Door hinges, cyclohexane, and a library of 24-membered [s]-triazine dimers; The power of analogies for understanding design of beyond-the-rule-of-five pharmaceutical space
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2025-04-28
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Abstract
As intracellular protein-protein interactions are identified as drug targets, the popularity of macrocyclic drugs increases. While small molecule permeation is well defined by the Rule of Five, macrocycles, existing beyond the Rule of Five (bRo5) chemical space, often achieve permeability by adopting various conformations to match the environment.
Previously, our group studied triazine-containing macrocycles composed of amino acid, hydrazone, and auxiliary amine positions. Due to the dynamic hinging motion that was observed, the ability for these macrocycles to act as bRo5 drugs were investigated by probing four questions: can a diverse library of macrocycles be synthesized, can lipophilicity be predicted for these macrocycles, can their dynamic properties be controlled, and can their conformation be controlled?
This thesis describes the preparation of a library of triazine macrocycles using a common synthetic pathway. The route provided access to subfamilies of macrocycles varying in substitution site and substituent of choice. In total, five different substitution sites were targeted. By preserving substituent choice, comparisons across subfamilies can be made.
This work demonstrated that shortcomings of available empirical algorithms for predicting lipophilicity can be corrected to provide accurate prediction. Linear equations arising from the correlation between HPLC-determined logD values and empirically computed logD values allowed for the prediction of logD values with low errors of ~0.5 log units. Outliers of the prediction method are indicators for structural changes.
While previous work demonstrated that alkylating at the α-carbon increased ΔG‡ by ~3 kcal/mol, this work showed that alkylation on the hydrazone afforded more modest effects, augmenting the hinge barrier by 0.3-0.7 kcal/mol when compared to the glycine-containing macrocycle. An exceptional macrocycle containing an isopropyl group displayed a barrier 0.9 kcal/mol lower. Another hinge-amenable position was demonstrated through benzylation of the amide.
The triazine macrocycles were shown to achieve conformational homogeneity through an intramolecular-hydrogen bond network. Deprotonation of the triazine or alkylation of the α-nitrogen increased conformational heterogeneity, with macrocycles now displaying multiple rotational isomers depending on the alkyl group employed.
Overall, this work demonstrated that the macrocycles exhibited acceptable lipophilicity and permeability values despite their large size and numerous hydrogen-bond acceptors, demonstrating this library as beyond-the-Rule-of-Five.
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Chemistry