Studies On Synthesis And Antitumor Activity Of Two Hydrogen Fluoroquinolone Chalcone Derivatives

1,3diphenyl-allyl ketone or α,β-unsaturated ketone is the basic framework of chalcones. Chalcone derivatives widely exist in many medicinal plants and have many kinds of pharmacological activities, they have been attracted much attention. Besides the structure modification on the changes of benzene ring, a heterocyclic ring or fused heterocyclic ring used as a replacement for the classic benzene to improve their pharmacodynamics or pharmacokinetics and to promote their druggability is being the research focus of the new chalcone compounds. Fluoroquinolone is a new antibacterial drugs, which is characterized by a common skeleton,1-substituted-6-fluoro-7-heterocyclic-quinoline-4-ketone-3-carboxylic acid, its targeting topoisomerase (TOPO) is also an important target of antitumor drugs. An attempt to transfer its antibacterial activity to antitumor activity is being the new challenge in the development of fluoroquinolones. However, many antitumor fluoroquinolones were derived from bioisosteric changes on the N-1, C-7and C-3substituent groups, resulting candidate compounds could not been reached clinical trials because of their in vivo urgent problems such as bioavailability or toxicity or stability. Therefore, it is a key to discover a new structural modification route to further promote druggability.Based on the existing structure-activity relationship of antitumor fluoroquinolones, C-3carboxyl group is not an essential pharmacophore for antitumor activity and can be replaced by a bioisostere. In this article, in order to find a new modification method on antibacterial fluoroquinolones, according to the structure characteristics and widespread antitumor activities of the chalcone compounds, a new series of fluoroquinolone chalcone-like derivatives were designed and synthesised from the C-3carboxyl group modification on antibacterial fluoroquinolones. Finally, a rational suggestion for fluoroquinolone modification was summarized according to the results of their antitumor activity for the design of new fluoroquinolone chalcone-like compounds in the future.1. The design and synthesis of target compoundsIn this article, the key intermediates, C-7diethanolamino dihydrogen fluoroquinolones were synthesized starting from commercial fluoroquinolone carboxylic acids by a nucleophilic substitution reaction and sodium borohydride reduction decarboxylation reaction, then, new title fluoroquinolone chalcone-like derivatives were obtained by Claisen-Schmidt condensation reaction of the resultant intermediates with aromatic aldehydes, respectively. The structures of target compounds were characterized by IR and1H NMR spctural data.2. The evaluation of antitumor activity in vitroThe in vitro growth inhibitory activity of the newly synthesized twenty-eight compounds against Pan Pancreatic, T24bladder, PU145prostatic, HGC27stomach and Capan pancreatic five cancer cell lines was tested by a MTT assay. The results showed that most compounds had stronger inhibitory activity against the tested cancer cells than that of parents compounds. 3. ConclusionIn this article, twenty-eihgt diethanol amino substituted fluoroquinolone chalcone-like derivatives were designed and synthesized, and their structures were confirmed by1H NMR and IR spectral data. The results of antitumor activity in vitro revealed that the title compounds had varying inhibitory effects against five tested cancer cell lines. It suggests that it is not necessary for the C-3carboxylic acid group and the C-7piperazinyl group to develop anti-tumor fluoroquinolone lead compounds, they could be replaced by methylene group and diethanolamino group, respectively.