化药合成,抗肿瘤新药

Synthesis,acute toxicities,and antitumor e?ects of novel

9-substituted b -carboline derivatives

Rihui Cao,Qi Chen,Xuerui Hou,Hongsheng Chen,Huaji Guan,Yan Ma,

Wenlie Peng and Anlong Xu *

Department of Biochemistry and Center for Biopharmaceutical Research,College of Life Sciences,Sun Yat-sen (Zhongshan)University,135Xin Gang Xi Road,Guangzhou 510275,PR China

Received 3May 2004;revised 27June 2004;accepted 28June 2004

Abstract—A series of novel 9-substituted b -carboline derivatives was synthesized from harmine and L -tryptophan,respectively.Cy-totoxic activities of these compounds in vitro were investigated.The results showed that most compounds of 9-substituted b -carb-oline derivatives had more remarkable cytotoxic activities in vitro than their corresponding parent compounds.Acute toxicities and antitumor e?ects of the selected b -carboline derivatives in mice were also examined.The results demonstrated that a short alkyl or benzyl substituent at position-9increased the antitumor activities signi?cantly and a ethoxycarbonyl or carboxyl substituent at posi-tion-3reduced the acute toxicity and neurotoxicity of these b -carboline derivatives dramatically.Moreover the compounds both with an alkoxycarbonyl or carboxyl substituent at position-3and a short alkyl or benzyl substituent at positon-9exhibited more signi?cant 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-9and 3,respectively,was found to have the highest antitumor e?ect and the lowest acute toxicity and neurotoxicity.These data suggested that (1)appropriate substituents at both position-9and 3of b -carboline derivatives might play a crucial role in determining their enhanced antitumor activities and decreased acute toxicities and neurotoxic e?ects;(2)the b -carboline derivatives have the potential to be used as antitumor drug leads.Ó2004Published by Elsevier Ltd.

1.Introduction

b -Carbolines are a large group of naturally occurring and syntheti

c indole alkaloids with di?erent degrees of aromaticity,some of which are widely distribute

d in nat-ure,including various plants,1–3marin

e creatures,4in-sects,5mammalians as well as human tissues and body ?uids.6–9These compounds are o

f great interest due to their various biological activities such as intercalatin

g into DNA,10,11inhibiting CDK,12and Topisom-erase,13,14inhibiting monoamine oxidase 15,16as well as interacting wit

h benzodiazepine receptors 17–19and 5-hydroxy serotonin receptors,20and their broad spectrum pharmacological properties including anxiolytic,hyp-notic,anticonvulsant,21–23parasiticidal,24antiviral 25as well as antimicrobial activities.30Recent work 26–28and

our preliminary investigation results demonstrated that the compounds with b -carboline nucleus have potential antitumor activities.Yet we also found that this class of compounds caused remarkable acute neurotoxicity characterized by tremble,twitch,and jumping in exper-imental mice models.

Many previous reports focused on the e?ects of these compounds on the central nervous system (CNS),such as their a?nity with benzodiazepine receptors,17–195-HT 2A and 5-HT 2C receptors 20and imidazoline recep-tor 32,and so on.However so far there have been few such literatures about their cytotoxic activities of these compounds in vitro,even no reports are available deal-ing with systematic and detailed studies of structure–activity relationships on both antitumor activities and neurotoxic activities in vivo.A probable reason for this is that many of the b -carboline derivatives of interest are not readily available.One goal of the present investiga-tions was to synthesize a series of novel b -carboline derivatives and elucidate their preliminary relationships between structures and antitumor activities as well as

0968-0896/$-see front matter Ó2004Published by Elsevier Ltd.doi:10.1016/j.bmc.2004.06.038

Keywords :b -Carboline;Synthesis;Acute toxicity;Antitumor;Neuro-toxicity.

*Corresponding author.Tel.:+86-20-84113655;fax:+86-20-84038377;e-mail:

ls36@

Bioorganic &Medicinal Chemistry 12(2004)

4613–4623

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