School of Chemistry and Chemical Engineering, Nantong University, Nantong 226019, China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
Molecules. 2022 Apr 8;27(8):2404. doi: 10.3390/molecules27082404.
A series of new thiophene-containing triaryl pyrazoline derivatives, -, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of the tested compounds indicated potent PI3K inhibitory potency, with this series of compounds showing more potency for PI3Kγ than PI3Kα. The top hit seemed more potent than the positive control on inhibiting PI3Kγ (IC values: 0.066 μM versus 0.777 μM) and more selective from PI3Kα (Index values: 645 versus 1.74). It could be inferred that the combination of - and -, as well as the modification of the electron-donating moieties, led to the improvement in potency. The anti-proliferation inhibitory activity and the enzymatic inhibition potency indicated consistent tendencies. The top hit could inhibit the phosphorylation of Akt by inhibiting PI3K through the PI3K-Akt-mTOR pathway. The molecular docking simulation indicated that the binding pattern of into PI3Kγ was preferable than that of PI3Kα, with more hydrogen bond, more π-involved interactions, and fewer π-sulfur interactions. The information in this work is referable for the further development of selective inhibitors for specific isoforms of PI3K.
一系列新的含噻吩的三芳基吡唑啉衍生物、-、被合成并评估了其对 PI3K 抑制活性和抗肿瘤活性，这是基于引入显著部分的尝试，包括吡唑啉和噻吩，并简化了平行环结构。大多数测试的化合物表现出很强的 PI3K 抑制活性，这一系列化合物对 PI3Kγ 的活性比 PI3Kα 更强。顶级命中物似乎比阳性对照物在抑制 PI3Kγ 方面更有效（IC 值：0.066 μM 对 0.777 μM），对 PI3Kα 的选择性更高（指数值：645 对 1.74）。可以推断，-和-的结合以及供电子部分的修饰导致了活性的提高。抗增殖抑制活性和酶抑制活性显示出一致的趋势。顶级命中物-通过抑制 PI3K 途径通过 PI3K-Akt-mTOR 途径抑制 Akt 的磷酸化。分子对接模拟表明，与 PI3Kα 相比，-与 PI3Kγ 的结合模式更可取，具有更多的氢键、更多的π 参与相互作用和更少的π-硫相互作用。这项工作中的信息可用于进一步开发针对特定 PI3K 同工型的选择性抑制剂。
