Stokes Gretel A, Patterson-Gardner Casey J, Engstrom Alexander M, Menke Alexander J, Vardhan Reddy K Harsha, Lokey R Scott, Simanek Eric E
Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76109, United States.
Department of Chemistry, University of California, Santa Cruz, California 95064, United States.
ACS Med Chem Lett. 2025 Jun 2;16(6):1017-1023. doi: 10.1021/acsmedchemlett.5c00078. eCollection 2025 Jun 12.
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.
获得了一个三嗪大环化合物库，以评估使用加和算法预测亲脂性的策略。研究了两条合成路线。虽然两条路线都成功了，但其中一条被证明适用于溶液相库合成。使用反相高效液相色谱法在pH 10下测量辛醇-水分配系数（logP）。当比较实验值和计算值（AlogP）时，观察到线性相关性。也就是说，虽然加和算法将疏水性低估了100倍，但一个简单的校正就能得出准确的预测结果。两个大环化合物在高pH下表现出异常的疏水性，这在膜转运（PAMPA）研究中得到了证实。含有两个伯胺的同二聚体比含有一个胺和一个疏水基团的相应异二聚体更疏水。结构分析和计算为这种行为提供了一个解释：胺参与了分子内氢键的形成。
