Synthesis And Antitumor Activity Of Fluoroquinolone Ryrimidine Compounds

Surgical treatment,chemotherapy,radiotherapy,hormonal therapy and traditional Chinese medicine therapy are the traditional main means of treating cancer.Chemotherapy is one of the most common and effective methods.Chemotherapy,as a systemic treatment for cancer,exerts a curative effect and at the same time damages normal cells,and the resistance of tumor cells to chemotherapy drugs often leads to chemotherapy failure.Therefore,the development of new anti-tumor drugs with targeted,low toxic side effects and Patient convenience still has a very broad prospect.Quinolone antibacterials are widely used in clinical treatment of various bacterial infections due to their advantages of good antibacterial activity,low drug resistance rate,wide distribution in the body,and broad antibacterial spectrum.The representative drugs of quinolone antibacterial drugs are ciprofloxacin and norfloxacin.Fluoroquinolone exerts antibacterial effect through DNA gyrase and DNA topoisomerase ?.Research has shown that topoisomerase is also an important target for antitumor,and there are already topoisomerase inhibitors on the market,such as camptothecin,etoposide,doxorubicin,mitoxantrone and etc.The structure-activity relationship indicates that fluoroquinolone C-3 carboxyl is known as an indispensable group for antibacterial,but not for anti-tumor activities.Therefore,the modification of C-3 position of fluoroquinones is expected to transform its antibacterial effect into antitumor effect.Targeted drug therapy has become a hot topic in anti-tumor study because of its excellent characteristics of small side effects,strong targeting,and convenience for patients.Among them,the research of small molecule targeted tyrosine kinase inhibitors(PTKIs)is the most hottest..In the structural types of small molecule targeted tyrosine kinase inhibitor compounds(quinolines,pyrimidine amines and pyrimidines,quinazolines,aromatic ureas,etc.)all have active groups aromatic amine and amino-pyrimidine structures.In this paper,33 fluoroquinoline-pyrimidine derivatives were designed by replacing fluoroquinolone C-3 carboxyl group with the dominant pharmacophore amino-pyrimidine based on the principle of pharmacophore combination.Through the combination of pharmacophores,the superposition of activities is realized,which provides a new way and reference for the construction of new structures of fluoroquinolones.In this paper,ciprofloxacin and norfloxacin,which are clinically used antibacterial drugs,are used as raw materials to react with acylating acid anhydride-acetic acid to form acetylciprofloxacin/ acetylnorfloxacin,norfloxacin and norfloxacin was reacted with amino protecting reagent BOC-a nhydride(Di-tert-butyl pyrocarbonate)to form BOC-norfloxacin.Three kinds of raw material in the solvent of DMF and carbonyl imidazole(CDI)reaction to generate acetyl ciprofloxacin / norfloxa cin / boc-norfloxacin imidazole amide,and then react with hydroxylamine hydrochloride in pyridine to generate acetylciprofloxacin / acetylnorfloxacin / BOC-norfloxacin hydroxamic acid,after Losse n rearrangement reaction fluoroquinolone-3-amine.The fluoroquinolone intermediate was substituted with 2,4-dichloropyrimidine to generate chloropyrimidine fluoroquinolone 3-position amine,and final ly it was condensed with aromatic amine to form fluoroquinolone pyrimidine derivatives,whose str uctures were confirmed by 1HNMR,LC-MS and IR.The MTT method was used to evaluate the i n vitro anti-cell proliferation activity of the 33 target compounds synthesized on human non-small cell lung cancer A549,human liver cancer cells SMMC-7721 and colon cancer cells CT-26.The r esults showed that the anti-proliferative activity of the synthesized compound against three cancer c ells was stronger than that of the raw drug ciprofloxacin and norfloxacin.In general,the compoun d has stronger antitumor effect on A549 and CT-26 than SMMC-7721(except that the IC50 of co mpound 7j on SMMC-7721 is lower than the control Product doxorubicin),A549 had the best eff ect.The IC50 of fluoroquinolone pyrimidine derivatives 7d,7f,7i,8b,8d,8e,9a,9b,9c,9f and 9j for the antitumor activity of A549 was less than 10 ?g / m L.The experimental results show th at the anti-tumor activity of electron-withdrawing substituted compounds is better than that of elect ron-donating groups,In particular,the substituents containing 3,4-dichloro and m-trifluoromethyl sho wed higher antitumor activity against A549 than other substituents,and the activity of 7d,7f,8d,9b and 9f was similar to that of the control doxorubicin.The target product of aromatic amine su bstituted pyrimidine quinolinone hydrochloride has stronger anti-proliferative effect on A549 than S MMC-7721 and CT-26,and has the worst effect on SMMC-7721.Among them,the IC50 of 9b a nd 9f to A549 is lower than that of the control Product doxorubicin.To sum up,it is beneficial to improve the anti-tumor activity of fluoroquinolone pyrimidine derivatives by constructing fluoroquinolone pyrimidine derivatives by replacing the C-3 carboxyl group of fluoroquinolone with aminopyrimidine,which also provides new ideas and directions for the research of fluoroquinolone anti-tumor aspects.