Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia.
Division of Physical Chemistry, "Ruđer Bošković" Institute, Bijenička Cesta 54, P.O. Box 1016, HR-10000 Zagreb, Croatia; Division of Physical Chemistry, Faculty of Natural Sciences, University of Zagreb, Horvatovac 102A, HR-10000 Zagreb, Croatia.
Eur J Med Chem. 2014 Jan;71:267-81. doi: 10.1016/j.ejmech.2013.11.010. Epub 2013 Nov 15.
A series of new anilides (2a-c, 4-7, 17a-c, 18) and quinolones (3a-b, 8a-b, 9a-b, 10-15, 19) with nitrogen-bearing substituents from benzo[b]thiophene and thieno[2,3-c]thiophene series are prepared. Benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones (3a-b, 8a-b) are synthesized by the reaction of photochemical dehydrohalogenation from corresponding anilides. Anilides and quinolones were tested for the antiproliferative activity. Fused quinolones bearing protonated aminium group, quaternary ammonium group, N-methylated and protonated aminium group, amino and protonated amino group (8a, 9b, 10-12) showed very prominent anticancer activity, whereby the hydrochloride salt of N',N'-dimethylaminopropyl-substituted quinolone (14) was the most active one, having the IC50 concentration at submicromolar range in accordance with previous QSAR predictions. On the other hand, flexible anilides were among the less active. Chemometric analysis of investigated compounds was performed. 3D-derived QSAR analysis identified solubility, metabolitic stability and the possibility of the compound to be ionized at pH 4-8 as molecular properties that are positively correlated with anticancer activity of investigated compounds, while molecular flexibility, polarizability and sum of hydrophobic surface areas were found to be negatively correlated. Anilides 2a-b, 4-7 and quinolones 3a-b, 8a-b, 9b and 10-14 were evaluated for DNA binding propensities and topoisomerases I/II inhibition as part of their mechanism of action. Among the anilides, only compound 7 presented some DNA binding propensity whereas the quinolones 8b, 9b and 10-14 intercalate in the DNA base pairs, compounds 8b, 9b and 14 being the most efficient ones. The strongest DNA intercalators, compounds 8b, 9b and 14, were clearly distinguished from the other compounds according to their molecular descriptors by the PCA and PLS analysis.
一系列含有氮取代基的苯并[b]噻吩和噻吩[2,3-c]噻吩系列的新的酰苯胺（2a-c、4-7、17a-c、18）和喹诺酮（3a-b、8a-b、9a-b、10-15、19）被制备。苯并[b]噻吩[2,3-c]和噻吩[3',2':4,5]噻吩[2,3-c]喹诺酮（3a-b、8a-b）是通过相应的酰苯胺的光化学脱卤化反应合成的。酰苯胺和喹诺酮被测试了其抗增殖活性。带有质子化铵基团、季铵基团、N-甲基化和质子化铵基团、氨基和质子化氨基的稠合喹诺酮（8a、9b、10-12）表现出非常显著的抗癌活性，其中 N',N'-二甲基氨基丙基取代的喹诺酮盐酸盐（14）是最活跃的，其 IC50 浓度在亚微摩尔范围内，符合之前的 QSAR 预测。另一方面，柔性酰苯胺的活性较低。对所研究的化合物进行了化学计量学分析。3D 衍生的 QSAR 分析确定了溶解度、代谢稳定性以及化合物在 pH 4-8 下可电离的可能性，这些分子特性与所研究化合物的抗癌活性呈正相关，而分子柔性、极化率和疏水性表面积总和与抗癌活性呈负相关。酰苯胺 2a-b、4-7 和喹诺酮 3a-b、8a-b、9b 和 10-14 被评估了 DNA 结合倾向和拓扑异构酶 I/II 抑制作用，作为其作用机制的一部分。在酰苯胺中，只有化合物 7 表现出一些 DNA 结合倾向，而喹诺酮 8b、9b 和 10-14 则嵌入 DNA 的碱基对中，化合物 8b、9b 和 14 是最有效的。根据 PCA 和 PLS 分析，最强的 DNA 嵌入剂，化合物 8b、9b 和 14，与其他化合物根据其分子描述符明显区分开来。
