Synthesis and structure-activity relationships of asymmetric dimeric β-carboline derivatives as potential antitumor agents.
A series of newly asymmetric dimeric β-carbolines with a spacer of 4-6 methylene units between the indole nitrogen and the harmine oxygen were synthesized. Structures of all the novel synthesized compounds were confirmed by their spectral and analytical studies. All of the synthesized compounds were screened for their in vitro cytotoxic activity against nine cancer cell lines. The results revealed that compounds 7c, 7o and 7s exhibited the highest cytotoxic activities with IC50 values of less than 20 μM against the tumor cell lines tested. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, and compound 7o exhibited potent antitumor activities with the tumor inhibition rate of over 40%. The wound healing assay displayed a specific impairment in the motility of the HT-29 cells, which suggested the anti-metastatic potential of compound 7o. Moreover, compound 7o had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay. Preliminary structure-activity relationship (SAR) analysis indicated that: (1) 3-phenylpropyl substituent at the N9-position of the indole ring was the most suitable group giving rise to potent cytotoxic agents; (2) the spacer length affected the antitumor potencies, and four methylene units were more favorable.
['Guo|Liang|L|', 'Chen|Wei|W|', 'Cao|Rihui|R|', 'Fan|Wenxi|W|', 'Ma|Qin|Q|', 'Zhang|Jie|J|', 'Dai|Bin|B|']
D020533:Angiogenesis Inhibitors D000818:Animals D000970:Antineoplastic Agents D002243:Carbolines D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D019281:Dimerization D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D006801:Humans D051379:Mice D008815:Mice, Inbred Strains D015394:Molecular Structure D009389:Neovascularization, Pathologic D013329:Structure-Activity Relationship D014945:Wound Healing
Structure-activity relationship Asymmetric dimeric β-carboline Antitumor Harmine Cytotoxic