Limits...
Novel harmine derivatives for tumor targeted therapy.

Li S, Wang A, Gu F, Wang Z, Tian C, Qian Z, Tang L, Gu Y - Oncotarget (2015)

Bottom Line: 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.Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.

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.

No MeSH data available.


Related in: MedlinePlus

A. synthetic scheme of harmine derivatives 2DG-Har-01 and MET-Har-02. B. and C. Mass spectrums of 2DG-Har-01 (B) and MET-Har-02 (C) D. and E.1H-NMR spectrums of 2DG-Har-01 (D) and MET-Har-02 (E).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496197&req=5

Figure 1: A. synthetic scheme of harmine derivatives 2DG-Har-01 and MET-Har-02. B. and C. Mass spectrums of 2DG-Har-01 (B) and MET-Har-02 (C) D. and E.1H-NMR spectrums of 2DG-Har-01 (D) and MET-Har-02 (E).

Mentions: 2DG-Har-01 and MET-Har-02 were synthesized by following the series of steps as depicted (Fig. 1A). The N9-alkylated harmine derivative 2 was prepared according to the synthetic protocol described before [33]. The preparation of compounds 3 followed a common synthetic scheme [34], characterized by demethylation of compounds 2 using acetic acid and hydrobomic acid as reaction solvent. To modify the molecules with 2DG and Met, a key intermediate, the alky halide, was designed. Compound 4 was obtained by O-alkylation of compound 3 in the presence of cesium carbonate with the ethyl bromoacetate. Then, hydrolyzation of compound 4 lead to the production of –COOH-functionalized compound 5. Finally, 2DG-Har-01 and compound 6 were synthesized with the conjunction of 2DG and Met, respectively. MET-Har-02 is the N2-benzylated product of compound 6. The successful synthesis of 2DG-Har-01 and MET-Har-02 were evidenced by MS (Fig.1B, 1C) and 1H NMR (Fig. 1D, 1E). The molecular weights of 2DG-Har-01 and MET-Har-02 are 536 and 596, respectively (Fig. 1B, 1C).


Novel harmine derivatives for tumor targeted therapy.

Li S, Wang A, Gu F, Wang Z, Tian C, Qian Z, Tang L, Gu Y - Oncotarget (2015)

A. synthetic scheme of harmine derivatives 2DG-Har-01 and MET-Har-02. B. and C. Mass spectrums of 2DG-Har-01 (B) and MET-Har-02 (C) D. and E.1H-NMR spectrums of 2DG-Har-01 (D) and MET-Har-02 (E).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496197&req=5

Figure 1: A. synthetic scheme of harmine derivatives 2DG-Har-01 and MET-Har-02. B. and C. Mass spectrums of 2DG-Har-01 (B) and MET-Har-02 (C) D. and E.1H-NMR spectrums of 2DG-Har-01 (D) and MET-Har-02 (E).
Mentions: 2DG-Har-01 and MET-Har-02 were synthesized by following the series of steps as depicted (Fig. 1A). The N9-alkylated harmine derivative 2 was prepared according to the synthetic protocol described before [33]. The preparation of compounds 3 followed a common synthetic scheme [34], characterized by demethylation of compounds 2 using acetic acid and hydrobomic acid as reaction solvent. To modify the molecules with 2DG and Met, a key intermediate, the alky halide, was designed. Compound 4 was obtained by O-alkylation of compound 3 in the presence of cesium carbonate with the ethyl bromoacetate. Then, hydrolyzation of compound 4 lead to the production of –COOH-functionalized compound 5. Finally, 2DG-Har-01 and compound 6 were synthesized with the conjunction of 2DG and Met, respectively. MET-Har-02 is the N2-benzylated product of compound 6. The successful synthesis of 2DG-Har-01 and MET-Har-02 were evidenced by MS (Fig.1B, 1C) and 1H NMR (Fig. 1D, 1E). The molecular weights of 2DG-Har-01 and MET-Har-02 are 536 and 596, respectively (Fig. 1B, 1C).

Bottom Line: 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.Results suggested that the two newharmine derivatives displayed much higher therapeutic effects than non-modified harmine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Arlington, TX, USA.

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.

No MeSH data available.


Related in: MedlinePlus