Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
Molecules. 2018 Jul 4;23(7):1628. doi: 10.3390/molecules23071628.
A number of new trisubstituted triazine phosphatidylinositol 3-kinase (PI3K) inhibitors were prepared via a three-step procedure utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. All were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor, ZSTK474. The most active inhibitors prepared here were 2⁻4 times more potent than ZSTK474. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by a prostate-specific antigen, and it did not prevent inhibition of protein kinase B (Akt) phosphorylation, and hence, the inhibition of PI3K by the modified inhibitor.
通过利用顺序亲核芳香取代和交叉偶联反应的三步法，制备了许多新型的三取代三嗪类磷脂酰肌醇 3-激酶 (PI3K) 抑制剂。所有这些抑制剂都相对于经过充分表征的 PI3K 抑制剂 ZSTK474 作为 PI3K 抑制剂进行了筛选。这里制备的最活性抑制剂比 ZSTK474 强 2-4 倍。由于在被前列腺特异性抗原裂解后，任何含肽的前药上都会保留亮氨酸接头，并且不会阻止蛋白激酶 B（Akt）磷酸化，因此也不会阻止修饰抑制剂对 PI3K 的抑制，因此将其连接到最活性抑制剂上。
