Reactive radical intermediates formed from illuminated nifedipine

Nifedipine, (1,4-dihydro-2,6,dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester) a calcium channel blocker widely used in treatment of hypertension, is strongly photolabile. This may represent a problem in patients taking nifedipine and in handling of nifedipine samples. Reactive radical intermediates were determined and characterized in the process of nifedipine illumination using EPR spectroscopy. On illumination of nifedipine by daylight or by a mercury lamp, a nitroxide radical, R^I_IL-NIFNO^.X was observed (in the first step), in various solvents like benzene, cyclohexane, methanol, acetonitrile, dimethylsulphoxide, or aqueous suspensions of liposomes. R^I_IL-NIF represents the nifedipine skeleton centered with phenyl group, and X is an EPR silent substituent. The generation of R^I_IL-NIFNO^.X is coupled with the formation of nitroso compound, R^I_IL-NIFNO, as characterized by UV-visible spectroscopy. In a further step, R^I_IL-NIFNO abstracts hydrogen from nifedipine skeleton under the formation of R^I_IL-NIFNO^.H radical. In addition to this, in system containing R^I_IL-NIFNO and unsaturated lipids, nitroxide radicals R_IL-INF^INO^.R_LIPIDS are formed probably via a pseudo Diels-Alder mechanism (R_LIPIDSrepresents lipidic skeleton). The unusually easy photochemical activation of nifedipine is probably stimulated by photosensitization of its nitro group interacting with suitably positioned hydrogen or carboxylic mehtyl ester group from the pyridynl ring.