Discovery of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purines containing a carboxamide moiety as potential selective anti-lung cancer agents

• Published in: European journal of medicinal chemistry 2018-05, Vol.151, p.327-338
• Main Authors: Zhao, Tao-Qian, Zhao, Yuan-Di, Liu, Xin-Yang, Wang, Bo, Li, Zhong-Hua, He, Zhang-Xu, Zhang, Xin-Hui, Liang, Jian-Jia, Ma, Li-Ying, Liu, Hong-Min
• Format: Article
• Language: English
• Subjects: 6-Chloro-purine-8-carboxamide; Antiproliferative activity; Apoptosis; Migration
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.03.084

A new series of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purine-8-caboxamide derivatives were designed, synthesized, and further evaluated for their antiproliferative activities on four human cancer cell lines (A549, MGC803, PC-3 and TE-1). The structure-activity relationships (SARs) studies were conducted through the variation in the two regions, which including position 8 and 9, of purine core. One of the compounds, 8, containing a terminal piperazine appendage with a carboxamide moiety at position 8 and phenyl group at position 9 of 6-chloro-8,9-dihydro-7H-purine core, showed the most potent antiproliferative activity and good selectivity between cancer and normal cells (IC50 values of 2.80 μM against A549 and 303.03 μM against GES-1, respectively). In addition, compound 8 could inhibit the colony formation and migration of A549 cells in a concentration-dependent manner, as well as induce the apoptosis possibly through the intrinsic pathway. A series of novel 6-chloro-2-(propylthio)-8,9-dihydro-7H-purines containing a carboxamide moiety were synthesized and evaluated for their antiproliferative activity. SAR studies showed that compound 8 could inhibit the colony formation and migration as well as induce apoptosis of A549 cells. [Display omitted] •A novel 6-chloro-purine-8-carboxamide-based scaffold was established as a potential antiproliferative agent.•Compound 8 exerted the potent activity and good selectivity between cancer and normal cells.•Compound 8 could inhibit migration and induce the apoptosis of A549 cells.