目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。
Abstract
OBJECTIVE To further discover an efficiently structural modification strategy for improving antitumor activity of fluoroquinolones.CONCLUSION Based on pharmacophore combination drug design principle, novel 3-arylidenethiazolone-fluoroquinolin-4-ones as ofloxacin derivatives(6a-6l) were designed and synthesized with a thiazolone ring as an is isostere of the C-3 carboxylic group and an arylidene fragment as a functionalized modifier, respectively. The structures of the synthesized compounds were characterized by spectral data and elemental analysis, and the in vitro antitumor activity against three tumor cell lines was measured by MTT assay.RESULTS Twelve new title compounds were synthesized, and they exhibited more potent in vitro antitumor activity than parent 1. The SAR analysis exhibited that halophenyl compounds displayed better activity than the control compounds, especially the chlorophenyl compound(6k), of which the IC50 against Capan-1 cell growth was comparable to doxorubicin.CONCLUSION A arylidenethiazolone scaffold appears to be a desirable isostere of the C-3 carboxylic acid group of fluoroquinolones for the improvement of antitumor activity.
关键词
氟喹诺酮 /
氧氟沙星 /
噻唑 /
不饱和酮 /
等排体取代 /
抗肿瘤活性
{{custom_keyword}} /
Key words
fluoroquinolone /
ofloxacoin /
thiazole /
unsaturated ketone /
isostere /
antitumor activity
{{custom_keyword}} /
中图分类号：
R965
R95
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] WANG X, SONG K, LI L,et al. Structure-based drug design strategies and challenges [J]. Curr Top Med Chem,2018, 18(12):998-1006.
[2] MARTINEZ-GUALDA B, SUN L, MARTI-MARI O, et al. Scaffold simplification strategy leads to a novel generation of dual human immunodeficiency virus and enterovirus-A71 entry inhibitors [J]. J Med Chem, 2020, 63(1): 349-361.
[3] MENDGEN T, STEUER C, KLEIN C D. Privileged scaffolds or promiscuous binders: A comparative study on rhodanines and related heterocycles in medicinal chemistry [J]. J Med Chem, 2012, 55(2): 743-753.
[4] LIU Y, HUANG Q W, LI Q Z, et al. Highly chemo-and diastereoselective construction of quaternary stereocenters through palladium-catalyzed [3 + 2] cyclization of 5-alkenyl thiazolones [J]. Org Lett,2019, 21(18):7478-7483.
[5] STUDZINSKA R, KOLODZIEJSKA R, KUPCZYK D, et al. A novel derivatives of thiazol-4(5H)-one and their activity in the inhibition of 11β-hydroxysteroid dehydrogenase type 1 [J]. Bioorg Chem, 2018, 79:115-121.
[6] BRYANT Z E, JANSER R F, JABARKHAIL M, et al. Inhibitory effects of ethacrynic acid analogues lacking the α,β-unsaturated carbonyl unit and para-acylated phenols on human cancer cells [J]. Bioorg Chem Lett, 2011, 21(3): 912-915.
[7] KOLET S P, NILOFERJAHAN S, HALDAR S, et al. Biocatalyst mediated production of 6β,11α-dihydroxy derivatives of 4-ene-3-one steroids [J]. Steroids, 2013, 78(11):1152-1158.
[8] SONG M.Progress in discovery of KIF5B-RET kinase inhibitors for the treatment of non-small-cell Llung cancer [J]. J Med Chem, 2015, 58(9): 3672-3681.
[9] JACKSON P A, WIDEN J C, HARKI D A, et al. Covalent modifiers: A chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-michael addition reactions [J]. J Med Chem, 2017, 60(3):839-885.
[10] ABDEL-AAL M A A, ABDEL-AZIZ S A, SHAYKOON M S A, et al. Towards anticancer fluoroquinolones: A review article [J]. Arch Pharm(Weinheim),2019,352(7):e1800376.doi: 10.1002/ardp.201800376.
[11] HU W,HUANG X S, WU J F, et al. Discovery of novel topoisomerase II inhibitors by medicinal chemistry approaches [J]. J Med Chem, 2018, 61(20): 8947-8980.
[12] WU S M, YAN Q Q, NI L L, et al. Synthesis and antitumor activity of fluoroquinolone C-3 fused heterocyclic thiazolo[3,2-b][1,2,4]triazole derivatives(VI) [J]. Chin Pharm J(中国药学杂志),2016, 51(5): 353-357.
[13] LI T, GAO L Z, XIE Y S, et al. Synthesis and antitumor activity fluoroquinolon-3-yloxadiazole sulfanylacetylhydrazone derivatives [J]. Chin Pharm J(中国药学杂志),2014, 49(24): 2206-2209.
[14] WANG X M, LI S P YANG T, et al. Synthesis and antitumor activity evaluation of C-3(rhodanine unsaturatedketone) amides as ofloxacin derivatives [J]. Chin Pharm J(中国药学杂志),2018, 53(3): 174-177.
[15] ZHANG C X, ZHANG H L, HUANG W L, et al. Synthesis and antitumor activity of C-3arylidene thiazolotriazone of ofloxacin derivatives [J]. Chin Pharm J(中国药学杂志),2020, 55(6): 428-431.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
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)
{{custom_fund}}
PDF(946 KB)
