Novel harmine derivatives for tumor targeted therapy

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.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…To improve the therapeutic efficacy of 59, several derivatives were synthesized by modification of substituents in positions 2, 7, and 9 of harmine (59) ring and with other two different groups-2-amino-2-deoxy-D-glucose and methionine-two derivatives were obtained, 2DG-Har-01 (60) and MET-Har-02 (61), respectively. This study found that substitution at position 7 reduced natural toxicity and increased tumor cell uptake ability, at position 9 enhanced cytotoxicity, and at position 2 enhanced the antiproliferative effect [132], and also showed that substituents at position 1 could be crucial to antitumor potency [136]. SAR studies confirmed that substituents in position 2 and 9 displayed an important role in modulation of antitumor activities [134].…”

“…This study found that substitution at position 7 reduced natural toxicity and increased tumor cell uptake ability, at position 9 enhanced cytotoxicity, and at position 2 enhanced the antiproliferative effect [132], and also showed that substituents at position 1 could be crucial to antitumor potency [136]. SAR studies confirmed that substituents in position 2 and 9 displayed an important role in modulation of antitumor activities [134].…”

“…Harmine (59) is a β-carboline alkaloid found in plants, mammalians, insects, and marine organisms [130], e.g., the marine brown alga Melanothamnus afaqhusainii [131,132]. The plant extracts containing 59 were traditionally used to treat alimentary tract cancer and malaria in Northwest China [133].…”

“…Studies on the biological function of 59 reported this alkaloid as a potent antiproliferative and cytotoxic agent, with MDR reversal activity by inhibiting BCRP in a BCRP overexpressing breast cancer cell line (MDA-MB-123) and by reducing the resistance of mitoxantrone and camptothecin mediated by BCRP, but did not inhibit MDR-1 overexpressing cells growth [135]. More detailed studies of 59 revealed that this compound failed clinical in applications due to its low pharmacological effects and neurotoxicity [132,134]. To improve the therapeutic efficacy of 59, several derivatives were synthesized by modification of substituents in positions 2, 7, and 9 of harmine (59) ring and with other two different groups-2-amino-2-deoxy-D-glucose and methionine-two derivatives were obtained, 2DG-Har-01 (60) and MET-Har-02 Compound 57 was synthesized by two different approaches-Gang's and Rawal's.…”

“…To the best of our knowledge, there is no report on the total synthesis of 59. Most of the harmine analogs were synthesized from the harmine scaffold using the Friedel-Crafts reaction, molecular modifications, and N-oxidation [132,[140][141][142].…”