Synthesis ( IF 2.2 ) Pub Date : 2018-08-29 , DOI: 10.1055/s-0037-1609945 Christian Olsen 1 , Carlos Moreno-Yruela
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Abstract
Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylase (HDAC) inhibitors, because HDAC enzymes contain a Zn2+ ion which may be chelated by this functionality. Interestingly, TFMKs are exceptional Zn2+-binding groups for targeting the intriguing class IIa HDAC isozymes, involved in transcription factor recruitment and gene regulation. Here, we have developed a scalable and inexpensive synthetic procedure for preparation of the enantiomerically pure TFMK-containing amino acid building block (S)-2-amino-9,9,9-trifluoro-8-oxononanoic acid (Atona). In addition, we propose a protecting group strategy applicable to automated solid-phase peptide synthesis and demonstrate the ability of Atona-containing peptides to inhibit the enzymatic activity of class IIa HDACs with nanomolar potency. We envision that this synthesis will motivate the further development of peptide-based probes for the study of class IIa HDACs.
Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylase (HDAC) inhibitors, because HDAC enzymes contain a Zn2+ ion which may be chelated by this functionality. Interestingly, TFMKs are exceptional Zn2+-binding groups for targeting the intriguing class IIa HDAC isozymes, involved in transcription factor recruitment and gene regulation. Here, we have developed a scalable and inexpensive synthetic procedure for preparation of the enantiomerically pure TFMK-containing amino acid building block (S)-2-amino-9,9,9-trifluoro-8-oxononanoic acid (Atona). In addition, we propose a protecting group strategy applicable to automated solid-phase peptide synthesis and demonstrate the ability of Atona-containing peptides to inhibit the enzymatic activity of class IIa HDACs with nanomolar potency. We envision that this synthesis will motivate the further development of peptide-based probes for the study of class IIa HDACs.
中文翻译：
含氨基酸结构单元的三氟甲基酮的合成，用于制备基于肽的组蛋白脱乙酰基酶（HDAC）抑制剂
摘要
三氟甲基酮（TFMK）是亲电子基团，可在水性介质中容易水合形成双酚。这种能力已被用于组蛋白脱乙酰基酶（HDAC）抑制剂的开发，因为HDAC酶含有Zn 2+离子，该离子可能被该功能螯合。有趣的是，TFMK是特殊的Zn 2+结合基团，用于靶向有趣的IIa类HDAC同工酶，参与转录因子募集和基因调控。在这里，我们开发了一种可扩展且廉价的合成方法，用于制备对映体纯的含TFMK的氨基酸构件（S）-2-氨基-9,9,9-三氟-8-氧代壬酸（阿托纳）。此外，我们提出了适用于自动化固相肽合成的保护基策略，并证明了含Atona的肽具有纳摩尔效价抑制IIa类HDAC的酶促活性的能力。我们预想，这种合成将促进IIa类HDAC研究的基于肽的探针的进一步发展。
三氟甲基酮（TFMK）是亲电子基团，可在水性介质中容易水合形成双酚。这种能力已被用于组蛋白脱乙酰基酶（HDAC）抑制剂的开发，因为HDAC酶含有Zn 2+离子，该离子可能被该功能螯合。有趣的是，TFMK是特殊的Zn 2+结合基团，用于靶向有趣的IIa类HDAC同工酶，参与转录因子募集和基因调控。在这里，我们开发了一种可扩展且廉价的合成方法，用于制备对映体纯的含TFMK的氨基酸构件（S）-2-氨基-9,9,9-三氟-8-氧代壬酸（阿托纳）。此外，我们提出了适用于自动化固相肽合成的保护基策略，并证明了含Atona的肽具有纳摩尔效价抑制IIa类HDAC的酶促活性的能力。我们预想，这种合成将促进IIa类HDAC研究的基于肽的探针的进一步发展。
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