Comin Maria J, Vu B Christie, Boyer Paul L, Liao Chenzhong, Hughes Stephen H, Marquez Victor E
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, P.O. Box B, Building 376, Frederick, MD 21702, USA.
ChemMedChem. 2008 Jul;3(7):1129-34. doi: 10.1002/cmdc.200800027.
The stereoselective syntheses of the (+)-D and (-)-L enantiomers of iso-methanocarbathymidine (iso-MCT) was achieved through two independent linear approaches that converged on two antipodal enantiomers, common to a key precursor used in the synthesis of racemic iso-MCT. In the study reported herein we identified (+)-3 [D-(+)-iso-MCT] as the active enantiomer that was exclusively recognized by the herpes simplex virus 1 thymidine kinase (HSV1-tk), as was predicted by molecular modeling. For this purpose, a human osteosarcoma (HOS) cell line modified to contain and express HSV1-tk from herpes simplex virus 1 (HSV1) was used to determine the cytotoxicity of the compounds by an assay that measures the level of ATP in the cells. The work demonstrates that changes in the substitution pattern of rigid bicyclo[3.1.0]hexane nucleosides, which, relative to normal nucleosides, appear unconventional, can lead to the spatial optimization of pharmacophores and vastly improved substrate recognition.
异甲硫代胸苷（iso-MCT）的（+）-D和（-）-L对映体通过两种独立的线性合成方法实现，这两种方法汇聚于两种对映体，这两种对映体对于外消旋iso-MCT合成中使用的关键前体来说是相同的。在本文报道的研究中，我们确定（+）-3 [D-（+）-iso-MCT]为活性对映体，分子建模预测它能被单纯疱疹病毒1胸苷激酶（HSV1-tk）特异性识别。为此，使用一种经过改造以包含并表达来自单纯疱疹病毒1（HSV1）的HSV1-tk的人骨肉瘤（HOS）细胞系，通过测量细胞中ATP水平的试验来确定化合物的细胞毒性。这项工作表明，相对于正常核苷而言看似非常规的刚性双环[3.1.0]己烷核苷取代模式的变化，可导致药效团的空间优化和底物识别的极大改善。
