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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives
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Synthesis of novel hybrid quinolino[4,3-b][1,5]naphthyridines and quinolino[4,3-b][1,5]naphthyridin-6(5H)-one derivatives and biological evaluation as topoisomerase I inhibitors and antiproliferatives

机译：新型杂交喹啉的合成[4,3-B] [1,5]萘啶和喹啉[4,3-B] [1,5]萘啶-6（5h） - 衍生物和生物学评价作为拓扑异构酶I抑制剂和抗原剂

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The topoisomerase I enzymatic inhibition of hybrid quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridines and quinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-ones was investigated. First, the synthesis of these fused compounds was performed by intramolecular [4 + 2]-cycloaddition reaction of functionalized aldimines obtained by the condensation of 3-aminopyridine and unsaturated aldehydes affording corresponding hybrid 5-tosylhexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one compounds with good to high general yields. Subsequent dehydrogenation led to the corresponding more unsaturated dihydro (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine and (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one derivatives in quantitative yields. The new polycyclic products show excellent-good activity as topoisomerase I (TopI) inhibitors that lead to Topl induced nicking of plasmids. This is consistent with the compounds acting as TopI poisons resulting in the accumulation of trapped cleavage complexes in the DNA. The cytotoxic effect on cell lines A549, SKOV3 and on non-cancerous MRCS was also screened. Tetrahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridin-6(5H)-one 9 resulted the most cytotoxic compound with IC50 values of 3.25 +/- 0.91 mu M and 2.08 +/- 1.89 mu M against the A549 cell line and the SKOV3 cell line, respectively. Also, hexahydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 8a and dihydroquinolino [4,3-b] (Siegel et al., 2013; Antony et al., 2003) [1,5]naphthyridine 10a showed good cytotoxicity against these cell lines. None of the compounds presented cytotoxic effects against non-malignant pulmonary fibroblasts (MRC-5). (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：杂交喹啉的拓扑异构酶I酶促抑制[4,3-b]（Siegel等，2013; Antony等，2003）[1,5]萘啶和喹啉[4,3-B]（Siegel等人。 ，2013; Antony等，2003）[1,5]萘啶-6（5H）进行了研究。首先，通过通过3-氨基吡啶和不饱和醛的缩合获得的官能化醛胺的分子内[4 + 2] -cycloaddition反应进行这些熔融化合物的合成，得到相应的杂交5-甲硅烷基甲基氧基喹啉啉基[4,3-B]（Siegel等Al。，2013; Antony等，2003）[1,5]萘吡啶和四氢喹诺啉基[4,3-B]（Siegel等，2013; Antony等，2003）[1,5]萘啶蛋白-6 （5H） - 良好至高一般收益率的化合物。随后的脱氢导致相应的更不饱和的二氢（Siegel等，2013; Antony等，2003）[1,5]萘萘啶和（Siegel等，2013; Antony等，2003）[1,5萘啶蛋白-6（5h） - 衍生物的定量产率。新的多环产品显示出优异的活性，作为拓扑异构酶I（TOPI）抑制剂，导致压制质粒的TOPL诱导的质粒。这与作为TOPI POISONS的化合物一致，导致DNA中被捕获的裂解复合物的积累。还筛选了对细胞系A549，SKOV3和非癌MRC的细胞毒性作用。四氢喹啉基[4,3-B]（Siegel等，2013; Antony等，2003）[1,5]萘啶-6（5h） - 9.导致最多的细胞毒性化合物与IC50值为3.25 +/-对抗A549细胞系和Skov3细胞系0.91μm和2.08 +/- 1.89 mu m。此外，六羟基喹啉[4,3-b]（Siegel等，2013; Antony等，2003）[1,5]萘吡啶8a和dihydroquinolino [4,3-b]（Siegel等，2013; Antony等人，2003）[1,5]萘葡萄酮10A针对这些细胞系显示出良好的细胞毒性。没有一种化合物呈现对非恶性肺成纤维细胞（MRC-5）的细胞毒性作用。 （c）2020 Elsevier Masson SAS。版权所有。

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