Shaban Rania M, Samir Nermin, Nissan Yassin M, Abouzid Khaled A M
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA) Giza Egypt
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University Abbassia Cairo 11566 Egypt
RSC Adv. 2023 Jun 7;13(25):17074-17096. doi: 10.1039/d3ra00446e. eCollection 2023 Jun 5.
In continuation of our efforts to discover new structural chemotypes with significant chemotherapeutic activities, a novel series of pyrazolo[3,4-]pyrimidine-based compounds linked to a piperazine ring, bearing different aromatic moieties, through different linkages was designed and synthesized as FLT3 inhibitors. All of the newly synthesized compounds were evaluated for their cytotoxicity on 60-NCI cell lines. Compounds with the piperazine acetamide linkage XIIa-f & XVI exhibited a remarkable anticancer activity among all of the tested compounds, especially against non-small cell lung cancer, melanoma, leukemia and renal cancer models. Furthermore, compound XVI (NSC no - 833644) was further screened with a 5-dose assay on nine subpanels and exhibited a GI between 1.17 and 18.40 μM. On the other hand, molecular docking and dynamics studies were performed to predict the binding mode of the newly synthesized compounds in the FLT3 binding domain. Finally, through a predictive kinetic study, several ADME descriptors were calculated.
为继续努力发现具有显著化疗活性的新结构化学类型，设计并合成了一系列新型的基于吡唑并[3,4 -]嘧啶且通过不同连接方式与哌嗪环相连、带有不同芳香基团的化合物作为FLT3抑制剂。对所有新合成的化合物进行了针对60种NCI细胞系的细胞毒性评估。在所有测试化合物中，具有哌嗪乙酰胺连接的化合物XIIa - f和XVI表现出显著的抗癌活性，尤其对非小细胞肺癌、黑色素瘤、白血病和肾癌模型。此外，化合物XVI（NSC编号 - 833644）在九个亚组上进行了5剂量测定的进一步筛选，其GI在1.17至18.40 μM之间。另一方面，进行了分子对接和动力学研究以预测新合成化合物在FLT3结合域中的结合模式。最后，通过预测动力学研究计算了几个ADME描述符。
