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首页> 外文期刊>RSC Advances >Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer
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Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer

机译：将基于哌嗪基 - 呋喃嘧啶基的支架作为磷酸肌醇-3-激酶酶α（PI3Kα）抑制剂，用于打击胰腺癌

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摘要

Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3- d ]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3- d ]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC _(50) values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.
机译：磷酸肌醇-3-激酶酶（PI3K）在促进各种哺乳动物细胞，特别是胰腺细胞的致癌生长方面起着至关重要的作用。在目前的研究中，设计并合成了一系列新型呋喃[2,3-D]嘧啶化合物作为潜在的PI3K-α抑制剂。根据已知的PI3K-α抑制剂的结构 - 活性关系（SAR）研究，将包括酰胺，尿素和乙醚的不同的接头与哌嗪基呋喃[2,3- D]嘧啶核连接。在Panc-1细胞系上测试了揭示了中度Pi3K-α抑制活性的合成化合物，以防止胰腺癌的抗增殖活性。化合物7B和8A分别显示出最高的抗增殖活性，IC _（50）值分别为4.5μm和6μm，相对，在新合成的化合物内最佳的体外PI3K抑制能力。另外，在60例人癌细胞系上测试所有新合成的最终化合物。对接研究在PI3K-α活性位点进行，显示与FDA批准的PI3K-α抑制剂的相当结合模式。这些新发现的脂质激酶抑制剂可被认为是开发新的靶向抗癌剂的潜在候选者。

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