Thionated aminofluorophthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells.
Thionated aminofluorophthalimides reduce classical markers of cellular inflammation in LPS-challenged RAW 264.7 cells.
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DOI：
10.1016/j.bmcl.2022.128972
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发表时间：
2022-11-15
影响因子：
2.7
通讯作者：
Greig, Nigel H.
中科院分区：
文献类型：
--
作者：
Scerba, Michael T.;Tweedie, David;Lecca, Daniela;Siegler, Maxime A.;Rais, Rana;Greig, Nigel H.
在此，我们提出了几种氟化泊马度胺衍生物和它们的硫代对应物的合成，随后对经典的细胞炎症标志物进行生物学评价。在LPS激发的细胞中处理引起分泌的TNF-α和亚硝酸盐水平相对于基础量不同程度的降低。虽然芳烃取代和硫代酰胺化对TNF-α的产生有轻微和零星的影响，但特定的7位取代结合随后羰基硫代的增加产生了化合物11、14和15，这些化合物表现出相应的和逐步增强的抗亚硝酸盐活性，同时具有最小的细胞毒性。在这方面，化合物15显示出大约96%的细胞活力，当供应给用60 ng/mL LPS攻击的RAW细胞时，亚硝酸盐产生下降65%。当直接比较氟化异构体的集中家族时，类似的5-氟化异构体17在用70 ng/mL LPS攻击的RAW细胞中显示出与15相当的最小毒性，但显著低于15的抗亚硝酸盐活性。随后在人肝微粒体中筛选化合物15用于初步的1期分析，其中其相对于其非氟化对应物3，6 ′-二硫代泊马度胺4显示出提高的稳定性，这一结果与在敏感的泊马度胺7-位上由NH 4提供的预期代谢耐力一致。
Herein, we present the synthesis of several fluorinated pomalidomide derivatives and their thionated counterparts with subsequent biological evaluation against classical markers of cellular inflammation. Treatment in LPS-challenged cells effected varying reductions in levels of secreted TNF-α and nitrite relative to basal amounts. While arene fluorination and thioamidation had marginal and sporadic effects on TNF-α production, specific 7-position fluorination combined with subsequent increases in carbonyl thionation produced compounds 11, 14, and 15 which demonstrated corresponding and escalating anti-nitrite activities concurrent with minimal cellular toxicity. In this regard, compound 15 displayed roughly 96 % cell viability combined with a 65 % drop in nitrite production when supplied to RAW cells challenged with 60 ng/mL LPS. When a focused family of fluorinated isomers were directly compared, the analogous 5-fluorinated isomer 17 displayed comparable minimal toxicity but markedly less anti-nitrite activity versus 15 in RAW cells challenged with 70 ng/mL LPS. Compound 15 was subsequently screened in human liver microsomes for preliminary Phase 1 analysis where it demonstrated heightened stability relative to its non-fluorinated counterpart 3,6′-dithiopomalidomide 4, a result in line with the expected metabolic fortitude provided by fluorination at the sensitive pomalidomide 7-position.
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影响因子：
5.6
作者：
Batsaikhan, Buyandelger;Wang, Jing-Ya;Wang, Jia-Yi
通讯作者：
Wang, Jia-Yi
DOI：
10.2174/1871529x18666180522073855
发表时间：
2019-01-01
影响因子：
--
作者：
Fuchs, Ota
通讯作者：
Fuchs, Ota
影响因子：
8.6
作者：
Boi, Laura;Pisanu, Augusta;Carta, Anna R.
通讯作者：
Carta, Anna R.
影响因子：
1.8
作者：
Hurth, Konstanze;Jacquier, Sebastien;Wilcken, Rainer
通讯作者：
Wilcken, Rainer
DOI：
10.1002/bdrc.21096
发表时间：
2015-06
期刊：
Birth defects research. Part C, Embryo today : reviews
影响因子：
--
作者：
Vargesson N
通讯作者：
Vargesson N