Synthesis And Antitumor Activity Of Fluoroquinol One C-3 Methylene Rhodanine Derivatives

With the increase in morbidity and mortality,cancer has developed into a serious public health problem.The emergence of antitumor drugs on cancer treatment is of great significance,but in view of the limitations of existing antitumor drugs in the clinical,such as poor selectivity,multi-drug resistance,and so on,the demand for new antitumor drugs gradually increases.Moreover,the studies of new drugs originate from the discovery of lead compounds.Therefore,the discovery of the new antitumor lead compounds with remarkable pharmacological activity,high selectivity and novel structures has become one of the hot topics in the field of drug development.Topoisomerases have been proved to be effective targetsof antitumor drugs for cancer chemotherapy.Taking the homology and similarity of prokaryotic and eukaryotic topoisomerases into account,it was workablethat the antibacterial activity of fluoroquinolones inhibiting type II topoisomerase evolved into antiproliferative activity against tumor cells,which has also been confirmed by current studies and articles.Rhodanine,one of the five-membered multiheterocyclic rings,wasregarded as a kind of privileged scaffold.Over the past few decades,many literaturesreported that rhodanines were applied for the structural design of lead compounds.It was found that the exocycylic sulfur atom in the rhodaninesscaffold played a decisive role in the hydrogen-bonding and polar interactions with the biological targets at the binding sites.And the substituents at N position of the ring turned out to be the key to its selectivity.Moreover,the performance in the affinity and selectivity with the biological targetswas more potent if the heterocycle became aromatic,such as 5-benzylidene rhodanines,which provided the strategy for its structural modification.A number of studies on the design and development of antitumor leads have demonstrated the potential for application of rhodanines to antitumor compounds.In this paper,a series of rhodanines with different substituents on N-positionwere prepared from primary amine.Subsequently,Knoevenagel type of condensation between the rhodanines and the prepared intermediates fluoroquinolone C-3 aldehydes waskey step for the synthesis of the fluoroquinolone C-3methylene rhodanine derivatives as the target compounds.In expectation,the target compounds should contain both the fluoroquinolone nucleus and the N-substituted 5-benzylidene rhodanine scafffoldas privileged scaffolds or pharmacophore to achieve the purposes of pharmacophore splicing and the introduction of the privileged scaffold.The antitumor activity of the target compounds was evaluated by MTT assay.In this paper,30 target compounds were synthesized and their structures were confirmed by ¹H NMR,HRMS and IR.In addition,three fluoroquinolone C-3 methylene hydantoin derivatives were synthesized for comparison with the target compounds roughly.As most of target compounds exhibited significant anti-proliferation activity against Capan-1 cells,the IC₅₀values of compound 5h、6h、7g、7hwere more favorable and similar to doxorubicin.There was an exciting discovery that the activity of compounds6a and7a were at nanomolarconcentration in especial.The preliminary study of SAR showed that fluoroquinolone C-3methylene rhodanine had a positive effect on the antitumor activity of Capan-1 cells.The inhibitory effects were better when the groups on rhodanine N-3poistion weresubstituented by p-methylphenyl（5i,6h,7g）,p-methoxyphenyl（5j,6i,7h）or nothing（6a,7a）.Interesting,the target compounds 7gand 7h exhibited better inhibitory activity with their fluoroquinolone nucleus were Levofloxain,which probably on account of their good solubility.The study showed that,privilegedstructurescould be usefulfor the discovery of new antitumor fluoroquinolones as an effcient synthetic strategy.However,as the target compound 5h,6a and7a have the potential to develop a new type of antitumor lead compounds,there still need more evidence from further research.