a Pharmaceutical Chemistry Department, Faculty of Pharmacy , The British University in Egypt , El-Sherouk City , Egypt.
b The Center for Drug Research and Development (CDRD), Faculty of Pharmacy , The British University in Egypt , El-Sherouk City , Egypt.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):858-866. doi: 10.1080/14756366.2018.1462801.
Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted.
引入了具有结构多样性的化学实体，作为针对具有不同临床活性的腺苷受体的候选物，其中包含 3,7-二氢-1H-嘌呤-2,6-二酮，特别是腺苷 3 受体（ADORA3）。我们的初步方法从 ADORA3 调节剂的药效团筛选开始；选择已批准的抗糖尿病药物利格列汀（LIN）作为二肽基肽酶-4 抑制剂，研究其对 ADORA3 的调节作用。随后，对氧化降解产物（DEG）进行了生成、纯化、分析方法开发和结构阐明。LIN 和 DEG 均显示出对肝癌细胞系的抑制谱，诱导细胞凋亡进入 G2/M 期，同时 caspase-3 水平升高，ADORA3 的基因和蛋白表达水平下调，随后 cAMP 增加。还进行了定量体外评估 LIN 对 ADORA3 的结合亲和力，以显示 Ki 为 37.7 nM 的抑制谱。进行了计算机分子模拟，显示了 LIN 和 DEG 对 ADORA3 的结合亲和力。
