title: Synthesis, acute toxicities, and antitumor effects of novel 9-substituted beta-carboline derivatives.
abstract: A series of novel 9-substituted beta-carboline derivatives was synthesized from harmine and l-tryptophan, respectively. Cytotoxic activities of these compounds in vitro were investigated. The results showed that most compounds of 9-substituted beta-carboline derivatives had more remarkable cytotoxic activities in vitro than their corresponding parent compounds. Acute toxicities and antitumor effects of the selected beta-carboline derivatives in mice were also examined. The results demonstrated that a short alkyl or benzyl substituent at position-9 increased the antitumor activities significantly and a ethoxycarbonyl or carboxyl substituent at position-3 reduced the acute toxicity and neurotoxicity of these beta-carboline derivatives dramatically. Moreover the compounds both with an alkoxycarbonyl or carboxyl substituent at position-3 and a short alkyl or benzyl substituent at positon-9 exhibited more significant antitumor activities and lower acute toxicities and neurotoxicities than the other compounds. The compound 8c, having an n-butyl and a carboxyl substituent at position-9 and 3, respectively, was found to have the highest antitumor effect and the lowest acute toxicity and neurotoxicity. These data suggested that (1) appropriate substituents at both position-9 and 3 of beta-carboline derivatives might play a crucial role in determining their enhanced antitumor activities and decreased acute toxicities and neurotoxic effects; (2) the beta-carboline derivatives have the potential to be used as antitumor drug leads.
authors.affiliation: Department of Biochemistry and Center for Biopharmaceutical Research, College of Life Sciences, Sun Yat-sen (Zhongshan) University, 135 Xin Gang Xi Road, Guangzhou 510275, PR China.
authors.forename: Rihui
authors.initials: R
authors.lastname: Cao
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Xuerui
authors.initials: X
authors.lastname: Hou
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Chen
authors.forename: Huaji
authors.initials: H
authors.lastname: Guan
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Wenlie
authors.initials: W
authors.lastname: Peng
authors.forename: Anlong
authors.initials: A
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology; D064420:Drug-Related Side Effects and Adverse Reactions; D006247:Harmine / Q000737:chemistry; D020128:Inhibitory Concentration 50; D051379:Mice; D009498:Neurotoxins / Q000633:toxicity; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D009498:Neurotoxins; D006247:Harmine; D014364:Tryptophan