Abdelkarim Hazem, Neelarapu Raghupathi, Madriaga Antonett, Vaidya Aditya S, Kastrati Irida, Karumudi Bhargava, Wang Yue-Ting, Taha Taha Y, Thatcher Gregory R J, Frasor Jonna, Petukhov Pavel A
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA.
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 South Wolcott, Chicago, IL, 60612, USA.
ChemMedChem. 2017 Dec 19;12(24):2030-2043. doi: 10.1002/cmdc.201700449. Epub 2017 Nov 30.
Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-aminoheptanohydroxamic acid-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. The secondary amines were found to be generally more potent than the corresponding tertiary amines. Docking studies suggested that the SBGs of tertiary amines cannot be favorably accommodated at the gorge region of the binding site. The secondary amines with naphthalen-2-ylmethyl, 5-phenylthiophen-2-ylmethyl, and 1H-indol-2-ylmethyl (2 j) substituents exhibited the highest potency against class I HDACs: HDAC1 IC 39-61 nm, HDAC2 IC 260-690 nm, HDAC3 IC 25-68 nm, and HDAC8 IC 320-620 nm. The cytotoxicity of a representative set of secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors against HT-29, SH-SY5Y, and MCF-7 cancer cells correlated with their inhibition of HDAC1, 2, and 3 and was found to be similar to or better than that of suberoylanilide hydroxamic acid (SAHA). Compounds in this series increased the acetylation of histones H3 and H4 in a time-dependent manner. DMPK studies indicated that secondary amine 2 j is metabolically stable and has plasma and brain concentrations >23- and >1.6-fold higher than the IC value for class I HDACs, respectively. Overall, the secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors exhibit excellent lead- and drug-like properties and therapeutic capacity for cancer applications.
组蛋白去乙酰化酶（HDACs）是多种治疗应用中很有前景的药物靶点。在此，我们描述了一系列仲胺和叔胺N-取代的基于7-氨基庚酸异羟肟酸的HDAC抑制剂的设计、合成、在癌症细胞模型中的生物学评价以及初步的药物代谢和药代动力学研究（DMPK）。引入带有一个或两个表面结合基团（SBGs）的氨基产生了一种成功的策略来开发新型强效HDAC抑制剂。发现仲胺通常比相应的叔胺更有效。对接研究表明，叔胺的SBGs不能很好地容纳在结合位点的峡谷区域。带有萘-2-基甲基、5-苯基噻吩-2-基甲基和1H-吲哚-2-基甲基（2j）取代基的仲胺对I类HDACs表现出最高的活性：HDAC1的IC为39 - 61 nM，HDAC2的IC为260 - 690 nM，HDAC3的IC为25 - 68 nM，HDAC8的IC为320 - 620 nM。一组代表性的仲胺和叔胺N-取代的基于7-氨基庚酸羟基酰胺的抑制剂对HT-29、SH-SY5Y和MCF-7癌细胞的细胞毒性与其对HDAC1、2和3的抑制作用相关，并且发现其与辛二酰苯胺异羟肟酸（SAHA）相似或更好。该系列化合物以时间依赖性方式增加组蛋白H3和H4的乙酰化。DMPK研究表明，仲胺2j代谢稳定，其血浆和脑浓度分别比I类HDACs的IC值高>23倍和>1.6倍。总体而言，仲胺和叔胺N-取代的基于7-氨基庚酸羟基酰胺的抑制剂表现出优异的先导物和类药物性质以及在癌症应用中的治疗能力。
