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Authors Chen, Q; Chao, RH; Chen, HS; Hou, XR; Yan, HF; Zhou, SF; Peng, WL; Xu, AL
Author Full Name Chen, Q; Chao, RH; Chen, HS; Hou, XR; Yan, HF; Zhou, SF; Peng, WL; Xu, AL
Title Antitumor and neurotoxic effects of novel harmine derivatives and structure-activity relationship analysis
Source INTERNATIONAL JOURNAL OF CANCER
Language English
Document Type Article
Author Keywords harmine; beta-carboline alkaloid; antitumor effect; apoptosis; structure-activity relationship
Keywords Plus BETA-CARBOLINE ALKALOIDS; TOPOISOMERASE-II INHIBITORS; MONOAMINE-OXIDASE-A; PARKINSONS-DISEASE; PROTEIN COMPLEXES; GAMMA-CARBOLINE; PC12 CELLS; DNA; APOPTOSIS; DEATH
Abstract Beta-carboline alkaloids such as harmine are present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In our study, 9 harmine derivatives (including harmine) were investigated for their antitumor effects and acute toxicities in mice, and the structure-activity relationship (SAR) was also analyzed. Administration of these compounds resulted in tumor inhibition rates of 15.3-49.5% in mice bearing Lewis Lung Cancer, sarcoma180 or HepA tumor, with the highest value of 49.5% from compound 6. Acute toxicity studies showed that all these compounds except compounds 2 and 5 caused remarkable acute neurotoxicities manifested by tremble, twitch and jumping. SAR analysis indicated that the formate substitution at R3 of the tricyclic skeleton reduced their neurotoxicity, while the short alkyl or aryl substitution at R9 increased the antitumor activity. The harmine and its derivatives resulted in in vitro Cytotoxicity (IC50) values of 0.011-0.021 mumol/ml in HepG2 cells, with compound 8 being the most potent among all agents tested. Compounds 1, 6, 7 and 8 induced apoptosis in HepG2 cells, with the highest apoptotic rate (55.34%) from compound 6. Western blotting analysis demonstrated that compound 6 completely inhibited the expression of Bcl-2 gene, and compounds I and 8 produced a significant inhibition by 40 and 60%, respectively, compared to the control, while compound 7 did not alter the level of Bcl-2. Compounds 1, 6, 7 and 8 upregulated the expression of death receptor Fas by approximately 50-120%. All these findings indicate that compounds with both substitutions at R3 and R9 (such as compound 5) have high antitumor activity and low toxicity, which might be chosen as lead molecules for further development. Further studies on the effects of harmine derivatives on key regulators for tumor cell apoptosis are needed. (C) 2004 Wiley-Liss, Inc.
Author Address Sun Yat Sen Univ, Coll Life Sci, Dept Biochem, Guangzhou 510275, Peoples R China; Sun Yat Sen Univ, Coll Life Sci, Ctr Biopharmaceut Res, Guangzhou 510275, Peoples R China; Shanghai Inst Pharmaceut Ind, Shanghai, Peoples R China; Natl Univ Singapore, Fac Sci, Dept Pharm, Singapore 117548, Singapore
Reprint Address Xu, AL (corresponding author), Sun Yat Sen Univ, Coll Life Sci, Dept Biochem, 135 Xin Gang Xi Rd, Guangzhou 510275, Peoples R China.
E-mail Address ls36@zsu.edu.cn
ResearcherID Number Chen, Qi/D-8278-2015
ORCID Number Chen, Qi/0000-0002-7173-8411
Times Cited 102
Total Times Cited Count (WoS, BCI, and CSCD) 105
Publisher WILEY
Publisher City HOBOKEN
Publisher Address 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
ISSN 0020-7136
29-Character Source Abbreviation INT J CANCER
ISO Source Abbreviation Int. J. Cancer
Publication Date MAY 1
Year Published 2005
Volume 114
Issue 5
Beginning Page 675
Ending Page 682
Digital Object Identifier (DOI) 10.1002/ijc.20703
Page Count 8
Web of Science Category Oncology
Subject Category Oncology
Document Delivery Number 904YX
Unique Article Identifier WOS:000227535600001
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