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 IC₅₀ 39–61 nm, HDAC2 IC₅₀ 260–690 nm, HDAC3 IC₅₀ 25–68 nm, and HDAC8 IC₅₀ 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 IC₅₀ 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.

中文翻译：

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新型基于胺的组蛋白脱乙酰基酶抑制剂的设计，合成，分子建模和生物学评估

组蛋白脱乙酰基酶（HDAC）是用于各种治疗应用的有希望的药物靶标。本文中，我们描述了一系列基于二级和三级N-取代的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估以及初步的药物代谢和药代动力学研究（DMPK）。引入具有一个或两个表面结合基团（SBG）的氨基产生了开发新型有效的HDAC抑制剂的成功策略。发现仲胺通常比相应的叔胺更有效。对接研究表明，叔胺的SBG不能很好地容纳在结合位点的峡谷区域。具有萘-2-基甲基，5-苯基噻吩-2-基甲基和1 H的仲胺吲哚-2-基甲基（2 j）取代基对I类HDAC表现出最高的效力：HDAC1 IC ₅₀ 39-61 n m，HDAC2 IC ₅₀ 260-690 n m，HDAC3 IC ₅₀ 25-68 n m和HDAC8 IC ₅₀ 320-620ñ米。一组代表性的基于N和取代的7-氨基庚酸羟酰胺的仲和叔胺类抑制剂对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，并被发现类似于或优于辛二酰苯胺异羟肟酸（SAHA）。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2 j在代谢上稳定，血浆和大脑的浓度比IC ₅₀高23倍和1.6倍以上I类HDAC的值分别。总体而言，基于N和N取代的7-氨基庚酸羟酰胺的仲和叔胺抑制剂具有优异的铅样和药物样特性以及对癌症应用的治疗能力。