Multicomponent synthesis and in vitro screening of new prodrug derivatives of 5-aminolaevulinic acid for Photodynamic Therapy

GABRIEL F. GOLA; DANIEL A. SÁENZ; GABRIELA DI VENOSA; ADRIANA G. CASAS; LYDIA R. GALAGOVSKY; JAVIER A. RAMÍREZ

San Francisco

Congreso; 248th American Chemical Society National Meeting; 2014

American Chemical Society

Photodynamic Therapy (PDT) is a non-thermal technique for inducing tissue damage with light following administration of a light-activated photosensitising drug which can be selectively retained in malignant or diseased lesions relative to normal adjacent tissues. The exogenous administration of 5-aminolaevulinic acid (ALA) is a relatively new approach in PDT since it is a naturally precursor of protoporphyrin IX (PPIX) which is an intermediate in the haem biosynthetic pathway. PDT treatment is carried out using red light to activate the PPIX, resulting in the generation of cytotoxic reactive oxygen species. Because conversion of PPIX to haem is a rate-limiting step, the exogenous administration of ALA can induce significant intracellular levels of PPIX, which is an effective photosensitiser. At present, the main clinical PDT application of ALA is the treatment of basal cell carcinomas (BCCs), using topical administration. However, ALA is a zwitterion at physiological pH and therefore has low lipid solubility, which limits its clinical application. More lipophilic ALA prodrugs are expected to cross cellular membranes more easily than ALA itself, resulting both in an enhanced depth of penetration and a shorter topical application time. It has been reported that long chain ALA esters are taken up, desterified, and converted into PPIX with higher efficiency than ALA, leading to higher photosensitiser levels both in vivo and in vitro. We aimed at choosing a synthetic strategy allowing a simple and fast generation of new ALA prodrugs having a high structural diversity. Multicomponent reactions based on the exceptional reactivity of the isocyanide functional group are best suited to achieve this goal. In this work we describe the synthesis of a library of ALA derivatives using both the Passerini and the Ugi reactions, and the preliminary screening of the new compounds as potential pro-photosensitizers for PDT of cancer cell lines of different tissues.