Azinyl and diazinyl hydrazones derived from aryl N-heteroaryl ketones:: Synthesis and antiproliferative activity
Azinyl and diazinyl hydrazones derived from aryl N-heteroaryl ketones:: Synthesis and antiproliferative activity
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DOI：
10.1021/jm970255w
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发表时间：
1997-12-19
影响因子：
7.3
通讯作者：
Hofmann, J
中科院分区：
文献类型：
--
作者：
Easmon, J;Heinisch, G;Hofmann, J
为了寻找潜在的新型抗肿瘤剂，制备了一系列由芳基 N-杂芳基或双-N-杂芳基甲酮衍生的 N-杂芳基腙。这些化合物的立体化学是通过核磁共振波谱法确定的。在一组人类肿瘤细胞系（CCRF-CEM、伯基特淋巴瘤、HeLa、ZR-75-1、HT-29 和 MEXF 276L）中体外测定了抗增殖活性。一般来说，新化合物比核糖核苷酸还原酶抑制剂羟基脲 (IC(50) = 140 μM) 具有更高的专利性 (IC(50) = 0.011-0.436 μM)。大多数化合物对伯基特淋巴瘤表现出最高的活性，IC(50) 为 0.011-0.035 μM。 [(14)C]胞苷掺入 DNA对选定的腙（Z-A、E-1、Z-3、Z-4、E-5、Z-5、E-13、E-18、Z-19、Z-24 和 E-26）进行定量，作为伯基特淋巴瘤细胞中核糖核苷酸还原酶抑制的量度。发现E-构型化合物比Z-异构体(IC(50)=7.20至>10μM)更大程度地抑制[(14)C]胞苷掺入(IC(50)=0.67-5.05μM)。对细胞增殖抑制作用获得的 IC(50) 值的主成分分析表明，所测试的细胞系可分为三个主要家族，对我们系列中的化合物表现出不同的敏感性 [(i) CCRF-CEM、伯基特淋巴瘤和 Hela；(i) CCRF-CEM、伯基特淋巴瘤和 Hela； HT-29； (iii) MEXF 276 L]。
A series of N-heteroaryl hydrazones derived from aryl N-heteroaryl or bis-N-heteroaryl methanones was prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was established by means of NMR spectroscopy. Antiproliferative activity was determined in a panel of human tumor cell Lines (CCRF-CEM, Burkitt's lymphoma, HeLa, ZR-75-1, HT-29, and MEXF 276L) in vitro. Generally, the new compounds were found to be more patent (IC(50) = 0.011-0.436 mu M) than the ribonucleotide reductase inhibitor hydroxyurea (IC(50) = 140 mu M) Most of the compounds exhibited the highest activity against Burkitt's lymphoma with an IC(50) Of 0.011-0.035 mu M. [(14)C]Cytidine incorporation into DNA was quantitated for selected hydrazones (Z-A, E-1, Z-3, Z-4, E-5, Z-5, E-13, E-18, Z-19, Z-24, and E-26) as a measure of the inhibition of-ribonucleotide reductase in Burkitt's lymphoma cells. The E-configurated compounds were found to inhibit [(14)C]cytidine incorporation to a greater extent (IC(50) = 0.67-5.05 mu M) than the Z-isomers (IC(50) = 7.20 to > 10 mu M). Principal component analysis of the IC(50) values obtained for inhibition of cell proliferation revealed that the cell lines tested can be grouped into three main families showing different sensitivities toward the compounds in our series [(i) CCRF-CEM, Burkitt's lymphoma, and Hela; (ii) HT-29; and (iii) MEXF 276 L].