Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou 515063, China.
Chem Res Toxicol. 2022 Jan 17;35(1):89-98. doi: 10.1021/acs.chemrestox.1c00315. Epub 2021 Dec 28.
Carprofen (CP), one kind of a nonsteroidal anti-inflammatory drug, exhibits phototoxic side effects in physiology, while its phototoxic mechanism is ambiguous. To uncover CP's photophysical and photochemical reaction processes, femtosecond to nanosecond transient absorption spectroscopies were employed to directly detect excited states and transient intermediates of CP upon UV irradiation in pure acetonitrile (MeCN), MeCN/water 1:1, and acid/alkaline buffer solutions. The transient absorption data together with DFT calculations were integrated to elucidate mechanisms for photochemical reactions of CP in different solutions. The associated photophysical and photochemical reaction pathways are dependent on various solution environments. In a pure MeCN solvent, CP is excited to a singlet state (S) and rapidly interacts with the solvent to proceed solvent rearrangement (SR). It then undergoes vibrational cooling (VC) and proceeds intersystem crossing (ISC) to produce the lowest triplet state (CP). CP finally decays to the ground state. While in a MeCN/water 1:1 solution, deprotonated S of CP experiences SR and VC processes, and then it is promoted to a deprotonated triplet state (CP). CP undergoes the parallel reactions: dechlorination to a phenyl radical (CP) and decarboxylation to a T anion (CP(de-CO)). Finally, both intermediates produce the radical anion species CP(de-CO). In a pH = 7.4 (MeCN/PBS 1:1) solution, CP can be converted into CP(de-CO) more quickly. Interestingly, we found that the dechlorination step can be promoted in an alkaline solution. Phenyl and chlorine radicals produced in an aqueous solution may be the root cause of the drug's harmful side effects on the human body. This may be useful to guide the design of related CP drugs with minimal phototoxicity in the pharmaceutical process.
卡洛芬（CP）是一种非甾体抗炎药，在生理学上表现出光毒性副作用，但其光毒性机制尚不清楚。为了揭示 CP 的光物理和光化学反应过程，我们采用飞秒到纳秒瞬态吸收光谱法直接检测 CP 在纯乙腈（MeCN）、MeCN/水 1:1 和酸/堿性缓冲溶液中经紫外光辐照后的激发态和瞬态中间体。瞬态吸收数据与 DFT 计算相结合，阐明了 CP 在不同溶液中光化学反应的机制。相关的光物理和光化学反应途径取决于不同的溶液环境。在纯 MeCN 溶剂中，CP 被激发到单重态（S），并迅速与溶剂相互作用进行溶剂重排（SR）。然后，它经历振动冷却（VC）并进行系间窜越（ISC），产生最低三重态（CP）。CP 最终回到基态。而在 MeCN/水 1:1 溶液中，CP 的去质子化 S 经历 SR 和 VC 过程，然后被激发到去质子化三重态（CP）。CP 经历平行反应：脱氯生成苯自由基（CP）和脱羧生成 T 阴离子（CP(de-CO)）。最后，两种中间体都生成自由基阴离子 CP(de-CO)。在 pH = 7.4（MeCN/PBS 1:1）溶液中，CP 可以更快地转化为 CP(de-CO)。有趣的是，我们发现脱氯步骤可以在堿性溶液中被促进。在水溶液中产生的苯和氯自由基可能是药物对人体产生有害副作用的根本原因。这可能有助于指导相关 CP 药物在药物过程中设计出最小光毒性的药物。
