药学学报, 2015, 50(8): 1008-1012
引用本文:
高留州, 谢玉锁, 闫强, 吴淑敏, 倪礼礼, 赵辉, 黄文龙, 胡国强. 氟喹诺酮(绕丹宁不饱和酮)酰胺衍生物的合成与抗肿瘤活性[J]. 药学学报, 2015, 50(8): 1008-1012.
GAO Liu-zhou, XIE Yu-suo, YAN Qiang, WU Shu-min, NI Li-li, ZHAO Hui, HUANG Wen-long, HU Guo-qiang. Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives[J]. Acta Pharmaceutica Sinica, 2015, 50(8): 1008-1012.

氟喹诺酮(绕丹宁不饱和酮)酰胺衍生物的合成与抗肿瘤活性
高留州1, 谢玉锁1, 闫强1, 吴淑敏1, 倪礼礼1, 赵辉1, 黄文龙2, 胡国强1
1. 河南大学化学生物学研究所, 河南 开封 475001;
2. 中国药科大学新药研究中心, 江苏 南京 210009
摘要:
为发现新型抗肿瘤绕丹宁不饱和酮衍生物, 以氟喹诺酮酰胺骨架作为载体, 设计合成了氟喹诺酮 (绕丹宁α, β-不饱和酮) 酰胺类目标化合物5a~5r, 其结构经元素分析、1H NMR、MS确证。采用MTT法评价了目标化合物对人肝癌Hep-3B细胞、人Capan-1胰腺癌细胞及人HL60白血病细胞的体外增值抑制活性。结果表明, 18个目标化合物对3种实验癌细胞的抗增殖活性均显著高于母体环丙沙星1的活性, 其中对Capan-1细胞的活性最强, 尤其是芳杂环或苯环带有吸电子羧基及磺酰氨基类化合物的活性与对照抗肿瘤药物阿霉素相当。为此, 氟喹诺酮 (绕丹宁不饱和酮) 酰胺衍生物是一类有发展前景的抗肿瘤活性先导物。
关键词:    氟喹诺酮C-3酰胺      绕丹宁      不饱和酮      抗细胞增殖活性     
Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives
GAO Liu-zhou1, XIE Yu-suo1, YAN Qiang1, WU Shu-min1, NI Li-li1, ZHAO Hui1, HUANG Wen-long2, HU Guo-qiang1
1. Institute of Chemistry and Biology, Henan University, Kaifeng 475001, China;
2. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Abstract:
To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, β-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, β-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.
Key words:    fluoroquinolon-3-yl amide    rhodanine    unsaturated ketone    anti-cell proliferation activity   
收稿日期: 2015-03-26
基金项目: 国家自然科学基金资助项目 (20872028, 21072045); 河南省高等学校重点科研项目基金资助项目 (15A350004).
通讯作者: 赵辉, 胡国强
Email: hdyxzhh@163.com;hgqxy@sina.com.cn
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参考文献:
[1] Erlanson DA, McDowell RS, O'Brien T. Fragment-based drug discovery [J]. J Med Chem, 2004, 47: 3463-3482.
[2] Devine SM, Mulcair MD, Debono CO. Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold [J]. J Med Chem, 2015, 58: 1205-1214.
[3] Tomašić T, Šink R, Zidar N, et al. Dual inhibitor of MurD and MurE ligases from Escherichia coli and Staphylococcus aureus [J]. ACS Med Chem Lett, 2012, 3: 626-630.
[4] Li HQ, Yang J, Ma S, et al. Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein [J]. Bioorg Med Chem, 2012, 20: 4194-4200.
[5] Li W, Zheng CJ, Sun LP, et al. Novel arylhydrazone derivatives bearing a rhodanine moiety: synthesis and evaluation of their antibacterial activities [J]. Arch Pharm Res, 2014, 37: 852-861.
[6] Zhang YQ, Wang SZ, Wu SC, et al. Facile construction of structurally diverse thiazolidinedione-derived compounds via divergent stereoselective cascade organocatalysis and their biological exploratory studies [J]. ACS Comb Sci, 2013, 15: 298-308.
[7] Sirivolu VR, Vernekar SKV, Marchand C, et al. 5-Arylidenethioxothiazolidinones as inhibitors of tyrosyl-DNA phosphodiesterase I [J]. J Med Chem, 2012, 55: 8671-8684.
[8] Mendgen T, Steuer C, Klein CD. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry [J]. J Med Chem, 2012, 55: 743-753.
[9] Nitsche C, Schreier VN, Behnam MAM, et al. Thiazolidinone-peptide hybrids as dengue virus protease inhibitors with antiviral activity in cell culture [J]. J Med Chem, 2013, 56: 8389-8403.
[10] Behnam MAM, Nitsche C, Vechi SM. C-Terminal residue optimization and fragment merging: discovery of a potent peptide-hybrid inhibitor of dengue protease [J]. ACS Med Chem Lett, 2014, 5: 1037-1042.
[11] Gao LZ, Xie YS, Li T, et al. Synthesis, antitumor activity and SAR of C-3 oxadiazole sulfanyl-acetylhydrazone-substituted fluoroquinolone analogues [J]. Acta Pharm Sin (药学学报), 2014, 49: 1964-1968.
[12] Li T, Gao LZ, Xie YS, et al. Synthesis and anti-proliferative activity of fluoroquinolone C-3 fused heterocyclic α, β-un­saturated ketones derived from ciprofloxacin [J]. Acta Pharm Sin (药学学报), 2015, 50: 569-573.
[13] Hu GQ, Hou LL, Wang GQ, et al. Part IV: Design, synthesis and antitumor activity of fluoroquinolone C-3 heterocycles: bis-oxadiazole methylsulfide derivatives derived from cipro-floxacin [J]. Acta Pharm Sin (药学学报), 2012, 47: 1017- 1022.
[14] Brown FC, Bradsher CK, Morgan EC, et al. Some 3-substi­tuted rhodanines [J]. J Am Chem Soc, 1956, 78: 384-388.