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Structure/activity relationships among photosensitizers related to pheophorbides and bacteriopheophorbides

Abstract A series of long wavelength absorbing photosensitizers related to pheophorbide-a, pyropheophorbide-a, bacteriopheophorbide-a and chlorin-e 6 were synthesized and evaluated for their comparative in vivo tumorcidal activity and skin phototoxicity vis-a-vis Photofrin®. Structure/function relationships are discussed. All new photosensitizers were found to have high production of 1 O 2 and reduced skin phototoxicity compared to Photofrin®.

PHOTOSENSITIZATION WITH BACTERIOCHLORINS

Abstract— Biophysical and photobiological properties of a group of bacteriochlorins were compared with efficacy of these products for photodynamic therapy of murine tumors. Predictive factors for selective photosensitization in vivo include affinity binding to lipoproteins greater than albumin, extinction coefficient at the wavelength of irradiation and tumor/skin distribution. Efficacy was correlated with circulating plasma levels of the different sensitizers but not with the photodynamic therapy response in cell culture.

Efficient synthesis of porphyrin dimers with carbon-carbon linkages

Abstract Porphyrin dimers with carbon-carbon linkages were synthesized in excellent yield from (1-hydroxyethyl)porphyrins by treatment with triflic acid under mild reaction conditions. The method is used to prepare dimers which show promising tumorcidal activity in photodynamic therapy.

Regioselective syntheses of ether-linked porphyrin dimers and trimers related to photofrin-II®

Abstract Using isomerically pure 4-(1-hydroxyethyl)deuteroporphyrin-IX dimethyl ester 10 , 2-(1-hydroxyethyl)deuteroporphyrin-IX dimethyl ester 11 , 2-acetyl-4-(1-hydroxyethyl)deuteroporphyrin-IX dimethyl ester 12 and 4-acetyl-2-(1-hydroxyethyl)deuteroporphyrin-IX dimethyl ester 13 as starting materials, a series of regiochemically pure ether-linked porphyrin dimers 25–41 and trimers 42–47 related to an anticancer drug known as Photofrin-II® were synthesized. Proton NMR nuclear Overhauser enhancement experiments and variable temperature proton NMR spectroscopy were used to characterize the isomers. Some of these compounds were tested for their in vivo photosensitizing ability vis-a-vis Photofrin-II® and the preliminary results are briefly described.

Syntheses of new bacteriochlorins and their antitumor activity

Abstract Purpurin-18 methyl ester 1a was converted into a series of new bacteriochlorins 2b , 2c , 2f and 4b . These stable bacteriochlorins have strong long wavelength absorptions in the range of 760 to 816 nm, and were tested for in vivo photosensitizing activity using the standard screening system of DBA/2 mice bearing transplanted SMT/F tumors. In preliminary screening, among the photosensitizers tested so far, bacteriochlorins 2f and 4b have shown promising anti-tumor activity.

Substituent effects in tetrapyrrole subunit reactivity and pinacol-pinacolone rearrangements: Vic-dihydroxychlorins and vic-dihydroxybacteriochlorins

Regiospecificity of pyrrole subunit OsO4 oxidation in porphyrins is affected significantly by the presence of electron-withdrawing groups on the macrocycle, the oxidation taking place at the subunit in the quadrant opposite to the electronegative group. Migratory aptitudes in subsequent pinacol-pinacolone rearrangements of porphyrin and pheophorbide vic-dihydroxy systems are likewise dependent upon the presence of electron-withdrawing functionalities.

Syntheses of water-soluble cationic porphyrins and chlorins

Abstract Reactions of vinylchlorins and vinylporphyrins with N,N-dimethylmethyleneammonium iodide (“Eschenmosers Reagent”) gives Mannich adducts in which substitution (with CH2NMe2) has taken place on the terminal carbon of the vinyl group to yield a trans-3-(N,N-dimethylaminomethyl)prop-1-enyl derivative. Under no circumstances was meso substitution observed. Use of zinc(II) vinylchlorins or zinc(II) vinylporphyrins afforded the corresponding zinc(II) trans-vinyl adducts at a significantly faster rate than the metal-free substrates. Reaction of Eschenmosers reagent with deuteroporphyrin-IX dimethyl ester (29) (which possesses two peripherally unsubstituted positions) produces the bis-(N,N-dimethylaminomethyl) product (30). Treatment of the dimethylamino chlorins and porphyrins with methyl iodide, in all cases, gives an excellent yield of the corresponding quaternary ammonium iodides, and these compounds are highly water-soluble.

Long wavelength photosensitizers related to chlorins and bacteriochlorins for use in photodynamic therapy

A series of long wavelength photosensitizers related to chlorins and bacteriochlorins has been synthesized from the Diels–Alder reaction of protoporphyrin III dimethyl ester 6, or protoporphyrin II dimethyl ester 29. These porphyrins were prepared either by copper(II)-promoted cyclization of the corresponding a,c-biladienes or by following the modified MacDonald dipyrromethane approach. To eliminate the possibility of isomer formation in synthesis of so-called ‘benzoporphyrin derivatives’ and also to understand structure–activity relationships among various photosensitizers, Diels–Alder reactions were also performed on 13,17-bis(2-methoxycarbonylethyl)-2,3,8,12,18-pentamethyl-7-vinylporphyrin 21 and 3-(1-hydroxyethyl)-13,17-bis(2-methoxycarbonylethyl)-2,7,12,18-tetra-methyl-8-vinylporphyrin 22.

Syntheses, stability, and tumorcidal activity of porphyrin dimers and trimers with ether linkages

Abstract The first syntheses of a series of regiochemically pure porphyrin dimers and trimers with ether linkages which are structurally related to Photofrin-II® are described. Stability of these oligomers was investigated using variable temperature proton NMR spectroscopy, and preliminary biological results reveal that manupulation of peripheral substituents causes a remarkable difference in photosensitizing ability in vivo.

Syntheses of new porphyrin-type photosensitizers for photodynamic therapy

In the first part of this paper, syntheses of water-soluble photosensitizers for use in photodynamic therapy are described. Vinylporphyrins and vinylchlorins react with N.N- dimethylmethyleneammonium iodide (Eschenmosers reagent) to give 2- (dimethylaminomethyl)vinyl derivatives which can be readily quaternized with methyl iodide to give highly water-soluble quaternary ammonium salts. Deuteroporphyrin-IX dimethyl ester undergoes direct substitution with dimethylaminomethyl at the nuclear 2- and 4-positions. The second part of this report describes the syntheses of bacteriochlorin analogues of natural chlorophyll derivatives; these are obtained by osmium tetraoxide oxidation of chlorins to give vic-dihydroxybacteriochlorins. Acid catalyzed pinacol-pinacolone rearrangements of a number of vic-dihydroxybacterochlorins to given ketobacteriochlorins are described, and the chemistry of the rearrangement is investigated. Biological studies of all sensitizers described will be reported elsewhere.