ARE PORPHYRIN MIXTURES FAVORABLE PHOTODYNAMIC ANTICANCER DRUGS - A MODEL STUDY WITH COMBINATORIAL LIBRARIES OF TETRAPHENYLPORPHYRINS

Reported here is the preparation of tetraphenylporphyrin libraries via efficient combinatorial solution-phase syntheses, their purification, and preliminary results from a bioorganic study on their uptake in li posome membranes. Libraries with up to 666 components were prepared wi th substituents including Br, CF3, Cl, CN, CO2Me, Et, F, OAc, and Ph. Further, a first example for the synthesis of more diverse libraries v ia a ''latent libraries'' approach is presented. This involves masking polar groups with lipophilic protecting groups. After purification of the latent library, the masking protecting groups are removed in a qu antitative reaction that produces the library compounds as the only no n-volatile components. Libraries were characterized by laser desorptio n time-of-flight mass spectrometry, NMR, and UV-vis spectroscopy. In v itro uptake into membranes of small sonicated liposomes was measured, both in terms of total porphyrin incorporation and in terms of structu re-incorporation relationships. The latter were determined from isotop ically-resolved laser-desorption mass spectra under conditions that yi eld quantitative results. Smaller libraries showed increased uptake of porphyrins bearing OH and CF3 substituents and lower uptake of ester- , alkyl-, and halide-bearing porphyrins. This structure-dependent sele ctivity disappears for larger libraries, however, where uniformly high uptake is observed, i.e., at a constant lipid:porphyrin ratio the tot al porphyrin incorporation is higher for libraries than for single com pounds of similar polarity. We propose that the decreased concentratio n of individual compounds in large libraries is responsible for this e ffect. Membrane incorporation has previously been shown to correlate w ith photodynamic activity in vitro and in vivo.(16) Therefore, these r esults may help to explain why photodynamic therapy of tumors, a moder n anti-cancer treatment modality, is successfully performed with a com plex mixture of porphyrins. (C) 1998 John Wiley & Sons, Inc.