Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, North Campus Research Complex, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
J Med Chem. 2023 Feb 9;66(3):1990-2019. doi: 10.1021/acs.jmedchem.2c01769. Epub 2023 Jan 24.
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 (JR1-157) and (JR2-298) bind σ2R with of 47 and 10 nM, respectively. Importantly, compound 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 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.
西格玛 2 受体（σ2R）在某些癌症中过度表达，被认为是肿瘤增殖的生物标志物。σ2R 配体作为癌症和神经退行性疾病的有前途的治疗方法正在出现。本文描述了一系列新型喹啉吡嗪酰胺的设计和合成，这些化合物是选择性和有效的 σ2R 配体，在胰腺癌细胞系中表现出亚微摩尔的效力。化合物 (JR1-157) 和 (JR2-298) 分别与 σ2R 的结合亲和力为 47 和 10 nM。重要的是，化合物 的口服生物利用度为 60%，在胰腺癌的同基因模型中显示出显著的体内疗效，且无明显毒性。在铜存在的情况下，喹啉吡嗪酰胺的细胞毒性显著增强，而在铜螯合剂四硫钼酸盐存在的情况下则减弱。总之，化合物 水溶性好、代谢稳定、口服活性强，并能增加自噬标志物 LC3B 的表达，值得进一步开发用于治疗胰腺癌。
