Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74.
Synthesis, Enantiomeric Resolution and Biological Evaluation of HIV Capsid Inhibition Activity for Racemic, (S)- and (R)-PF74.
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DOI：
10.3390/molecules26133919
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发表时间：
2021-06-26
期刊：
影响因子：
--
通讯作者：
France DJ
中科院分区：
文献类型：
--
作者：
Ruddell S;Sugrue E;Memarzadeh S;Hellam LM;Wilson SJ;France DJ
PF 74是一种靶向HIV复制抑制剂，可有效干扰高度敏感的病毒脱壳过程。由于缺乏关于PF 74的单一立体中心的光学纯度（对映体过量）的信息，导致该化合物不同样品的效力不明确。本文描述了对映体富集的（S）-和（R）-PF 74的合成以及使用手性HPLC拆分进一步富集样品（≥98%）。然后评价每种对映异构体的生物活性，确定（S）-PF 74（IC 50 1.5 μM）的活性显著高于（R）-PF 74（IC 50 19 μM）。然后进行计算对接研究，以合理化这一巨大的差异，在活动中，这表明不同的结合构象的每一个对映异构体。计算出活性较高的（S）-PF 74所采用的构象的结合能（ΔG = −73.8 kcal/mol）比活性较低的（R）-对映体所采用的构象（ΔG = −55.8 kcal/mol）更有利，与实验观察结果一致。
PF74 is a capsid-targeting inhibitor of HIV replication that effectively perturbs the highly sensitive viral uncoating process. A lack of information regarding the optical purity (enantiomeric excess) of the single stereogenic centre of PF74 has resulted in ambiguity as to the potency of different samples of this compound. Herein is described the synthesis of enantiomerically enriched (S)- and (R)-PF74 and further enrichment of the samples (≥98%) using chiral HPLC resolution. The biological activities of each enantiomer were then evaluated, which determined (S)-PF74 (IC50 1.5 µM) to be significantly more active than (R)-PF74 (IC50 19 µM). Computational docking studies were then conducted to rationalise this large discrepancy in activity, which indicated different binding conformations for each enantiomer. The binding energy of the conformation adopted by the more active (S)-PF74 (ΔG = −73.8 kcal/mol) was calculated to be more favourable than the conformation adopted by the less active (R)-enantiomer (ΔG = −55.8 kcal/mol) in agreement with experimental observations.
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