Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine asicididemin:: Structure-activity relationship
Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine asicididemin:: Structure-activity relationship
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DOI：
10.1021/jm0208774
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发表时间：
2002-08-15
影响因子：
7.3
通讯作者：
Kiss, R
中科院分区：
文献类型：
--
作者：
Delfourne, E;Darro, F;Kiss, R
具有吡啶并吖啶骨架的海洋化合物具有抗肿瘤活性。已经报道了Ascidemin在体外显示出显著的抗肿瘤活性，并且还发现其在体内具有相对高的总体毒性。我们合成了一系列的16个类似物（其中11个化合物是从以前描述的不同），目的是开发新的抗癌药物具有显着改善的疗效/耐受性比。这些化合物是由5，8-喹啉二酮和取代的2-氨基苯乙酮通过全合成或由海鞘素直接取代得到的。在不同组织病理学类型（胶质母细胞瘤和乳腺癌、结肠癌、肺癌、前列腺癌和膀胱癌）的12种不同人癌细胞系上以6种不同浓度测试不同化合物和用作对照化合物的海鞘苷脂。IC 50值（即，这些化合物抑制12种细胞系的平均生长值50%的药物浓度范围超过5个对数浓度，即，在10000和0.1 nM之间。对于几种新的化学实体，抗肿瘤活性（体外测定）和耐受性（体内测定）上级母体生物碱，即，海鞘素和2-溴来普利酮。
Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significant improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC50 value (ie., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.