Design Synthesis And Anti-cancer Activity Study Of 8-Hydroxyquinoline Derivative Library

Copper is an essential trace element in hunman body.Recently,many studies have demonstrated the close relationship between tumorigenesis and serum copper level.Elevated copper have been detected in many kinds of cancer cells.Amounting studies have confirmed the efficacy of copper-reducing and copper-chelating agents in animal models and clinical trials.According to the results from in vitro and in vivo studies,copper chelators or copper-reducing agents alone or in combination with other therapeutic approaches such as surgery and classic chemotherapy constitute a potential strategy for cancer treatment.However,there are certain limitations of anti-copper compounds in antitumour treatment,for example,to obtain therapeutic effects,a long time drug administration is required.Thus,more work has to be done to explore the mechanisms of copper-reducing agents in cancer treatment,and more importantly,to define the effects of a long-term copper deficiency.Recently,a series of organic-copper compounds,(8-hydroxyquinoline) 8-OHQ and(5-chloro-7-iodo-8-hydroxyquinoline) CQ have been found to inhibit the chymotrypsin-like activity of the proteasome in human tumor cell culture.Varia group analyzed the crystal structure of CQ-Cu(â…¡) complex by X ray diffractometry and proved the binding of CQ-Cu(â…¡) is depended on the 8-hydroxyl and N of pyridine.Based on the previous study,we hypothesized that 8-hydroxyl of 8-OHQ and CQ is able to bind to Cu(â…¡) and has antitumor bioactivity.When 8-hydroxyl is substituted, it is unable to bind to Cu(â…¡) and loses its bioactivity.This project includes two parts.Firstly,the 8-hydroxyl of 8-OHQ and CQ is substituted by alkane.UV-Vis titration was used to study the binding constant between 8-OHQ derivatives and Cu(â…¡).In addition,the bioactivity of 8-OHQ,CQ and four derivatives for MCF10DCIS.com(DCIS) cell line was also studied.Secondly, the library of 8-OHQ derivatives was synthesized by combinatory chemistry approach and the bioactivity of these compounds was examined in MDA-MB-231 by measuring cell viability.Results:1.UV-Vis titration evidenced that 8-OHQ and CQ is able to bind to Cu(â…¡) in methanol solvent and the stoichiometry is 2:1,but the derivatives hav't the ability.2.The mixture of 8-OHQ-Cu(â…¡) and CQ-Cu(â…¡) have anti-proliferation activity on DCIS cell line but the derivatives have not this potential.3.The 8-OHQ derivatives library was screened for their anticancer activity on MDA-MB-231 cell line.There were four compounds,#11,#12,#13 and #414, were active on MDA-MB-231 cell line.They are as potent as CQ and 8-OHQ.Conclusions:1.Cu(â…¡) is able to bind to 8-hydroxyl of 8-OHQ and CQ.The complex is highly active on cancer cell lines.Four 8-OHQ derivatives are unable to bind to Cu(â…¡) in methanol solvent and are inactive on DCIS cell line.2.Cu(â…¡) has significant function on the anti-cancer activity of 8-OHQ and CQ.3.In the 8-OHQ derivatives library,compounds #11,#12,#13 and #414 are active on MDA-MB-231 cell line,suggesting that electro-donor groups are important for their anti-cancer activity.We presumed that Cu(â…¡) can bind to 8-hydroxyl of 8-OHQ and CQ,thus form an active complex to kill cancer cells.UV-vis titration was used to study the binding constant of 8-OHQ and CQ with Cu(â…¡) in methanol,which explains the relationship between the binding constant and bioactivity.For the first time,we applied combinatory chemistry to synthesize the library of 8-OHQ analogs and examined the effects of these compounds on MDA-MB-231 cell viability.The mechanism of anti-cancer activity of 8-OHQ analogs was also discussed.This study provides some significant information to understand the anti-cancer mechanisms of 8-OHQ and its analogs,and to develop novel anti-cancer copper ligand as well.