Doria Filippo, Richter Sara N, Nadai Matteo, Colloredo-Mels Stefano, Mella Mariella, Palumbo Manlio, Freccero Mauro
Dipartimento di Chimica Organica, Università di Pavia, Italy.
J Med Chem. 2007 Dec 27;50(26):6570-9. doi: 10.1021/jm070828x. Epub 2007 Nov 30.
Mild photoactivation of new BINOL-amino acid and -amino ester conjugates (BINOLAMs) yielded alkylating and DNA cross-linking agents with high photoefficiency and superior cytotoxicity. Detection of the transient electrophile, by laser flash photolysis (LFP), suggests that BINOL-quinone methides (QMs) are key intermediates in the process. QMs trapping by water, monitored in a time-dependent product distribution analysis, demonstrated that the phototriggered reactivity of BINOLAMs as bis-alkylating agents is the result of a two-step process involving sequential photogeneration of monoalkylating QMs. Light activation of the BINOL-L-amino esters produced cytotoxic QMs very effective against human tumor LoVo cells with EC50 in the 130-230 nM range. Trimethylpsoralen (PS) is about 4 times less potent than our newly tested compounds. BINOL-L-proline methyl ester showed notable photoselectivity because it displayed cytotoxic effects upon irradiation only and was able to efficiently reach the target DNA inside the cells, where it forms both alkylated and cross-linked species.
新型联萘酚 - 氨基酸和 - 氨基酯共轭物（BINOLAMs）的轻度光活化产生了具有高光效率和优异细胞毒性的烷基化剂和DNA交联剂。通过激光闪光光解（LFP）检测瞬态亲电试剂表明，联萘酚 - 醌甲基化物（QMs）是该过程中的关键中间体。在时间依赖性产物分布分析中监测到水对QMs的捕获，这表明BINOLAMs作为双烷基化剂的光触发反应性是一个两步过程的结果，该过程涉及单烷基化QMs的顺序光生成。联萘酚 - L - 氨基酯的光活化产生了对人肿瘤LoVo细胞非常有效的细胞毒性QMs，其半数有效浓度（EC50）在130 - 230 nM范围内。三甲基补骨脂素（PS）的效力约为我们新测试化合物的四分之一。联萘酚 - L - 脯氨酸甲酯表现出显著的光选择性，因为它仅在照射时显示出细胞毒性作用，并且能够有效地到达细胞内的靶DNA，在那里它形成烷基化和交联的物种。
