Faculty of Pharmacy, Pharmaceutical Chemistry Department, Ain Shams University, Cairo, Egypt.
Faculty of Pharmacy, Department of Organic and Medicinal Chemistry, University of Sadat City, Menoufia, Egypt.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):315-332. doi: 10.1080/14756366.2021.2010729.
Cancer is one of the most aggressive diseases characterised by abnormal growth and uncontrolled cell division. PI3K is a lipid kinase involved in cancer progression which makes it fruitful target for cancer control. 28 new morpholine based thieno[2,3-] pyrimidine derivatives were designed and synthesised as anti-PI3K agents maintaining the common pharmacophoric features of several potent PI3K inhibitors. Their antiproliferative activity on NCI 60 cell lines as well as their enzymatic activity against PI3K isoforms were evaluated. Three compounds revealed good cytotoxic activities against breast cancer cell lines, especially T-47D. Compound exhibited the best enzymatic inhibitory activity (72% & 84% on PI3Kβ & PI3Kγ), respectively and good activity on most NCI cell lines especially those with over expressed PI3K. Docking was carried out into PI3K active site which showed comparable binding mode to that of the PI-103 inhibitor. Compound could be optimised to serve as a new chemical entity for discovering new anticancer agents.
癌症是一种最具侵袭性的疾病，其特征是异常生长和不受控制的细胞分裂。PI3K 是一种参与癌症进展的脂质激酶，是癌症控制的富有成效的靶点。设计并合成了 28 种基于吗啉的噻吩并[2,3-d]嘧啶衍生物，作为抗 PI3K 药物，保持了几种有效的 PI3K 抑制剂的常见药效特征。评估了它们对 NCI 60 细胞系的抗增殖活性及其对 PI3K 同工型的酶活性。三种化合物对乳腺癌细胞系，特别是 T-47D 表现出良好的细胞毒性。化合物 表现出最好的酶抑制活性（对 PI3Kβ 和 PI3Kγ 的抑制活性分别为 72%和 84%），对大多数 NCI 细胞系也表现出良好的活性，特别是那些 PI3K 过表达的细胞系。进行了对接到 PI3K 活性部位，结果表明与 PI-103 抑制剂具有可比的结合模式。化合物 可以被优化为发现新的抗癌药物的新的化学实体。
