Novel harmine derivatives for tumor targeted therapy

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// Siwen Li 1, * , Aqin Wang 1, * , Fan Gu 1 , Zhaohui Wang 1 , Caiping Tian 1 , Zhiyu Qian 2 , Liping Tang 3 , Yueqing Gu 1 1 Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA 2 Department of Biomedical Engineering, School of Automation, Nanjing University of Aeronautics and Astronautics, Nanjing, China 3 Department of Bioengineering, University of Texas at Arlington, Arlington, TX, USA * These authors have contributed equally to this work Correspondence to: Yueqing Gu, e-mail: guyueqingsubmission@hotmail.com Keywords: harmine, structural modification, 2DG, met, tumor targeting therapy Received: November 26, 2014 Accepted: April 10, 2015 Published: April 22, 2015 ABSTRACT 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 newharmine 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.