Kawasaki Takeshi, Nagatsugi Fumi, Ali Md Monsur, Maeda Minoru, Sugiyama Kumiko, Hori Kenji, Sasaki Shigeki
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
J Org Chem. 2005 Jan 7;70(1):14-23. doi: 10.1021/jo048298p.
Recently, we have proposed a new concept for cross-linking agents with inducible reactivity, in which the highly reactive cross-linking agent, the 2-amino-6-vinylpurine nucleoside analogue (1), can be regenerated in situ from its stable precursors, the phenylsulfide (4) and the phenylsulfoxide (3) derivatives, by a hybridization-promoted activation process with selectivity to cytidine. The phenylsulfide precursor (4) exhibited cross-linking ability despite its high stability toward strong nucleophiles such as amines and thiols. In this study, we investigated the substituent effects of the phenylsulfide group on the cross-linking reaction, and determined the 2-carboxy substituent of the phenylsulfide derivative (11k) as an efficient cross-linking agent with inducible reactivity. Detailed investigations have shown that the phenylsulfoxide (3) and phenylsulfide (4) precursors produce the 2-amino-6-vinylpurine nucleoside (1) as the common reactive species. It has been concluded that the nature of the inducible reactivity of the precursors (3 and 4) is acceleration of their elimination to the 2-amino-6-vinylpurine nucleoside (1) through the selective process in the duplex with the ODN having cytidine at the target site.
最近，我们提出了一种具有可诱导反应性的交联剂新概念，其中高反应性交联剂2-氨基-6-乙烯基嘌呤核苷类似物（1）可通过与胞苷具有选择性的杂交促进活化过程，从其稳定前体苯硫醚（4）和苯亚砜（3）衍生物原位再生。尽管苯硫醚前体（4）对胺和硫醇等强亲核试剂具有高稳定性，但仍表现出交联能力。在本研究中，我们研究了苯硫醚基团对交联反应的取代基效应，并确定苯硫醚衍生物（11k）的2-羧基取代基为具有可诱导反应性的有效交联剂。详细研究表明，苯亚砜（3）和苯硫醚（4）前体产生2-氨基-6-乙烯基嘌呤核苷（1）作为共同的反应物种。已经得出结论，前体（3和4）的可诱导反应性的本质是通过与在靶位点具有胞苷的ODN在双链体中的选择性过程加速它们消除为2-氨基-6-乙烯基嘌呤核苷（1）。
