Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4′-Ethynyl-2-fluoro-2′-deoxyadenosine),Journal of Medicinal Chemistry

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Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4′-Ethynyl-2-fluoro-2′-deoxyadenosine)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-09-28 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00141
François-René Alexandre ₁ , Rachid Rahali ₁ , Houcine Rahali ₁ , Sandra Guillon ₂ , Thierry Convard ₁ , Kerry Fillgrove ₃ , Ming-Tain Lai ₃ , Jean-Christophe Meillon ₂ , Min Xu ₃ , James Small ₃ , Cyril B. Dousson ₁ , Izzat T. Raheem ₃

Affiliation

MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4′-Ethynyl-G derivative (±)-29 displayed a promising IC₅₀ of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC₅₀ of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC₅₀ of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.

中文翻译：

核苷逆转录酶易位抑制剂MK-8591（4'-乙炔基-2-氟-2'-脱氧腺苷）碳环核苷类似物的合成及抗病毒评价

MK-8591（4'-乙炔基-2-氟-2'-脱氧腺苷）是一种新型核苷类似物，与批准的NRTIs相比，它作为核苷逆转录酶易位抑制剂（NRTTI）表现出不同的作用机制。在这里，我们描述了我们最近的努力，以通过碳环衍生物的合成和抗病毒评估来探索结构变化对MK-8591性质的影响。评估合成的类似物的抗病毒活性，并合成相应的三磷酸酯并在生化分析中进行评估。4'-乙炔基-G衍生物（±）-29在基于hPBMC细胞的抗病毒测定中显示出有希望的IC ₅₀，为33 nM，其三磷酸（TP），（±）-29 - TP显示出IC ₅₀生化RT-聚合酶测定中324 nM的浓度通过制备单一对映异构体29b的相应的氨基磷酸酯前药可实现改善的TP合成代谢物质递送，从而提高体外效能，其中6-乙氧基G衍生物34b的IC ₅₀显着提高至3.0 nM，为此类新的研究方向铺平了道路核苷类似物。

更新日期：2018-09-28

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