Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of 4N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines
Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of 4N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines
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DOI：
10.1021/jm000979z
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发表时间：
2001-06-21
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;Pürstinger, G;Hofmann, J
以3-酰基哒嗪、4-乙酰基嘧啶和2-乙酰基吡嗪（1-8）为原料，合成了一系列具有抗肿瘤活性的缩氨基硫脲类化合物。TSC 1-8对人急性淋巴细胞白血病CCRF-CEM细胞（IC 50 = 0.05-0.77 μ M）和结肠腺癌HT-29细胞（IC 50 = 0.011-2.22 μ M）表现出强的细胞毒活性。TSC 1-8的铜II络合物显示出对HT-29细胞的细胞毒活性（IC 50 = 0.004-1.51 μ M）显著提高3倍。然而，配体1、2、4和6与Fe（II）的络合导致细胞毒活性降低约7倍。在涉及不同肿瘤来源的人肿瘤细胞的克隆形成试验中，化合物5、7、8及其铜络合物5Cu（II）、7 Cu（II）和8 Cu（II）表现出显著的细胞毒性活性，平均IC 50值分别为6、0.18、1、1、0.37和0.37 nM。特别地，所述化合物对人结肠癌和大细胞和小细胞肺癌细胞高度有效。在携带LXFL 529人大细胞肺癌细胞的裸鼠中体内评价TSC衍生物5。关于抗肿瘤活性，应用30 mg/kg/d导致肿瘤生长中度抑制（42%）。在10 mg/kg/d剂量下未观察到对肿瘤生长的影响。然而，40或60 mg/kg/d的剂量分别导致给药小鼠50%和75%死亡，表明这些化合物的毒性较高。使用人肝微粒体，发现化合物5在体外快速且高度代谢。实际上，5分钟后在孵育培养基中仅检测到2%的未代谢化合物。这些化合物引起的细胞增殖的IC 50（0.006-0.022 μ M）远低于抑制[C-14]胞苷掺入DNA的IC 50（0.18-3.32 μ M）。这些化合物也是非细胞周期特异性试剂。有趣的是，发现化合物5、5Cu（II）和8是伯基特淋巴瘤细胞中细胞凋亡的有效诱导剂。
A series of thiosemicarbazones (TSCs) (bearing a N-4-azabicyclo[3.2.2]nonane moiety) derived from 3-acylpyridazines, 4-acetylpyrimidines, and 2-acetylpyrazines (1-8) were synthesized as potential antitumor agents. TSCs 1-8 exhibited potent cytotoxic activity against human acute lymphoblastic leukemia CCRF-CEM cells (IC50 = 0.05-0.77 muM) and colon adenocarcinoma HT-29 cells (IC50 = 0.011-2.22 muM). Copper II complexes of TSCs 1-8 showed significant improvement in cytotoxic activity against HT-29 cells (IC50 = 0.004-1.51 muM) by a factor of 3. However, complexation of ligands 1, 2, 4, and 6 with Fe(II) results in lowering of cytotoxic activity by a factor of similar to7. In clonogenic assays involving human tumor cells of different tumor origins, compounds 5, 7, 8, and their copper complexes 5Cu(II), 7Cu(II), and 8Cu(II) exhibited remarkable cytotoxic activities with mean IC50 values of 6, 0.18, 1, 1, 0.37, and 0.37 nM, respectively. In particular, the compounds were highly effective against human colon carcinoma and large and small cell lung carcinoma cells. The TSC derivative 5 was evaluated in vivo in nude mice bearing LXFL 529 human large cell lung carcinoma cells. With respect to antitumor activity, application of 30 mg/kg/d resulted in moderate inhibition (42%) of tumor growth. No effect on tumor growth was observed at a dose of 10 mg/kg/d. However, a dose of 40 or 60 mg/kg/d resulted in 50 and 75% death, respectively, in the treated mice, indicating the high toxicity of these compounds. Using human liver microsomes, compound 5 was found to be rapidly and highly metabolized in vitro. In actual fact, only 2% of the unmetabolized compound could be detected in the incubation medium after 5 min. The IC50 for cell proliferation (0.006-0.022 muM) elicited by these compounds is much lower than that of the inhibition of [C-14]cytidine incorporation into DNA (0.18-3.32 muM). These compounds are also noncell cycle specific agents. Interestingly, compounds 5, 5Cu(II), and 8 were found to be potent inducers of apoptosis in Burkitt's lymphoma cells.