Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
ChemMedChem. 2010 Aug 2;5(8):1386-96. doi: 10.1002/cmdc.201000192.
A series of cycloSal-phosphate prodrugs of a recently described new class of nucleoside cytostatics (6-hetaryl-7-deazapurine ribonucleosides) was prepared. The corresponding 2',3'-isopropylidene 6-chloro-7-deazapurine nucleosides were converted into 5-O'-cycloSal-phosphates. These underwent a series of Stille or Suzuki cross-couplings with diverse (het)arylstannanes or -boronic acids to yield the protected 6-(het)aryl-7-deazapurine pronucleotides that were subsequently deprotected to give 12 derivatives of free pronucleotides. The in vitro cytostatic effect of the pronucleotides was compared with parent nucleoside analogues. In most cases, the activity of the pronucleotide was similar to or somewhat lower than that of the corresponding parent nucleosides, with the exception of 7-fluoro pronucleotides 13 a, 13 b, and 13 d, which had exhibited GIC(50) values that were improved by one order of magnitude (to the low nanomolar range). The presence of a cycloSal-phosphate group also influenced selectivity toward various cell lines. Several pronucleotides were found which strongly inhibit human adenosine kinase but only weakly inhibit the MTB adenosine kinase.
我们合成了一系列最近新描述的核苷类抗肿瘤药物（6-杂芳基-7-脱氮嘌呤核苷）的环磷酰基前药。相应的 2',3'-异亚丙基 6-氯-7-脱氮嘌呤核苷被转化为 5-O'-环磷酰基。这些经过一系列 Stille 或 Suzuki 交叉偶联反应，与不同的（杂）芳基锡烷或硼酸反应，得到保护的 6-（杂）芳基-7-脱氮嘌呤前核苷，然后脱保护得到 12 个游离前核苷衍生物。前核苷的体外细胞毒性作用与母体核苷类似物进行了比较。在大多数情况下，前核苷的活性与相应的母体核苷相似或略低，除了 7-氟前核苷 13a、13b 和 13d，它们的 GIC(50) 值提高了一个数量级（达到低纳摩尔范围）。环磷酰基的存在也影响了对各种细胞系的选择性。发现了几种前核苷，它们强烈抑制人腺苷激酶，但对 MTB 腺苷激酶的抑制作用较弱。
