Instituto Mixto de Tecnología Química. Consejo Superior de Investigaciones Científicas/Universidad Politécnica de Valencia (CSIC/UPV) Avd. Los Naranjos s/n, 46022, Valencia, Spain.
Instituto de Investigación Sanitaria (IIS) La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026, Valencia, Spain.
Free Radic Biol Med. 2019 Sep;141:150-158. doi: 10.1016/j.freeradbiomed.2019.06.010. Epub 2019 Jun 10.
Phototoxic effects of 6,8 dihalogenated quinolones confers to this type of molecules a potential property as photochemotherapeutic agents. Two photodehalogenation processes seem to be involved in the remarkable photoinduced cellular damage. In this context, a new 6,8 dihalogenated quinolone 1 (1-methyl-6,8-difluoro-4-oxo-7-aminodimethyl-1,4-dihydroquinoline-3-carboxylic acid) was synthetized looking for improving the phototoxic properties of fluoroquinolones (FQ) and to determine the role of the photodegradation pathways in the FQ phototoxicity. With this purpose, fluorescence emissions, laser flash photolysis experiments and photodegradation studies were performed with compound 1 using 1-ethyl-6,8-difluoro-4-oxo-7-aminodimethyl-1,4-dihidroquinoline-3-carboxylic acid (2) and lomefloxacin (LFX) as reference compounds. The shortening of alkyl chain of the N(1) of the quinolone ring revealed a lifetime increase of the reactive aryl cation generated from photolysis of the three FQ and a significant reduction of the FQ photodegradation quantum yield. The fact that these differences were smaller when the same study was done using a hydrogen donor solvent (ethanol-aqueous buffer, 50/50 v/v) evidenced the highest ability of the reactive intermediate arising from 1 to produce intermolecular alkylations. These results were correlated with in vitro 3T3 NRU phototoxicity test. Thus, when Photo-Irritation-Factor (PIF) was determined for 1, 2 and LFX using cytotoxicity profiles of BALB/c 3T3 fibroblasts treated with each compound in the presence and absence of UVA light, a PIF more higher than 30 was obtained for 1 while the values for 2 and LFX were only higher than 8 and 10, respectively. Thereby, the present study illustrates an approach to modulate the photosensitizing properties of FQ with the purpose to improve the chemotherapeutic properties of antitumor quinolones. Moreover, the results obtained in this study also evidence that the key pathway responsible for the phototoxic properties associated with dihalogenated quinolones is the aryl cation generation.
光毒性作用的 6,8 二卤代喹诺酮赋予这类分子作为光化疗剂的潜在特性。两种光脱卤过程似乎都参与了显著的光诱导细胞损伤。在这种情况下，新合成了一种 6,8 二卤代喹诺酮 1（1-甲基-6,8-二氟-4-氧代-7-氨基二甲基-1,4-二氢喹啉-3-羧酸），以期提高氟喹诺酮（FQ）的光毒性，并确定光降解途径在 FQ 光毒性中的作用。为此，使用 1-乙基-6,8-二氟-4-氧代-7-氨基二甲基-1,4-二氢喹啉-3-羧酸（2）和洛美沙星（LFX）作为参考化合物，对化合物 1 进行了荧光发射、激光闪光光解实验和光降解研究。喹诺酮环 N(1)上的烷基链缩短，表明三种 FQ 光解生成的反应性芳基阳离子的寿命延长，而 FQ 光降解量子产率显著降低。当在使用氢供体溶剂（乙醇-水缓冲液，50/50v/v）进行相同研究时，这些差异较小，这表明 1 产生的反应性中间体具有产生分子间烷基化的最高能力。这些结果与体外 3T3NRU 光毒性试验相关。因此，当使用 BALB/c 3T3 成纤维细胞的细胞毒性曲线确定 1、2 和 LFX 的光刺激因子（PIF）时，在存在和不存在 UVA 光的情况下，用每种化合物处理，1 的 PIF 大于 30，而 2 和 LFX 的 PIF 分别大于 8 和 10。因此，本研究说明了一种调节 FQ 光致敏特性的方法，旨在提高抗肿瘤喹诺酮的化疗特性。此外，本研究还表明，与二卤代喹诺酮相关的光毒性特性的关键途径是芳基阳离子的生成。
