异香豆素是选择性碳酸酐酶IX和XII抑制剂，对癌细胞系具有细胞毒性作用。
Heterocoumarins Are Selective Carbonic Anhydrase IX and XII Inhibitors with Cytotoxic Effects against Cancer Cells Lines.
作者信息
Angeli Andrea, Trallori Elena, Carta Fabrizio, Di Cesare Mannelli Lorenzo, Ghelardini Carla, Supuran Claudiu T
机构信息
University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
出版信息
ACS Med Chem Lett. 2018 Aug 29;9(9):947-951. doi: 10.1021/acsmedchemlett.8b00362. eCollection 2018 Sep 13.
Abstract
We have synthesized a new series of coumarin-based compounds demonstrating high selectivity and potent effects with low nanomolar affinity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII. A number of these compounds were evaluated against human prostate (PC3) and breast (MDA-MB-231) cancer cell lines. Compounds and revealed effective cytotoxic effects after 48 h of incubation in both normoxic and hypoxic conditions with PC3 cancer cell line. However, compound showed selective cytotoxic effects against MDA-MB-231 in hypoxic condition. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a selective carbonic anhydrase CA IX inhibitor (SLC-0111) is presently in phase II clinical trials.
摘要
我们合成了一系列新型香豆素类化合物，这些化合物对肿瘤相关碳酸酐酶（CA，EC 4.2.1.1）同工型hCA IX和XII表现出高选择性和强效作用，亲和力低至纳摩尔级别。其中一些化合物针对人前列腺癌（PC3）和乳腺癌（MDA-MB-231）细胞系进行了评估。化合物 和 在常氧和低氧条件下与PC3癌细胞系孵育48小时后显示出有效的细胞毒性作用。然而，化合物 在低氧条件下对MDA-MB-231表现出选择性细胞毒性作用。考虑到选择性碳酸酐酶CA IX抑制剂（SLC-0111）目前正处于II期临床试验阶段，这些结果对于未来靶向低氧肿瘤和转移灶的候选药物的选择可能具有特别重要的意义。
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