Coronnello Marcella, Ciciani Giovanna, Mini Enrico, Guerrini Gabriella, Caciagli Barbara, Selleri Silvia, Costanzo Annarella, Mazzei Teresita
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Anticancer Drugs. 2005 Jul;16(6):645-51. doi: 10.1097/00001813-200507000-00009.
We report the synthesis and biological evaluation of a new series of 3-nitropyrazolo[5,1-c][1,2,4]benzotriazine derivatives (compounds 1-4) bearing appropriate substitutions in positions 7 and/or 8. The objective of this investigation was to study the effects of these substitutions on the cytotoxic activity of four new compounds against established human cancer cell lines (i.e. HT29 and HCT-8, colon carcinoma, MCF7, breast carcinoma, and A549, lung carcinoma cells). The inhibitory effects of compounds 1-4 on cell growth were assessed by the sulforhodamine B assay. Also, the effects of these compounds on cell cycle distribution of human colon carcinoma cells (HCT-8) were analyzed by flow cytometry. 3-Nitropyrazolo[5,1-c][1,2,4]benzotriazine derivatives displayed IC(50) values in the micromolar range on the growth of the four cell lines tested. Cell cycle perturbations induced on HCT-8 cells by study compounds at the IC(50) values consisted prevalently of a slight accumulation of cells in G(0)/G(1) phase and a slight decrease in G(2)/M phase. However, compound 3 induced a marked accumulation of cells into S phase with concomitant decrease in G(0)/G(1) and G(2)/M phases. Cytotoxicity data, compared to those obtained with 3-cyano-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (compound 5, NSC 683334) and other compounds previously synthesized in our laboratory, demonstrated a similar or even improved cytotoxic potency. Cell cycle perturbations caused by these compounds support the hypothesis that they may act by a direct or an indirect inhibition of DNA synthesis.
我们报道了一系列新的3-硝基吡唑并[5,1-c][1,2,4]苯并三嗪衍生物（化合物1-4）的合成及其生物学评价，这些衍生物在7位和/或8位带有适当的取代基。本研究的目的是研究这些取代基对四种新化合物针对已建立的人类癌细胞系（即HT29和HCT-8，结肠癌细胞；MCF7，乳腺癌细胞；以及A549，肺癌细胞）的细胞毒性活性的影响。通过磺酰罗丹明B测定法评估化合物1-4对细胞生长的抑制作用。此外，通过流式细胞术分析了这些化合物对人结肠癌细胞（HCT-8）细胞周期分布的影响。3-硝基吡唑并[5,1-c][1,2,4]苯并三嗪衍生物对所测试的四种细胞系的生长显示出微摩尔范围内的IC(50)值。研究化合物在IC(50)值下对HCT-8细胞诱导的细胞周期扰动主要包括G(0)/G(1)期细胞的轻微积累以及G(2)/M期的轻微减少。然而，化合物3诱导细胞明显积累进入S期，同时G(0)/G(1)期和G(2)/M期减少。与用3-氰基-8-氯吡唑并[5,1-c][1,2,4]苯并三嗪5-氧化物（化合物5，NSC 683334）和我们实验室先前合成的其他化合物所获得的数据相比，细胞毒性数据表明其细胞毒性效力相似甚至有所提高。这些化合物引起的细胞周期扰动支持了它们可能通过直接或间接抑制DNA合成起作用的假设。
