抗肿瘤氟喹诺酮C-3(稠)杂环化合物双噁二唑甲硫醚及其碘甲烷盐衍生物的合成(Ⅰ)  

Synthesis of Fluoroquinolone C-3 Heterocycles,Bis-oxadiazole Methylsulfides and Methiodides,and their Antitumor Activity

作　　者：胡国强[1] 陈寅生[1] 王国强[1] 段楠楠[1] 温晓漪[1] 曹铁耀[1] 银俊[1] 王伟[1] 谢松强[1] 黄文龙[2] 

机构地区：[1]河南大学化学生物学研究所,河南开封475004 [2]中国药科大学,南京210009

出　　处：《中国药学杂志》2012年第1期72-76,共5页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(20872028,21072045);河南大学科研基金资助

摘　　要：目的寻找由抗菌氟喹诺酮向抗肿瘤氟喹诺酮转化的有效结构修饰途径。方法以抗菌氟喹诺酮药物氧氟沙星1为原料,其相应的酰肼2与二硫化碳缩环合得C-3噁二唑硫醇3中间体,然后分别与5-取代苯基-2-氯甲基-1,3,4-噁二唑4a～4g缩合得含氟喹诺酮骨架的双噁二双唑甲硫醚5a～5g,接着用碘甲烷进行季铵化反应得相应的季铵盐6a～6g。用MTT方法评价了目标化合物5a～5g和6a～6g体外对肿瘤细胞的生长抑制活性。结果合成了14个新的目标化合物,体外均显示潜在的抗癌活性(IC50<25μmol.L-1),其中季铵盐6a～6g的活性高于相应游离碱5a～5g的活性。结论基于抗菌氟喹诺酮C-3杂环的抗肿瘤氟喹诺酮的设计值得进一步研究。OBJECTIVE To explore an efficient structure modification route to transform antibacterial fluoroquinolones to antitumot ones. METHODS Compound A [1,3, 4 ] oxadiazol-5-thiol 3 derived from ofloxacin 1 was subjected to nucleophilic substitution with each of chloromethyl-1,3,4-oxadiazoles 4a-4g gave di-oxadiazolyl methylsulfides 5a- 5g, followed by a quaternization to form the corresponding methiodides 6a -6g, respectively. The in vitro arltitumor activity of the title compounds 5a -5g and 6a -6g against three cancer cell lines was evaluated by MTT method. RESULTS Fourteen title compunds were synthesized and the structures were characterized by corresponding spectral data. The bioactive assay showed that compounds 5a -5g and 6a -6g exhibited a potential an- tieancer activity （IC50 〈 25 μmol·L^-1）. The activity of the quaternary ammoniums 6a -6g was higher than that of the corresponding free bases 5a -5g. CONCLUSION The design and synthesis of antitumor fluoroquinolone based on antibacterial fluoroquinolonc C- 3 heterocycle are worthy of further study.

关 键 词：抗肿瘤氟喹诺酮 双噁二唑 甲硫醚 碘甲烷盐 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]