Stenzel Katharina, Hamacher Alexandra, Hansen Finn K, Gertzen Christoph G W, Senger Johanna, Marquardt Viktoria, Marek Linda, Marek Martin, Romier Christophe, Remke Marc, Jung Manfred, Gohlke Holger, Kassack Matthias U, Kurz Thomas
Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstraße 1, 40225 Düsseldorf, Germany.
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University , Brüderstraße 34, 04103 Leipzig, Germany.
J Med Chem. 2017 Jul 13;60(13):5334-5348. doi: 10.1021/acs.jmedchem.6b01538. Epub 2017 Jun 19.
The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC values in the low μM and sub-μM range. 1g-i revealed low nM IC values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
本文描述了具有适度HDAC6偏好性和新型烷氧基脲连接单元连接区域的基于异羟肟酸的高效HDAC1/6双重抑制剂的合成及生物学评价。生物学研究包括评估其对人卵巢癌细胞系A2780、人鳞状癌细胞系Cal27及其顺铂耐药亚系A2780CisR和Cal27CisR的抗增殖作用和HDAC抑制活性。三种最有效的化合物1g - i的IC值处于低μM和亚μM范围。1g - i对HDAC6显示出低nM的IC值，对HDAC1的偏好性高达15倍，对HDAC4的选择性大于3500倍，对HDAC8的选择性大于100倍。此外，还分析了它们在Cal27和Cal27CisR细胞中增强顺铂敏感性的能力。值得注意的是，1g - i预孵育48小时可显著增强顺铂在Cal27和Cal27CisR中的抗增殖作用。1g - i与顺铂协同作用。这些作用在顺铂耐药亚系Cal27CisR中更为明显。
