Novel harmine derivatives for tumor targeted therapy.
Harmine is a beta-carboline alkaloid found in medicinal plant PeganumHarmala, which has served as a folk anticancer medicine. However, clinical applications of harmine were limited by its low pharmacological effects and noticeable neurotoxicity. In this study, we modified harmine to increase the therapeutic efficacy and to decrease the systemic toxicity. Specifically, two tumor targeting harmine derivatives 2DG-Har-01 and MET-Har-02 were synthesized by modifying substituent in position-2, -7 and -9 of harmine ring with two different targeting group2-amino-2-deoxy-D-glucose (2DG) and Methionine (Met), respectively. Their therapeutic efficacy and toxicity were investigated both in vitro and in vivo. Results suggested that the two new harmine derivatives displayed much higher therapeutic effects than non-modified harmine. In particular, MET-Har-02 was more potent than 2DG-Har-01 with promising potential for targeted cancer therapy.
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Siwen
S
Li
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Aqin
A
Wang
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Fan
F
Gu
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Zhaohui
Z
Wang
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Caiping
C
Tian
Department of Biomedical Engineering, School of Automation, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
Zhiyu
Z
Qian
Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA.
Liping
L
Tang
Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.
Yueqing
Y
Gu
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004354:Drug Screening Assays, Antitumor; D006247:Harmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D016716:PC12 Cells; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D051381:Rats; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; C000605534:N-(9-phenylpropyl-1-methyl-beta-carboline 7-oxyacetyl)-(2-amino-2-deoxy)glucose; C000605535:N-(9-phenylpropyl-1-methyl-beta-carboline-7-oxyacetyl)methionine; D006247:Harmine
2DG; harmine; met; structural modification; tumor targeting therapy