Arene Ruthenium (Ⅱ) Diamine Complexes Containing5-fluorouracil: Synthesis And Structure-activity Relationship

The arene ruthenium (Ⅱ) diamine complexes with "three-leggedpiano-stool" structure are a kind of metal anticancer drugs with highactivity and low toxicity. Based on the regulation mechanism ofhydrophobic-hydrophilic balance in drug delivery system (DDS), a seriesof arene ruthenium (Ⅱ) diamine complexes were synthesized by thereaction of arene-ruthenium precursor ([Ru(p-cymene)Cl2]2) and diaminechelating ligands (containing5-fluorouracil, aliphatic chain, aromaticnucleus and schiff-base diamine). These complexes possess the potentialfunctions of pH-regulated release and photo-induced activation.Besides, the computational chemistry software packages (Amber,AutoDock and Gaussian) were used to reveal the relationship ofstructure-activity. Significant structure-activity relationship can besummarized as follows:(1) The DNA and TS binding affinity of thediamine chelating ligands was improved by the melioration of drug’s hydrophobisity and hydrophobisity, and the effect of adjacent ring playeda crucial role in the recognition of active sites of DNA and TS.(2) Thetwo active centers could be activated in parallel after irradiation with thelight of certain specific energies, and the arene ruthenium (Ⅱ) diaminecomplexes using nitro group as photo-sensitive receptor could beactivated by the light with lower energy.(3) The bi-target areneruthenium (Ⅱ) complexes showed remarkable recognition capabilitiesof DNA, and the secondary molecular recognition of TS was exposedafter the release of active5-fluorouracil prodrug through pH-regulated orphoto-induced activation.The novel design in this essay possesses the advantages of regulationmechanism of hydrophobic-hydrophilic balance, functions ofpH-regulated release and photo-induced activation, and the coordinatedregulation of double active centers. These studies would enrich thetheoretical contents of metal anticancer drug with different active centers,and provide further understanding of multi-targeted drug design strategy.