【摘要】 目的 为筛选出低毒高效的抗癌剂，本研究基于考布他汀A-4（CA-4）和ABT-751的结构合成20个二苯乙烯腈磺酰胺衍生物。方法 通过MTT法在5种肿瘤细胞和2种正常细胞中测定其抗增殖活性和细胞毒性筛选出候选化合物，进行其细胞周期及凋亡实验并研究其对血管内皮生长因子（VEGF）与基质金属蛋白酶9 （MMP-9）表达量的影响。结果 大多数化合物对5种肿瘤细胞增殖表现出良好的抑制活性。其中，化合物8h对MCF-7乳腺癌细胞表现出强抗癌活性(IC₅₀=8.7μmol·L^-1),而对正常乳腺细胞MCF-10A却表现出低毒性(IC₅₀>100μmol·L^-1),具有选择性。化合物8h可以将MCF-7的细胞周期阻滞在G₂/M期。在缺氧和常氧条件下，8h能够浓度依赖性地抑制VEGF的表达，并且其抑制作用强于同浓度下的CA-4和紫杉醇。化合物8h能够浓度依赖性地抑制MMP-9的表达，且其抑制作用强于同浓度下的CA-4和紫杉醇。结论 作为低毒强效抗乳腺癌候选物质，化合物8h具有值得进一步研究的价值。更多还原

【Abstract】 OBJECTIVE To design and synthesize a novel set of 20 stilbenenitrile sulfonamide derivatives based on combretastatin A-4（CA-4） and ABT-751 possessing high potency and low toxicity. METHODS The anti-proliferation activity and toxicity of these compounds were evaluated by MTT assay with five kinds of cancer cell lines and two normal cell lines, and the candidates were selected out. Then the cell cycle and apoptosis assays were carried out and the effect of the candidate on the expressions of VEGF and MMP-9 were evalusted. RESULTS A majority of compounds demonstrated potent anti-proliferation activity in five kinds of tumor cell lines. Particularly, the compound 8h exhibited the most potent anticancer activity in MCF-7 cancer cell line(IC₅₀=8.7 μmol·L^-1), but low toxicity on normal human breast cell MCF-10A(IC₅₀>100 μmol·L^-1), which showed a selectivity. Simultaneously, compound 8h inhibited the proliferation of MCF-7 by arresting at the G₂/M phase. In addition, the inhibition of VEGF expression of compound 8h was concentration-dependent under hypoxia and normoxia and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. Synchronously, the inhibition of MMP-9 expression of compound 8h was concentration-dependent and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. CONCLUSION Compound 8h are worthy of further study as an efficient and low-toxicity anti-breast cancer drug.更多还原