Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
Eur J Pharm Sci. 2023 Jun 1;185:106424. doi: 10.1016/j.ejps.2023.106424. Epub 2023 Mar 12.
SIRT6 has emerged as a novel therapeutic target for a variety of diseases. In this study, a total of 102 pyrazolo [1,5-a]quinazoline derivatives were designed and synthesized. The result revealed that 2-methyl-N-(4-phenoxy-phenyl)pyrazolo [1,5-a]quinazoline-5-amine (21q) was the most active compound by structure-activity relationship study, which significantly enhanced SIRT6 defatty-acylation activity with an EC value of 1.85±0.41 μM and EC value of 11.15±0.33 μM. The biological activity of 21q was further verified by differential scanning fluorimetry assay (DSF) and surface plasmon resonance assay (SPR). Molecular docking showed that the pyrazolo [1,5-a]quinazoline of 21q formed a hydrogen bond with Val115 and four π- π interactions with Phe64, Phe82 and Phe86. 21q can significantly improve the thermal stability of SIRT6 protein and inhibit the PI3K/Akt signaling pathway in mouse embryonic fibroblasts (MEFs), thereby inhibiting the proliferation of MEFs. Collectively, we discovered a new potent SIRT6 activator, which can be taken as a lead compound for later studies.
SIRT6 已成为多种疾病的新型治疗靶点。在这项研究中，设计并合成了总共 102 种吡唑并[1,5-a]喹唑啉衍生物。通过构效关系研究表明，2-甲基-N-(4-苯氧基苯基)吡唑并[1,5-a]喹唑啉-5-胺（21q）是最具活性的化合物，其 SIRT6 去脂酰化活性的 EC 值为 1.85±0.41 μM，EC 值为 11.15±0.33 μM。通过差示扫描荧光法（DSF）和表面等离子体共振法（SPR）进一步验证了 21q 的生物学活性。分子对接表明，21q 的吡唑并[1,5-a]喹唑啉与 Val115 形成氢键，与 Phe64、Phe82 和 Phe86 形成四个π-π相互作用。21q 可显著提高 SIRT6 蛋白的热稳定性，并抑制小鼠胚胎成纤维细胞（MEFs）中的 PI3K/Akt 信号通路，从而抑制 MEFs 的增殖。综上所述，我们发现了一种新型有效的 SIRT6 激活剂，可作为进一步研究的先导化合物。
