Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs
Antitumor agents 259. Design, syntheses, and structure-activity relationship study of desmosdumotin C analogs
复制标题
DOI：
10.1021/jm0702534
复制
发表时间：
2007-07-12
影响因子：
7.3
通讯作者：
Lee, Kuo-Hsiung
中科院分区：
文献类型：
--
作者：
Nakagawa-Goto, Kyoko;Chen, Tzu-Hsuan;Lee, Kuo-Hsiung
Desmosdumotin C (1) 及其类似物先前表现出有效的、选择性的体外抗癌活性。为了探索 1 的构效关系并进一步提高效力和选择性，合成了 15 种新型类似物（7-15 和 21-26），并评估了其针对多种人类肿瘤细胞系的细胞毒性以及对人内皮细胞 (HUVEC) 复制的抑制作用。 4-Bromo-3',3',5'-三丙基类似物26对A549、A431、1A9和HCT-8表现出显着的细胞毒性，ED50值分别为1.0、1.2、0.9和1.3μg/mL。化合物26还强烈抑制匹配肿瘤细胞KB-VIN及其亲代细胞KB的生长。此外，类似物 13 和 21 对抗 KB-VIN 的效力比 KB 强 5 倍以上。 B 环的溴化和 A 环的三丙基官能化增强了活性，而 B 环的烷基化则提高了 KB-VIN/KB 选择性。 2-呋喃类似物 16 显示出针对 HUVEC 的选择性活性，表明它可能具有作为抑制血管生成的新原型的潜力。
Desmosdumotin C (1) and its analogs previously showed potent, selective in vitro anticancer activity. To explore structure-activity relationships of 1 and further increase potency and selectivity, 15 novel analogs (7-15 and 21-26) were synthesized and evaluated for cytotoxity against several human tumor cell lines, as well as inhibition of human endothelial (HUVEC) replication. 4-Bromo-3',3',5'-tripropyl analog 26 showed significant cytotoxity against A549, A431, 1A9, and HCT-8 with ED50 values of 1.0, 1.2, 0.9, and 1.3 mu g/mL, respectively. Compound 26 also strongly inhibited the growth of matched tumor cells, KB-VIN and its parent cell KB. Furthermore, analogs 13 and 21 were over 5-fold more potent against KB-VIN than KB. Bromination of ring-B and tripropyl functionalization of ring-A enhanced activity, while alkylation of ring-B promoted KB-VIN/KB selectivity. 2-Furyl analog 16 showed selective activity against HUVEC, suggesting that it may have potential as a new prototype for angiogenesis inhibition.