engleski

Synthesis of β-carboline/4-aminoquinoline hybrids

Naturally occurring β-carboline alkaloids (e.g., harmine) exhibit a wide range of biological activities, including anticancer [1]. The antimalarials chloroquine (CQ) and mefloquine (MQ) belong to the class of 4-substituted quinolines. Their anticancer properties are also well documented. They inhibit autophagy, affect the Toll-like receptor 9/nuclear factor kappa B, CXCL12/CXCR4, and the p53 signaling pathways, tumor vasculature and immune system, augment TRAIL-induced apoptosis and induce G2/M phase arrest in human cancer cells [2, 3]. To this end, we applied the molecular hybridization approach to develop novel hybrids, comprising β-carboline and CQ and MQ-based 4- aminoquinoline motifs linked by a urea spacer. CQ-based ureas 7a-d and MQ-based ureas 8a-d were obtained by the 1, 1′-carbonyldiimidazole (CDI)-mediated synthesis. The starting compounds required were 4-aminoquinoline-based amines 1 and 2 and β-carboline-based amines 3-6. The preparation of amines 3-6 at the C-3, O-6, O-7, and N-9 positions of the β-carboline core was previously described by us [4, 5]. Microwave-assisted synthesis was used in the preparation of quinoline-based amines 1 and 2 from ethanediamine and 4, 7-dichloroquinoline or 4-chloro-2, 8-bis-(trifluoromethyl)-quinoline, respectively. The scheme outlines the general pathway leading to the title compounds (Figure 1). The structures of the newly prepared ureas 7a-d and 8a-d were confirmed by standard techniques (IR, 1H, 13C NMR, MS). Evaluation of their antiproliferative activity is in progress. References 1) S. Aaghaz et al., Eur. J. Med. Chem. 2021, 216, 113321. 2) C. Verbaanderd et al., eCancer 2017, 11, 781. 3) H. Monma et al., PLoS One 2018, 13, e0193990. 4) M. Marinović et al., Molecules 2020, 25, 4376. 5) M. Marinović et al., Eur. J. Med. Chem. 2021, 224, 113687.

harmine, chloroquine, mefloquine, hybrid molecules, synthesis

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