Antiproliferative Activity In Cancer Cells Exerted By 8-aminomethylated Baicalein Analogues

Baicalein (5,6,7-trihydorxyflavone) is known to have a variety of attractive activities such as lipoxygenase inhibitory, antiviral, antibacterial, anti-inflammatory, hypotensive, and anticancer activities. For the reasons mentioned above, as well as its low toxicity and high efficacy, abundant resources and the advantage of low cost, baicalein has attracted more and more attention. However, the shortcomings such as its poor solubility and low bioavailability have limited its clinical application to some extents. In recent years, with profound development of the molecular mechanism of cancer, the theory of cell cycle regulation has obtained remarkable achievements, and CDK inhibitors are also being a hot topic. However, none of CDK inhibitors are in real clinical application. Thus, the design and synthesis of 8-aminomethylated baicalein analogues by Mannich reaction and assay for their CDK1/Cyclin B inhibitory activities by FRET have previously been done by State Key Laboratary of Fine Chemical of Dalian University of Technology, and nine of these compounds exhibited potent inhibitory activities against CDK1/Cyclin B.In this paper, nine BAs were screened for their antiproliferative activities in various human cancer cell lines, and three parameters of dose-response activities (GI50, TGI and LC50) were evaluated. Among these, BA-f, BA-i and BA-j, which were much more soluble in aqueous solution than the rest, showed more effective antiproliferative activities and yielded mean TGI values of 25.4±2.67,26.5±2.47,28.1±2.85μM, respectively, in Hela, SMMC-7721, SGC-7901, BGC-823, HL-60 and PC-3 cancer cell lines. In addition, G1 and G2 growth arrests and decrease of S phase cell number demonstrated that BAs not only acted as CDK1/Cyclin B inhibitors, but could also inhibit CDK2/Cyclin E and CDK9/Cyclin T1. Moreover, increased caspase-8 and caspase-3 expressions, down-regulation of Bcl-2 expression and mitochondrial membrane potential (ΔΨm), which could induce apoptosis, were found to be elements that mainly contributed to the antiproliferative activities of BA-f, i and j. However, BA-f, i and j were not inhibitory toward DNA Topoisomerase I, and could not have direct effect on DNA.In summary, the results suggested that 8-aminomethylated baicalein analogues is a novel class of CDK inhibitors which has high antiproliferative activity and could induce apoptosis, which is mediated by the mitochondrial mediated pathway and death receptor-related pathway. And because it could not inhibit DNA and DNA TopoⅠ, BAs is less toxic and may be explored as a possible novel drug with enhanced anticancer effect.