Abstract
A series of 1,2-, 1,4-disubstituted or 1,2,4-trisubstituted anthraquinone-based compounds was designed, synthesized, characterized and biologically evaluated for anticancer efficacy. 2- or 4-arylated 1-hydroxy-9,10-antraquinones (anthracene-9,10-diones) were prepared by Suzuki–Miyaura cross-coupling reaction of 1-hydroxy-2-bromoanthraquinone, 1-hydroxy-4-iodoanthraquinone or 1-hydroxy-2,4-dibromoanthraquinone with arylboronic acids. The cross-coupling reaction of 2,4-dibromo-9,10-anthraquinone with arylboronic acids provide a convenient approach to 2,4-bis arylated 1-hydroxyanthraquinones with a variety of aryl substituent in the 2 and 4 position. The cytotoxicity of new anthraquinone derivatives was evaluated using the conventional MTT assays. The data revealed that six of the aryl substituted compounds among the entire series 3, 15, 16, 25, 27, 28 were comparable potent with the commercially available reference drug doxorubicin on the human glioblastoma cells SNB-19, prostate cancer DU-145 or breast cancer cells MDA-MB-231 and were relatively safe towards human telomerase (h-TERT)immortalized lung fibroblasts cells. The results suggested that the in vitro antitumor activity of synthesized 2-aryl, 4-aryl- and 2,4-diaryl substituted 1-hydroxyanthraquinones depends on the nature of the substituent within the cyclic backbone. Docking interaction of 2-, 4-substituted and 2,4-disubstituted 1-hydroxyanthraquinones indicates intercalative mode of binding of compounds with DNA topoisomerase. The interaction with the DNA of 4-aryl-13, 15, 16 and 4-(furan-3-yl)-23 1-hydroxyanthraquinones was experimentally confirmed through a change in electroforetic mobility. Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines.
Highlights
The anthraquinone, a polycyclic aromatic core, is an important structural motif in a large number of organic molecules, is prevalent in nature
Further experiments with 1-hydroxy-4-phenyl-anthraquinone 13 demonstrated that the compound induced cell cycle arrest at sub-G1 phase in DU-145 cells in the concentration 1.1 μM, which is probably achieved by inducing apoptosis. 4-Arylsubstituted 1-hydroxyanthraquinones 13 and 16 induced the enhancement of DNA synthesis on SNB19 cell lines
Taking into account the interest to substituted 4-arylanthraquinones as anticancer agents [4,6,7], we evaluated the cytotoxicity of the synthesized compounds toward a panel of cancer cell lines in vitro and obtained some data about the potential mechanism of action of the new compounds
Summary
The anthraquinone (anthracene-9,10-dione), a polycyclic aromatic core, is an important structural motif in a large number of organic molecules, is prevalent in nature. The most successfully developed method of functionalization of the anthraquinone core represent the Pd-catalyzed C-C cross-coupling reaction of 9,10-anthraquinones bearing suitable leaving groups, including anthraquinoyl triflates and bistriflates [29,30,31,32,33], halides [34,35] or boronic acid pinacol ester of 9,10-anthraquinone [36,37] These processes enable the synthesis of site-specific organic materials for photonics and electronics [28,38,39,40] as well as biological active compounds [5,14,32,34]. The hydroxy substituent in the anthraquinones will be necessary for further improve the low druggability of the anthraquinone core
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