目的 进一步优化氟喹诺酮C-3羧基等排体以期提高其抗肿瘤活性。方法 基于片段和药效团骨架迁越药物分子设计策略,用C-3羧基的等排体-芳苄叉基与氟喹诺酮骨架的4-羰基构建新的α,β-不饱和酮药效团,设计合成了C-3芳苄叉基取代氧氟沙星不饱和酮目标化合物(3a~3l)。用元素分析和光谱数据确证化合物的结构,MTT法评价体外对SMMC-7721、Capan-1和HL60 3种癌细胞株的抗增值活性。结果 合成的12个新结构不饱和酮目标化合物体外抗肿瘤活性显著强于母体氧氟沙星(1),尤其是氯苯基化合物对Capan-1的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基替代氟喹诺酮C-3羧基构建的氟喹诺酮不饱和酮化合物有利于提高其抗肿瘤活性,提示α,β-不饱和酮片段可能是有潜力的药效团结构。
Abstract
OBJECTIVE To further optimize the bioisostere of the C-3 carboxylic group for improving antitumor activity of fluoroquinolones. METHODS A fragment or pharmacophore skeleton hopping-based drug molecular design, the title fluoroquinolone unsaturated ketones (3a-3l) were designed and synthesized with an arylidene group both as an isostere of the C-3 carboxylic group and as a fragment of α,β-unsaturated ketone from ofloxacin (1). The structures of title compounds were characterized by spectral data and elemental analysis, and the in vitro antitumor activity against the three tested tumor cell lines was evaluated by a MTT assay. RESULTS Twelve new title compounds were synthesized, and exhibited more potent than parent 1, especially the chlorophenyl compound showed a comparable activity to comparison doxorubicin against Capan-1 cell lines. CONCLUSION A arylidene group as an isostere of the C-3 carboxylic acid group is beneficial to improve antitumor activity, and it further suggests that an α,β-unsaturated ketone skeleton appears to be a promising pharmacophore for further design of lead antitumor fluoroquinolone.
关键词
氟喹诺酮 /
氧氟沙星 /
不饱和酮 /
等排体取代 /
抗肿瘤活性
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Key words
fluoroquinolone /
ofloxacin /
unsaturated ketone /
isosteric substitution /
antitumor activity
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中图分类号：
R284
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参考文献
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[7] ZHANG C X, ZHANG H L, HUANG W L, et al. Synthesis and antitumor activity of C-3 arylidene thiazolotriazone of ofloxacin derivatives [J]. Chin Pharm J(中国药学杂志), 2020, 55(4): 428-431.
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脚注
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基金
国家自然科学基金项目资助(20872028, 21072045);河南省科技发展计划项目资助(162102310392)
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