Synthesis, acute toxicities, and antitumor effects of novel 9-substituted beta-carboline derivatives.
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.
Cao
Rihui
R
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.
Chen
Qi
Q
Hou
Xuerui
X
Chen
Hongsheng
H
Guan
Huaji
H
Ma
Yan
Y
Peng
Wenlie
W
Xu
Anlong
A
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
D000970:Antineoplastic Agents; D002243:Carbolines; D009498:Neurotoxins; D006247:Harmine; D014364:Tryptophan