Triazine Macrocycle Libraries: Synthesis, logD Prediction, and a Surprisingly Hydrophobic, Membrane-Permeable Diamine.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-02 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00078

Gretel A Stokes, Casey J Patterson-Gardner, Alexander M Engstrom, Alexander J Menke, K Harsha Vardhan Reddy, R Scott Lokey, Eric E Simanek

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Abstract

A library of triazine macrocycles was obtained to evaluate strategies for predicting lipophilicity using additive algorithms. Two synthetic routes were examined. While both were successful, one proved amenable to solution-phase library synthesis. The octanol-water partition coefficients (logP) were measured using reverse-phase HPLC at pH 10. When experimental and computed values (AlogP) are compared, a linear correlation is observed. That is, while additive algorithms underestimate hydrophobicity by a factor of 100, a simple correction yields accurate predictions. Two macrocycles showed anomalous hydrophobicities at high pH that were borne out in membrane transit (PAMPA) studies. Homodimers containing two primary amines were more hydrophobic than the corresponding heterodimers containing a single amine and a hydrophobic group. Structural analysis and computation provide a rationale for this behavior: the amines engage in an intramolecular hydrogen bond.

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三嗪大环文库：合成，logD预测，和一个令人惊讶的疏水，膜透性二胺。

获得了一个三嗪大环文库，以评估使用加性算法预测亲脂性的策略。考察了两种合成路线。虽然两者都取得了成功，但其中一个证明适合溶液相库合成。采用反相高效液相色谱法测定pH值为10的辛醇-水分配系数（logP）。当实验值和计算值（AlogP）比较时，观察到线性相关。也就是说，虽然加性算法将疏水性低估了100倍，但一个简单的修正就能产生准确的预测。两个大环在高pH值下表现出异常疏水性，这在膜传输（PAMPA）研究中得到了证实。含有两个伯胺的同型二聚体比含有单胺和疏水性基团的异源二聚体更疏水。结构分析和计算为这种行为提供了一个基本原理：胺参与分子内氢键。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.