title: Pseudocyanides of sanguinarine and chelerythrine and their series of structurally simple analogues as new anticancer lead compounds: Cytotoxic activity, structure-activity relationship and apoptosis induction.
abstract: 6-Cyano dihydrosanguinarine (CNS) and 6-cyano dihydrochelerythrine (CNC) are respectively artificial derivatives of sanguinarine and chelerythrine, two anticancer quaternary benzo[c]phenanthridine alkaloids (QBAs) while 1-cyano-2-aryl-1,2,3,4-tetrahydroisoquinolines (CATHIQs) are a class of structurally simple analogues of CNS or CNC. This study investigated the inhibition activity of CNS, CNC and CATHIQs on cancer cells, apoptosis induction as well as their preliminary SAR. The results showed that CNS and 18 out of CATHIQs showed IC50 values of 0.53 and 0.62-2.24μM against NB4 and 1.53 and 2.99-11.17μM against MKN-45 cells, respectively, superior to a standard anticancer drug cis-platinum with IC50 of 2.39 and 11.36μM. CNC showed a higher activity against NB4 cells (IC50=1.85μM) and a moderate activity against MKN-45 cells (IC50=12.72μM). Among all CATHIQs, 2 and 17 gave the highest activity against NB4 cells and MKN-45 cells (IC50=0.62 and 2.99μM), respectively. DAPI staining, AO/EB staining and ultrastructure analysis of cells demonstrated that CATHIQs were able to induce apoptosis of the cells in a concentration-dependent manner. SAR showed that substitution patterns on the N-aromatic ring significantly influenced the activity of CATHIQs. The general trend was that the introduction of electron-withdrawing substituents like halogen atom, nitro, trifluoromethyl led to a significant improvement of the activity, while the presence of electron-donating groups like methyl, methoxyl caused a reduction of the activity. In most cases, the 2' site was the most favorable substitution position for the improvement of the activity. Thus, the present results strongly suggested that QBA-type pseudocyanides may serve as potential alternatives of anticancer QBAs while CATHIQs should be a class of promising lead compounds for the development of new QBA-like-type anticancer drugs. CNS exhibited the highest cytotoxicities with IC50 values of 0.53μM on NB4 cells and 1.53μM on MKN-45 cells.
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Fang-Jun
authors.initials: FJ
authors.lastname: Cao
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Lv
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Ma
authors.affiliation: College of Life Science, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: genghuiling5@163.com.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Geng
authors.affiliation: College of Science, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address: zhoulechem@nwsuaf.edu.cn.
authors.forename: Le
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003486:Cyanides / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006041:Goats; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D003486:Cyanides; D007546:Isoquinolines; C005705:sanguinarine; C016299:chelerythrine
keywords: Anticancer activity; Apoptosis induction; Benzo[c]phenanthridine alkaloid; Cytotoxicity; Isoquinoline; Structure–activity relationship