Small molecule purine and pseudopurine derivatives: synthesis, cytostatic evaluations and investigation of growth inhibitory effect in non-small cell lung cancer A549

Journal of Enzyme Inhibition and Medicinal Chemistry

Sanja Koštrun¹  Petra Grbčić²  Anja Harej²  Mirela Sedić²  Sandra Kraljević-Pavelić²  Andrea Bistrović³  Silvana Raić-Malić³  Damjan Makuc⁴  Janez Plavec⁵ 

[1] Chemistry Department, Fidelta Ltd., Zagreb, Croatia;Department of Biotechnology, Center for High-Throughput Technologies, University of Rijeka, Rijeka, Croatia;Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia;Slovenian NMR Centre, National Institute of Chemistry, Ljubljana, Slovenia;En-FIST Centre of Excellence, Ljubljana, Slovenia;Slovenian NMR Centre, National Institute of Chemistry, Ljubljana, Slovenia;En-FIST Centre of Excellence, Ljubljana, Slovenia;Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Sloveni;

关键词: Purine;    1,2,3-triazole;    purinomimetic;    non-small cell lung cancer A549;    p38 MAPK;   

DOI  :  10.1080/14756366.2017.1414807

来源: publisher

【 摘 要 】

Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-κB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer.

【 授权许可】

CC BY