Institute for Bioengineering of Catalonia (IBEC) , Barcelona Institute for Science and Technology , Barcelona 08028 , Spain.
Biomedical Research Networking Center in Bioengineering , Biomaterials and Nanomedicine (CIBER-BBN) , Madrid 28029 , Spain.
J Am Chem Soc. 2018 Nov 21;140(46):15764-15773. doi: 10.1021/jacs.8b08249. Epub 2018 Oct 22.
The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analogue of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.
系统给予的抗癌药物的疗效和耐受性受到其非靶向作用的限制。对其细胞毒性活性进行精确的时空控制将有助于改善化疗治疗，而光调节药物非常适合这一目的。我们开发了光蝶呤，这是第一个光开关人二氢叶酸还原酶 (DHFR) 的抑制剂，作为甲氨蝶呤的光致变色类似物，甲氨蝶呤是一种广泛用于治疗癌症和牛皮癣的化疗药物。光调节 DHFR 酶活性、细胞增殖和斑马鱼体内效应的定量分析表明，光蝶呤在其光激活的顺式构型中表现为一种有效的抗叶酸药物，而在其黑暗松弛的反式形式中几乎没有活性。因此，光蝶呤为设计光调节细胞毒性小分子提供了概念验证，并为开发具有局部疗效和减少不良反应的靶向抗癌光化疗迈出了一步。
