A series of amino acid conjugates of chlorin e6, containing lysine or aspartic acid residues in positions 173, 152 or 131 of the macrocycle were synthesized and investigated as photosensitizers for photodynamic therapy of tumors. All three regioisomers were synthesized in good yields and in 5 steps or less from pheophytin a (1). In vitro investigations using human carcinoma HEp2 cells show that the 152-lysyl regioisomers accumulate the most within cells, and the most phototoxic are the 131 regioisomers. The main determinant of biological efficacy appears to be the conjugation site, probably because of molecular conformation. Molecular modeling investigations reveal that the 173-substituted chlorin e6 conjugates are L-shaped, the 152 and 131 regioisomers assume extended conformations, and the 131 derivatives are nearly linear. It is hypothesized that the 131-aspartylchlorin e6 conjugate may be a more efficient photosensitizer for PDT than the commercial currently used 152 derivative.
Chlorin e6 is a tricarboxylic acid degradation product of chlorophyll a. Four chlorin e6 bis(amino acid) conjugates were regioselectively synthesized bearing two aspartate conjugates in the 131,173- and 152,173-positions, or at the 131,152 via an ethylene diamine linker. One additional conjugate bearing two different amino acids, lysine at 131 via an ethylene diamine linker and an aspartate at 152 via a β-alanine linker was also synthesized. The cytotoxicity and uptake of four di(amino acid) chlorin e6 conjugates were investigated in human HEp2 cells, and compared with chlorin e6. The most cytotoxic and most taken up conjugates were the zwitterionic 131,152-disubstituted conjugates 28 and 33; these also localized in multiple organelles. In contrast, the tetra-anionic 131,173- and 152,173-di-aspartyl chlorin e6 conjugates 12 and 13 showed low dark cytoxicity and lower phototoxicity compared with chlorin e6.
As eries of largely p-extended multichromophoric molecules including cross-conjugated, half cross-conjugated, conjugation-interrupted and linearly conjugated systems were synthesized and characterized.T hese multichromophoric molecular systems revealed interesting structural-property relationships.B isporphyrin-fused pentacenes Pen-1 b and Pen-2 a showed rich redox chemistry with 7a nd 8o bservable redox states,r espectively.T he linearly-conjugated bisporphyrin-fused pentacenes (Pen-1 b and Pen-2 a)p ossess much narrower HOMO-LUMO gaps (1.65 and 1.42 eV redox, respectively) and higher HOMO energy levels than those of their pentacene analogues (2.23 and 2.01 eV redox, respectively), similar to those of muchl ess stable hexacenes and heptacenes.A ne stimated half-life of > 945 hw as obtained for bisporphyrin-fused pentacene Pen-2 a,w hich is much longer than that of its pentacene analogue (BPE-P,h alf-life, 33 h).
The synthesis of a series of β-functionalized push-pull dibenzoporphyrins was realized. These porphyrins display subtle push-pull effects, demonstrating the exceptional tunability of their electronic and electrochemical properties. The UV-vis spectra of these porphyrins show unique absorption patterns with shouldered Soret bands and extra absorptions in the Q-band region. Stronger electron-withdrawing groups display more significant bathochromic shifts of the Soret bands. The fluorescence spectra of these porphyrins show strong near-IR emission bands (600-850 nm). In particular, fluorescence quenching effect was observed for pyridyl carrying push-pull porphyrin 4c in the presence of an acid. TFA titration study of 4c using UV-vis and fluorescence spectroscopy reveals that the fluorescence quenching can be mainly attributed to the protonation of the pyridyl groups of 4c. The versatile synthetic methods developed in this work may open a door to access a large number of functionalized organic materials that are currently unavailable. The structure-property studies provided in this work may provide useful guidelines for the design of new generations of materials in dye-sensitized solar cells, in nonlinear optical applications, as fluorescence probes, as well as sensitizers for photodynamic therapy.
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