新型CombretastatinA-4類似物的设计合成与抗肿瘤药物活性.docVIP

新型Combretastatin A-4类似物的设计、合成与抗肿瘤药物活性 单媛媛1，刘红雁2，刘兆鹏1? （1山东大学药学院，山东 济南，250012；2招远市中医院，山东 招远，265400） 摘要：目的 设计、合成新型Combertastatin A-4类似物，研究其抗肿瘤活性。方法 采用环状化合物构象限制的策略，结合磺酰胺类结构片段的生物、化学特点，设计苯并磺酰胺类新型Combertastatin A-4类似物；以N-取代邻甲苯磺酰胺为原料，通过邻位金属化作用，与芳香醛偶合；在利用我们开发的、由三甲基硅氯/NaI/乙腈试剂诱导的新型环合反应，合成一系列构象限制的CA-4类似物；通过SRB（磺酰罗丹明B）显色法，研究所合成的化合物对正常乳腺（MCF12A）细胞、人乳腺癌MCF7与耐药乳腺癌NCI/ADR-RES细胞生长的影响。结果 设计、合成了7个新型的苯并磺内酰胺类化合物，其结构经核磁共振氢谱及质谱确定；部分化合物体外细胞生长抑制活性试验表明，化合物4d对人乳腺癌MCF7具有较高的选择性，而对正常乳腺细胞没有影响。结论：新型苯并磺内酰胺类CA-4类似物对人乳腺癌细胞有抑制活性和选择性，值得进一步研究。 关键词：苯并磺内酰胺，Combertastatin A-4，抗肿瘤，活性研究 Design, synthesis, and antitumor activity studies of novel combertastatin A-4 analogues Shan Yuan-yuan1, Liu Hong-yan2, Liu Zhao-peng1? (1School of Pharmaceutical Sciences, Shandong University, Ji’nan 250012; Zhaoyuan Chinese ABSTRACT: OBJECTIVE Design and synthesis of a series of novel combertastatin A-4 analogues and study their inhibitory activities towards tumor cell growth. METHODS Based on the structure-activity relationship studies of combertastatin A-4 derivatives, and combining the biological characteristics of benzenesulfonamide pharmacophore, a series of novel conformationally restricted CA-4 analogues were designed. The benzosultams were synthesized from N-arylsubstituted benzenesulfonamides via ortho-mettalation, coupling with aryl aldehedes, oxidation and cyclization mediated by our TMSCl-NaI-MeCN reagent system. The inhibition of cell growth of some of the newly synthesized benzosultams were assayed employing MCF7 cells (breast cancer cells, Pgp-), NCI/ADR-RES cells (breast cancer cells, Pgp++), and MCF12A cells (immortalized normal breast cells, Pgp-). RESULRS 7 new CA-4 analogues were synthesized and characterized by 1H-NMR and MS studies. Several compounds exhibited potent inhibitory activities towards tumor cell growth. CONCLUSIONS The novel CA-4 analogues showed an unusual profile in that it inhibited the growth of the prototypical breast cancer cell line (MCF7) more effectively than the representative n