Furanonaphthoquinone analogs possessing preferential antitumor activity compared to normal cells.

K I Hirai, J Koyama, J Pan, E Simamura, H Shimada, T Yamori, S Sato, K Tagahara, T Tsuruo
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引用次数: 25

Abstract

The 50% growth inhibition toxicity (IC50 at 72 h) of 16 synthetic and 2 phytochemical natural analogs of furanonaphthoquinones (naphtho[2,3-b]furan-4,9-dione; FNQ) and 2 analogs of isofuranonaphthoquinones was assayed in vitro in respect to established human cervical cancer and lung adenocarcinoma cells in comparison with human uterine endocervical, tracheal and bronchiolar epithelial cells and fibroblasts. Prostate, cholangio, colon, laryngeal, and tongue carcinoma cell lines and two osteosarcoma cell lines were also used for the assay. The IC50 ratio of normal cells to cancer cells was estimated in order to represent preferential antitumor activity. Two analogs, 2-methylnaphtho[2,3-b]furan-4, 9-dione (FNQ3) and 2-methyl-5(or 8)-hydroxynaphtho[2,3-b]furan-4, 9-dione (FNQ13) showed 10.4 to 14.1 IC50 ratios for all carcinoma cells used, indicating a wide spectrum. Among different carcinomas, there was no difference or variety in the IC50 ratio of a single analog. A moderate IC50 ratio (3.1-4.7) was also found in nine analogs, but seven others were equally cytotoxic (less than 2.6) to both cancer and normal cells. Two isofuranonaphthoquinone derivatives were ineffective, but a thieno derivative was equally cytotoxic to all cells tested. On the basis of the IC50 ratio data and the structure of the furanonaphthoquinones, the following structural activity (selectivity) relationship can be postulated: (i) the presence of an alkyl group at position 2 enhances the IC50 ratio, particularly the methyl group; (ii) a hydroxyl group at position 5 or 8 enhances the IC50 ratio; and (iii) methylation of the phenolic hydroxyl group leads to a decrease of potency. These results indicate that FNQ3, 13, and some other analogs are more preferentially cytotoxic to human tumor cells than to normal cells, unlike mitomycin-C, adriamycin, carboplatin, and methotrexate which are cytotoxic to the both. In nude mouse xenograft tests, FNQ3 demonstrated a significant antitumor activity with T/C% values of 16. 6 to 41.6 against several human carcinoma and osteosarcoma cells.

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呋喃醌类似物与正常细胞相比具有更强的抗肿瘤活性。
16种呋喃醌合成物和2种植物化学天然类似物(萘[2,3-b]呋喃-4,9-二酮;体外测定了FNQ和2种异铀醌类似物对人宫颈癌和肺腺癌细胞的影响,并与人子宫宫颈内膜、气管和细支气管上皮细胞和成纤维细胞进行了比较。前列腺癌、胆管癌、结肠癌、喉癌和舌癌细胞系以及两种骨肉瘤细胞系也被用于检测。估计正常细胞与癌细胞的IC50比率,以表示优先的抗肿瘤活性。两种类似物,2-甲基萘[2,3-b]呋喃- 4,9 -二酮(FNQ3)和2-甲基-5(或8)-羟基萘[2,3-b]呋喃- 4,9 -二酮(FNQ13)在所有使用的癌细胞中显示10.4至14.1的IC50比率,表明谱宽。在不同的肿瘤中,单一类似物的IC50比值没有差异或变化。在9种类似物中也发现了中等的IC50比率(3.1-4.7),但其他7种类似物对癌细胞和正常细胞的细胞毒性相同(小于2.6)。两种异铀萘醌衍生物无效,但一种硫代衍生物对所有被试细胞具有相同的细胞毒性。根据IC50比数据和呋喃萘醌的结构,可以假设如下的结构活性(选择性)关系:(1)2位烷基的存在提高了IC50比,特别是甲基;(ii) 5号或8号位置的羟基提高IC50比;(3)酚羟基甲基化导致药效降低。这些结果表明,与丝裂霉素c、阿霉素、卡铂和甲氨蝶呤对肿瘤细胞的毒性不同,FNQ3、13和其他类似物对肿瘤细胞的毒性比对正常细胞的毒性更强。在裸鼠异种移植试验中,FNQ3显示出显著的抗肿瘤活性,T/C%值为16。6 - 41.6对几种人癌和骨肉瘤细胞的抑制作用。
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