Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center). Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain.
Departamento de Química Orgánica I, Facultad de Farmacia and Centro de Investigación Lascaray (Lascaray Research Center). Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), Paseo de la Universidad 7, 01006, Vitoria-Gasteiz, Spain; Department of Molecular Biology and Genetics and Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, 8000, Denmark.
Eur J Med Chem. 2020 Jun 1;195:112292. doi: 10.1016/j.ejmech.2020.112292. Epub 2020 Apr 3.
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 TopI 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 MRC5 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 IC values of 3.25 ± 0.91 μM and 2.08 ± 1.89 μM 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).
研究了混合喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶和喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶-6(5H)-酮的拓扑异构酶 I 酶抑制作用。首先，通过功能化亚胺的分子内环加成[4+2]反应合成这些稠合化合物，亚胺是通过 3-氨基吡啶和不饱和醛缩合得到的，得到相应的混合 5-甲苯磺酰基六氢喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶和四氢喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶-6(5H)-酮化合物，产率良好至高产率。随后的脱氢反应得到相应的更不饱和的二氢（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶和（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶-6(5H)-酮衍生物，产率定量。新的多环产物表现出作为拓扑异构酶 I（TopI）抑制剂的优异活性，导致 TopI 诱导的质粒断裂。这与化合物作为 TopI 毒物一致，导致在 DNA 中积累被捕获的断裂复合物。还对 A549、SKOV3 细胞系和非癌细胞系 MRC5 进行了细胞毒性筛选。四氢喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶-6(5H)-酮 9 是最具细胞毒性的化合物，对 A549 细胞系和 SKOV3 细胞系的 IC 值分别为 3.25±0.91 μM 和 2.08±1.89 μM。此外，六氢喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶 8a 和二氢喹啉并[4,3-b]（Siegel 等人，2013；Antony 等人，2003）[1,5]萘啶 10a 对这些细胞系也表现出良好的细胞毒性。这些化合物对非恶性肺成纤维细胞（MRC-5）均无细胞毒性作用。
