Dipartimento di Chimica Organica, Università di Pavia, V. le Taramelli 10, 27100 Pavia, Italy.
J Am Chem Soc. 2010 Oct 20;132(41):14625-37. doi: 10.1021/ja1063857.
A one-step protecting-group-free synthesis of both 6-hydroxy-naphthalene-2-carbaldehyde and the bifunctional binaphthalenyl derivative afforded 6-hydroxymethylnaphthalen-2-ol, 6-methylaminomethyl-naphthalen-2-ol, [(2-hydroxy-3-naphthyl)methyl]trimethyl ammonium iodide, and a small library of bifunctional binol analogues in good yields. Irradiation of naphthol quaternary ammonium salt and binol-derivatives (X = OH, NHR, NMe(3)(+), OCOCH(3), and L-proline) at 310 and 360 nm resulted in the photogeneration of the 2,6-naphthoquinone-6-methide (NQM) and binol quinone methide analogues (BQMs) by a water-mediated excited-state proton transfer (ESPT). The hydration, the mono- and bis-alkylation reactions of morpholine and 2-ethanethiol, as N and S prototype nucleophiles, by the transient NQM (λ(max) 310, 330 nm) and BQMs (λ(max) 360 nm) were investigated in water by product distribution analysis and laser flash photolysis (LFP). Both the photogeneration and the reactivity of NQM and BQMs exhibited striking differences. BQMs were at least 2 orders of magnitude more reactive than NQM, and they were generated much more efficiently from a greater variety of photoprecursors including the hydroxymethyl, quaternary ammonium salt and several binol-amino acids. On the contrary, the only efficient precursor of NQM was the quaternary ammonium salt. All water-soluble BQM precursors were further investigated for their ability to alkylate and cross-link plasmid DNA and oligonucleotides by gel electrophoresis: the BQMs were more efficient than the isomeric o-BQM (binol quinone methide analogue of 2,3-naphthoquinone-3-methide). Sequence analysis by gel electrophoresis, HPLC, and MS showed that the alkylation occurred at purines, with a preference for guanine. In particular, a BQM was able to alkylate N7 of guanines resulting in depurination at the oligonucleotide level, and ribose loss at the nucleotide level. The photoreactivity of BQM precursors translated into photocytotoxic and cytotoxic effects on two human cancer cell lines: in particular, one compound showed promising selectivity index on both cell lines.
一步法保护基脱除合成了 6-羟基萘-2-甲醛和双功能联萘基衍生物，产率高，得到了 6-羟甲基萘-2-醇、6-甲胺甲基萘-2-醇、[(2-羟基-3-萘基)甲基]三甲基碘化铵以及少量双功能联萘类似物文库。在 310nm 和 360nm 下，萘酚季铵盐和联萘衍生物（X=OH、NHR、NMe3+、OCOCH3和 L-脯氨酸）的辐照导致通过水介导的激发态质子转移（ESPT）生成了 2,6-萘醌-6-甲醚（NQM）和联萘醌甲醚类似物（BQMs）。通过产物分布分析和激光闪光光解（LFP）研究了作为 N 和 S 原型亲核试剂的吗啉和 2-乙硫醇的水合、单烷基化和双烷基化反应，瞬态 NQM（λmax310nm、330nm）和 BQMs（λmax360nm）。NQM 和 BQMs 的光生成和反应性表现出显著差异。BQMs 的反应性至少比 NQM 高 2 个数量级，并且它们从更多种类的光前体（包括羟甲基、季铵盐和几种联萘-氨基酸）中更有效地生成。相反，NQM 的唯一有效前体是季铵盐。进一步研究了所有水溶性 BQM 前体与质粒 DNA 和寡核苷酸的烷基化和交联能力：BQMs 比异构 o-BQM（2,3-萘醌-3-甲醚的联萘醌甲醚类似物）更有效。凝胶电泳的序列分析、HPLC 和 MS 表明，烷基化发生在嘌呤上，鸟嘌呤优先。特别是，BQM 能够烷基化鸟嘌呤的 N7，导致寡核苷酸水平的去嘌呤化和核苷酸水平的核糖丢失。BQM 前体的光反应性转化为两种人类癌细胞系的光细胞毒性和细胞毒性作用：特别是，一种化合物在两种细胞系上都表现出有希望的选择性指数。
