A Comprehensive Photochemical and Photophysical Assay Exploring the Photoreactivity of Drugs

Abstract

What are the interests of a pharmaceutical company in «Photochemistry of Drugs» ? First of all drug-safety: safety by avoiding adverse effects in humans caused by exposure to light after the administration of certain drugs. Secondly, the photochemotherapy of skin diseases and human tumors is an active field of photomedicine. For this purpose pharmaceutical research should provide appropriate photosensitizers and the understanding of their mode of action. Furthermore, approaches to the protection of human skin against the harmful effects of solar radiation are of general interest and stimulate the development of novel sunscreens. The synthesis of sophisticated novel compounds using light as a highly selective reagent is an additional result of photochemical drug degradation studies in vitro. This is also relevant to the drug development process since toxic photodegradation products may contaminate the formulation, if the final drug or intermediary products are light-sensitive. This presentation, however, focuses on the photochemical and photophysical aspects of harmful effects to human skin, which may be produced by interaction of light and drug, and their possible prevention. Drug-induced photosensitization causing numerous adverse cutaneous responses or ocular complications in humans represents a severe side effect in the application of several pharmaceutically useful compounds. The different clinical manifestations observed in humans are classified as phototoxic, photoallergic, and drug-induced photosensitivity diseases. Typical photosensitizing drugs are selected from the literature, e.g. 8-methoxypsoralen, chlorpromazine, azathioprine, and nitroimidazoles (radiosensitizers), to demonstrate the diversity of the chemical reactions which are considered to be involved in the in vivo photosensitization reactions. – Consequently, a photochemical and photophysical in vitro assay is proposed, emphasizing the potential of photochemistry in rational drug design to minimize the aforementioned side effects. Connections to appropriate in vivo tests are considered. The screening of the antimalarial pyrimethamine combined with sulfadoxine and the antibacterial trimethoprim according to this assay led to a novel synthesis of 4-amino-s-triazinylketones via dye-sensitized photo-oxygenation of 2,4-diaminopyrimidines. Scope and limitations of this reaction will be discussed.