Department of Anticancer Drug Development, Chittaranjan National Cancer Institute, Kolkata 700026, India.
J Exp Clin Cancer Res. 2010 Dec 31;29(1):175. doi: 10.1186/1756-9966-29-175.
Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents.
Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied.
6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron microscopic studies corroborated its apoptosis inducing efficacy at a concentration of 10 μM in MOLT-4 cells. Its apoptosis induction was also observed in HL-60 cells to an extent much greater than well known apoptosis inducing agents as camptothecin and cis-platin at 10 μM concentration each. It significantly inhibited DNA and RNA synthesis in S-180.
In essence, compound 1i showed potential as an antitumor agent.
几种取代萘并[de]异喹啉-1,3-二酮（1H-苯并[de]异喹啉-1,3-二酮）具有良好的抗癌活性。其中一些已进行了 I 期- II 期临床试验。目前，一系列十种 N-(羟烷基)萘并[de]异喹啉-1,3-二酮（化合物 1a-j）被评估为抗肿瘤药物。
首先在 MOLT-4、HL-60 和 U-937 人肿瘤细胞系中筛选化合物 1a-j，并将结果与已建立的临床药物进行比较。进一步评估化合物 1d 和 1i 在一系列人肿瘤细胞系和正常人外周血单个核细胞中的细胞毒性。通过流式细胞术研究化合物 1i 处理的 MOLT-4 细胞的细胞周期分析。通过流式细胞术使用 Annexin V-FITC/PI 双重染色法，在 MOLT-4 和 HL-60 细胞中进行化合物 1i 的诱导凋亡作用。用化合物 1i 孵育不同时间后，测量 MOLT-4 细胞中 caspase-3 和 caspase-6 的活性。用 1i 处理后，在光显微镜和透射电子显微镜下观察 MOLT-4 细胞的形态。用 8 μM 浓度的化合物 1d 和 1i 处理体外 S-180 细胞后，研究其 3H-胸腺嘧啶和 3H-尿嘧啶掺入情况。
6-硝基-2-(3-羟丙基)-1H-苯并[de]异喹啉-1,3-二酮（化合物 1i）表现出最大的活性，因为它在 13 种细胞系中的 8 种中诱导了显著的细胞毒性。有趣的是，它对人 PBMC 没有任何细胞毒性（IC50 值 273 μM）。化合物 1i 处理的 MOLT-4 细胞的细胞周期分析表明，亚 G1 部分增加，同时 S 和 G2/M 期的细胞积累，表明凋亡的上调，以及有丝分裂的阻滞和/或有丝分裂周期中细胞从有丝分裂周期的退出延迟。在 MOLT-4 和流式细胞术研究中证实了其诱导凋亡的作用，作用是通过激活 caspase 3 和 caspase 6 介导的。光和透射电子显微镜研究在 10 μM 浓度的 MOLT-4 细胞中证实了其诱导凋亡的功效。在 10 μM 浓度下，其诱导凋亡的作用在 HL-60 细胞中比众所周知的凋亡诱导剂喜树碱和顺铂更为显著。它显著抑制 S-180 的 DNA 和 RNA 合成。
本质上，化合物 1i 显示出作为抗肿瘤药物的潜力。
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