidine phosphorylase inhibitory activity. All analogs showed potent inhibitory potential with IC values ranging between 0.2 ± 0.01 and 42.20 ± 0.70 µM when compared with standard 7-Deazaxanthine (IC value of 38.68 ± 1.12 µM). Structure activity relationship has been also established for all newly synthesized compounds. Molecular docking studies revealed that these compounds established stronger hydrogen bonding networks with active site residues of enzyme.
胸苷磷酸化酶将嘧啶碱基磷酸化为胸腺嘧啶和 2-脱氧核糖 1-磷酸，后者经去磷酸化生成 2-脱氧核糖。它在肿瘤血管生成中起作用，肿瘤生长过程中血管的发育，因此是一个有吸引力的药物靶点。鉴于其抑制作用更为重要，在本研究中，我们合成了哌嗪类似物（1-18）并评估了它们对胸苷磷酸化酶的抑制活性。与标准 7-脱氮嘌呤（IC 值 38.68 ± 1.12 µM）相比，所有类似物均表现出很强的抑制潜力，IC 值范围在 0.2 ± 0.01 和 42.20 ± 0.70 µM 之间。还建立了所有新合成化合物的构效关系。分子对接研究表明，这些化合物与酶的活性位点残基建立了更强的氢键网络。
