Preparation And Biological Evaluation Of Zoledronic Acid Derivatives Dinuclear Platinum Complexes

Among the family of antitumour drugs, platinum complexes are widely utilized due tothe advantage of excellent anticancer property and broad spectrum of effect in tumour. But anawful lot of side effects limit their clinical application to a large extent. Targeted medicinerenders the problem a solution. Then to avoid side effects, bisphosphonate was put forward.Bisphosphonate had good adsorption performance towads hydroxy apatite which was themajor component of bone. The third generation representative is zoledronic acid which ischaracteristic of highest bone affinity. Moreover, clinical research has discovered thatzoledronic acid had direct antitumour activity. One commom sense is that drug should begiven where drug is due. Objective ahead is to seek drugs that can make a distinction betweennormal and abnormal tissues. On the basis of our former research, combination of the twoelements is really encouraging in searching for optimized antitumour drugs that exhibitanticancer ability with excellent bone affinity. Incorporation of the bisphosphonicfunctionality with the platinum moiety could promote the specific accumulation of theantitumour drug in the bone with consequent improvement of the biological effect andreduction of the systemic toxicity. This may lead to comprehensive pharmaceutical effect withlow side effects.In the presence of TBAB, the reaction of imidazole derivatives with ethyl bromoacetatein alkaline circumstances yielded the corresponding ester. And then, the product hydrolyzed tocorresponding acetic acid under acidic condition. Finally, phosphorus trichloride was added tothe carboxylic acid mixed with phosphoric acid. After hydrolysis, the ultimate product MIDPand EIDP was obtained. MIDP or EIDP and Ba(OH)2was dissolved in water separately. Andthen the mixture of both compouds was kept stirring.[Pt(en)(H2O)(OSO3)] was added to thewhite suspension. After stirring overnight, the suspension was centrifuged and the liquidsupernatant was filtrated. Finally, the filtrate was freeze-dried to afford white solid ultimateproduct {[Pt(en)]2MIDP} and {[Pt(en)]2EIDP}. The purity was confirmed by method ofHPLC. Characterization of the complexes was achieved by melting point, IR spectroscopy,elemental analysis, electrospray ionization mass spectrometry (ESI-MS),1H-NMR and13C-NMR.In five human derived cell lines (U2OS, HepG2, A549, MDA-MB-231and HCT-116),MTT assay confirmed the platinum complexes have antitumour activities to varying degrees.The cell viability for the five kinds of malignant tumor cell decreased with the increasingconcentration of complexes. Another obvious fact is that cell viability also decreaseddramatically as time went on. The two complexes against HepG2was the most effective withthe minimum IC50value at48and72h.{[Pt(en)]2MIDP} was55.0μM and32.8μM, and {[Pt(en)]2EIDP} was92.7μM and53.8μM. Cell apoptosis was observed by Hoechst33342/PInuclear staining and photographing. With regard to hepatotoxicity, the two newly syntheticdinuclear platinum drugs showed more favourable property than cisplatin.DNA binding study by circular dichorism preliminarily manifested the platinumcomplexes may function with DNA through the mode of intercalation. This gave rise toblocking of cell proliferation. The varying degrees of intercalation account for the reason whyfive human cell lines showed different antitumour activity.Basically speaking, the platinum complexes bearing representative bisphosphonatemoiety were designed to possess the ability of targeting. And the adsorption and desorptionexperiment towards HA ascertained the targeting properties of the drugs. In adsorptionequilibrium condition, adsorption rate of {[Pt(en)]2MIDP} and {[Pt(en)]2EIDP} was82.4%and77.3%, respectively. Adsorption amount was164μmol/g and154μmol/g. In desorptionaspect, desorption rate for {[Pt(en)]2MIDP} only reached around15.9%, and for{[Pt(en)]2EIDP} was22.2%. Corresponding concentration was127.9μmol/L and171.7μmol/L.The thin solution might be as the result of complex nice affinity with hydroxy apatite.Moreover, with assay towards hydroxy apatite, adsorption and desorption nature of the twodinuclear platinum complexes were also obtained for further study.