Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211, United States.
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211, United States.
Bioorg Chem. 2023 Nov;140:106769. doi: 10.1016/j.bioorg.2023.106769. Epub 2023 Aug 9.
Photoinduced DNA cross-linking process showed advantages of high spatio-temporal resolution and control. We have designed, synthesized, and characterized several 4,4'-dibromo binaphthalene analogues (1a-f) that can be activated by 350 nm irradiation to induce various DNA damage, including DNA interstrand cross-links (ICL) formation, strand cleavages, and alkaline labile DNA lesions. The degree and types of DNA damage induced by these compounds depend on the leaving groups of the substrates, pH value of the buffer solution, and DNA sequences. The DNA ICL products were produced from the carbocations formed via the oxidation of free radicals photo-generated from 1a-f. Most of these compounds alone exhibited minimum cytotoxicity towards cancer cells while 350 nm irradiation greatly improved their anticancer effects (up to 40-fold enhancement) because of photo-induced cellular DNA damage. This work provides guidance for further design of photo-inducible DNA cross-linking agents as potent photo-activated anticancer prodrugs with good control over toxicity and selectivity.
光诱导 DNA 交联过程具有高时空分辨率和可控性的优势。我们设计、合成并表征了几种 4,4'-二溴联萘类似物（1a-f），它们可以通过 350nm 照射激活，从而诱导各种 DNA 损伤，包括 DNA 链间交联（ICL）形成、链断裂和碱性不稳定 DNA 损伤。这些化合物诱导的 DNA 损伤程度和类型取决于底物的离去基团、缓冲溶液的 pH 值和 DNA 序列。DNA ICL 产物是由 1a-f 光生自由基氧化形成的碳正离子产生的。这些化合物中的大多数单独使用时对癌细胞的细胞毒性最小，而 350nm 照射大大提高了它们的抗癌效果（高达 40 倍增强），因为光诱导的细胞 DNA 损伤。这项工作为进一步设计光诱导 DNA 交联剂提供了指导，作为具有良好毒性和选择性控制的有效光激活抗癌前药。
