Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer.
Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer.
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DOI：
10.1021/acs.jmedchem.2c01769
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发表时间：
2023-01
影响因子：
7.3
通讯作者：
Joyeeta Roy;A. Kyani;Maha Hanafi;Yibin Xu;J. Takyi-Williams;Duxin Sun;E. E. A. Osman-E.;N. Neamati
中科院分区：
文献类型：
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作者：
Joyeeta Roy;A. Kyani;Maha Hanafi;Yibin Xu;J. Takyi-Williams;Duxin Sun;E. E. A. Osman-E.;N. Neamati
σ 2受体（σ 2 R）在选定的癌症中过表达，并且被认为是肿瘤增殖的生物标志物。σ 2 R配体正在成为癌症和神经退行性疾病的有前途的治疗诊断剂。在此，我们描述了一系列新型喹啉基吡嗪酰胺作为选择性和有效的σ 2 R配体的设计和合成，其在胰腺癌细胞系中显示亚微摩尔效力。化合物14（JR 1 -157）和17（JR 2 -298）分别以47和10 nM的Ki结合σ 2 R。重要的是，化合物14具有60%的口服生物利用度，并且在胰腺癌的同基因模型中显示出显著的体内功效而没有明显的毒性。喹啉基吡嗪酰胺的细胞毒性显着增强，在铜的存在下，并在铜螯合剂四硫代钼酸盐的存在下减少。总之，化合物14是水溶性的、代谢稳定的、口服活性的，并且增加了自噬标志物LC 3B的表达，并且保证了用于治疗胰腺癌的进一步开发。
Sigma 2 receptor (σ2R) is overexpressed in select cancers and is regarded as a biomarker for tumor proliferation. σ2R ligands are emerging as promising theranostics for cancer and neurodegenerative diseases. Herein, we describe the design and synthesis of a series of novel quinolyl pyrazinamides as selective and potent σ2R ligands that show sub-micromolar potency in pancreatic cancer cell lines. Compounds 14 (JR1-157) and 17 (JR2-298) bind σ2R with Ki of 47 and 10 nM, respectively. Importantly, compound 14 has an oral bioavailability of 60% and shows significant in vivo efficacy without obvious toxicity in a syngeneic model of pancreatic cancer. The cytotoxicity of the quinolyl pyrazinamides significantly enhanced in the presence of copper and diminished in the presence of the copper-chelator tetrathiomolybdate. In conclusion, compound 14 is water-soluble, metabolically stable, orally active, and increases the expression of the autophagy marker LC3B and warrants further development for the treatment of pancreatic cancer.