Sharma Poornima, Gangopadhyay Debraj, Mishra Phool Chand, Mishra Hirdyesh, Singh Ranjan K
Department of Physics, Banaras Hindu University , Varanasi 221005, India.
Physics Department, MMV, Banaras Hindu University , Varanasi 221005, India.
J Med Chem. 2016 Apr 14;59(7):3418-26. doi: 10.1021/acs.jmedchem.6b00088. Epub 2016 Apr 1.
The metabolic transformation of antirheumatic fluorescent drug leflunomide into its active metabolite teriflunomide through isoxazole ring opening has been monitored in vitro using steady state and time domain fluorescence spectroscopy and density functional theory. During metabolic reaction, absorption of leflunomide split into two bands resembling absorption spectra of teriflunomide. The fluorescence spectra reveal slow conversion of leflunomide to E and Z forms of teriflunomide in aqueous medium, which becomes faster at basic pH. The E form, which is more potent as a drug, becomes more stable with an increase in the basicity of the medium. Both molecules are associated with charge transfer due to twisting in the lowest singlet excited state. Excited state charge transfer followed by proton transfer was also observed in the Z form during the ring opening of leflunomide. Quantum yield and radiative decay rates have been observed to decrease for the metabolite because of an increase in nonradiative decay channels.
利用稳态和时域荧光光谱以及密度泛函理论，在体外监测了抗风湿荧光药物来氟米特通过异恶唑环开环代谢转化为其活性代谢物特立氟胺的过程。在代谢反应过程中，来氟米特的吸收分裂为两个谱带，类似于特立氟胺的吸收光谱。荧光光谱显示，在水性介质中来氟米特缓慢转化为特立氟胺的E型和Z型，在碱性pH条件下转化速度加快。作为药物活性更强的E型，随着介质碱性的增加变得更加稳定。由于在最低单重激发态发生扭曲，两个分子都与电荷转移有关。在来氟米特开环过程中，Z型也观察到了激发态电荷转移随后的质子转移。由于非辐射衰变通道的增加，已观察到代谢物的量子产率和辐射衰变率降低。
