Synthesis and Antiviral Evaluation of Unexplored Dioxolane-Derived 7-Deazapurine Nucleoside Analogues against Epstein–Barr Virus (EBV)

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI:10.1021/acsmedchemlett.5c00397

Uma S. Singh*, Ransom A. Jones, Yugandhar Kothapalli, Shuiyun Lan, Xing-Quan Zhang, Ryan L. Slack, Harischandra P. Thoomu, Robert T. Schooley, Stefan G. Sarafianos and Chung K. Chu,

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引用次数: 0

Abstract

Dioxolane-based nucleosides are characterized by their unique replacement of the sugar moiety by dioxolane-based cyclopentyl rings. A series of d-dioxolane-derived 7-deazapurine analogues (12–19) were synthesized and evaluated against Epstein–Barr virus (EBV) and human immunodeficiency virus (HIV). The 7-bromo-deazaadenosine analogue (15) demonstrated an EC₅₀ of 0.17 μM and the 7-iodo-deazaadeosine analogue (16) displayed an EC₅₀ of 0.47 μM, compared to ganciclovir (EC₅₀ = 2.5 μM) against EBV. Compound 15 was 14 times more potent than ganciclovir, with a high selectivity index (SI = 294). Additionally, the deazaadenosine analogue (12) and 7-fluoro-deazaadenosine (13) have shown moderate antiviral potency against HIV. The reported analogues of this series expressed both potency and selectivity against EBV. The development of prodrugs for analogues 12, 13, 15, and 16 may potentially enhance their antiviral activity against EBV and HIV, offering a promising avenue for identifying preclinical candidates effective against both DNA and RNA viruses.

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未开发的二氧唑烷衍生的7-去氮杂嘌呤核苷类似物的合成及对eb病毒的抗病毒作用评价

二恶唑烷基核苷的特点是其独特的糖部分被二恶唑烷基环戊基环取代。合成了一系列d-二恶唑烷衍生的7-去氮杂嘌呤类似物（12-19），并对其抗eb病毒（EBV）和人类免疫缺陷病毒（HIV）进行了评价。与更昔洛韦（EC50 = 2.5 μM）相比，7-溴-地氮杂腺苷类似物（15）对EBV的EC50为0.17 μM， 7-碘-地氮杂腺苷类似物（16）的EC50为0.47 μM。化合物15的效价是更昔洛韦的14倍，选择性指数高（SI = 294）。此外，地氮杂腺苷类似物（12）和7-氟地氮杂腺苷（13）显示出对艾滋病毒的中等抗病毒效力。已报道的该系列类似物对EBV均表现出效力和选择性。开发类似物12、13、15和16的前药可能会潜在地增强它们对EBV和HIV的抗病毒活性，为确定对DNA和RNA病毒有效的临床前候选药物提供了一条有希望的途径。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.