Abstract：
Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the central five-carbon precursors to all terpenes. Despite their significance, exogenous, independent delivery of IPP and DMAPP to cells is impossible as the negatively charged pyrophosphate makes these molecules membrane impermeant. Herein, we demonstrate a facile method to circumvent this challenge through esterification of the β-phosphate with two self-immolative esters (SIEs) that neutralize the negatively charged pyrophosphate to yield membrane-permeant analogs of IPP and DMAPP. Following cellular incorporation, general esterase activity initiates cleavage of the SIEs, resulting in traceless release of IPP and DMAPP for metabolic utilization. Addition of the synthesized IPP and DMAPP precursor analogs rescued cell growth of glioblastoma (U-87MG) cancer cells concurrently treated with the HMG-CoA reductase inhibitor pitavastatin, which otherwise abrogates cell growth via blocking production of IPP and DMAPP. This work demonstrates a new application of a prodrug strategy to incorporate a metabolic intermediate and promises to enable future interrogation of the distinct biological roles of IPP and DMAPP.
摘要：
焦磷酸异戊烯基（IPP）和焦磷酸二甲基烯丙基（DMAPP）是所有萜烯的中心五碳前体。尽管意义重大,外源性,IPP和DMAPP向细胞的独立递送是不可能的,因为带负电荷的焦磷酸盐使这些分子膜不渗透。在这里，我们证明了一种简便的方法，可以通过用两种自分解酯（SIE）中和带负电荷的焦磷酸盐的β-磷酸酯酯化来规避这一挑战，从而产生IPP和DMAPP的膜渗透类似物。细胞掺入后，一般酯酶活性启动SIE的裂解，导致IPP和DMAPP无痕释放，用于代谢利用。添加合成的IPP和DMAPP前体类似物可挽救同时用HMG-CoA还原酶抑制剂匹伐他汀治疗的成胶质细胞瘤（U-87MG）癌细胞的细胞生长，否则通过阻断IPP和DMAPP的产生来终止细胞生长。这项工作证明了前药策略的新应用，以纳入代谢中间体，并有望在未来研究IPP和DMAPP的不同生物学作用。
