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 liposome membranes. Libraries with up to 666 components were prepared with substituents including Br, CF3, Cl, CN, CO2Me, Et, F, OAc, and Ph. Further, a first example for the synthesis of more diverse libraries via 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 quantitative reaction that produces the library compounds as the only non-volatile components. Libraries were characterized by laser desorption time-of-flight mass spectrometry, NMR, and UV-vis spectroscopy. In vitro uptake into membranes of small sonicated liposomes was measured, both in terms of total porphyrin incorporation and in terms of structure-incorporation relationships. The latter were determined from isotopically-resolved laser-desorption mass spectra under conditions that yield 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 selectivity disappears for larger libraries, however, where uniformly high uptake is observed, i.e., at a constant lipid:porphyrin ratio the total porphyrin incorporation is higher for libraries than for single compounds of similar polarity. We propose that the decreased concentration of individual compounds in large libraries is responsible for this effect. Membrane incorporation has previously been shown to correlate with photodynamic activity in vitro and in vivo.16 Therefore, these results may help to explain why photodynamic therapy of tumors, a modern anti-cancer treatment modality, is successfully performed with a complex mixture of porphyrins.
Berlin
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K
Department of Chemistry, Tufts University, Medford, Massachusetts 02155, USA.
Jain
R K
RK
Richert
C
C
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017323:Dihematoporphyrin Ether / Q000737:chemistry; D008081:Liposomes / Q000378:metabolism; D013058:Mass Spectrometry; D008566:Membranes / Q000378:metabolism; D019151:Peptide Library; D010778:Photochemotherapy; D011166:Porphyrins / Q000737:chemistry / Q000627:therapeutic use*; D013678:Technology, Pharmaceutical / Q000379:methods*
D000970:Antineoplastic Agents; D008081:Liposomes; D019151:Peptide Library; D011166:Porphyrins; D017323:Dihematoporphyrin Ether