Sensitizers hematoporphyrin

Given stringent requirements for effective sensitizers and the desire to use wavelengths further to the red for therapeutic appHcations, definition of newer sensitizers has been a principal area of research since about 1987. Expanded theoretical and experimental understanding of photophysics has been a key element in identifying new classes of potential sensitizers (93—98). Research has focused on cationic derivatives of Nile Blue (93), metaHo-phthalocyanines (94), naphthalocyanines (95), chlorin-type compounds (96), expanded ring porphyrinoids (97), as well as porphyrins other than hematoporphyrin and its derivatives (98). This work has also been reviewed (10,91). Instmmentation for photodynamic therapy has been reviewed (99). 

Dye-Sensitized Photoisomerization. One technological appHcation of photoisomerization is in the synthesis of vitamin A. In a mixture of vitamin A acetate (all-trans stmcture) and the 11-cis isomer (23), sensitized photoisomerization of the 11-cis to the all-trans molecule occurs using zinc tetraphenylporphyrin, chlorophyU, hematoporphyrin, rose bengal, or erythrosin as sensitizers (73). Another photoisomerization is reported to be responsible for dye laser mode-locking (74). In this example, one metastable isomer of an oxadicarbocyanine dye was formed during flashlamp excitation, and it was the isomer that exhibited mode-locking characteristics. 

Other important porphyrins which can be derived from hemin are hematoporphyrin (5) and mesoporphyrin (6). Hematoporphyrin (5) which is commercially available at a relatively low price is sensitive towards acid due to the 1-hydroxyethyl groups, so commercial samples contain only 60 to 70% of hematoporphyrin. Pure hematoporphyrin dimethyl ester which is a racemic and diastereomeric mixture of four stereoisomers can be obtained by esterification with diazomethane and subsequent chromatography on neutral alumina.84 The pure stereoisomers can be prepared by enantioselective reduction of diacetyldeuteroporphyrin dimethyl ester.85a b The... 

Most clinically used PDT sensitizers are metal-free porphyrins and porphyrin derivatives such as 56. Hematoporphyrin and its deriva-... 

Competitive photooxygenation of the substrate pair 1-methyl-cyclopentene (AJ/l-methylcyclohexene (A2) was studied by Kopecky and Reich.123 Using rose bengal, erythrosin, and eosin, as well as methylene blue and hematoporphyrin as sensitizers, the ratio kg1/kg2 was found to be independent of the nature of the sensitizer used, in agreement with the assumption that singlet oxygen is the oxygenating intermediate. 

Soncin M, Busetti A, Fusi F, Jori G, Rodgers MAJ. Irradiation of amelanotic melanoma cells with 532 nm high peak power pulsed laser radiation in the presence of the photo-thermal sensitizer Cu(II)-hematoporphyrin a new approach to cell photoinactivation. Photochem Photobiol 1999 69 708-12. 

Selective photosensitized oxidation of some amino acids present in proteins can be also utilized for specific labeling with a chosen sensitizer (methylene blue and hematoporphyrin for methionine, crystal violet or cresol red for cysteine, proflavine for tryptophan, etc.). This topic is described by Scoffone et al. 

Addition to 3,S-cyeloheptadiene-l-oi (1). Photogenerated singlet oxygen (hematoporphyrin hydrochloride, sensitizer) adds to 1 in a stereoselective manner isyn to OH) to give mainly the endoperoxide 2. The reaction of the acetate of 1 is less selective because the acetyl derivative of 3 rearranges readily under both photolytic and thermal conditions to a diepoxide. Under the same conditions the acetyl derivative of 2 is relatively stable. ... 

Photofrin (a mixture of hematoporphyrin derivatives including various dimers) and Foscan (H2TOHPC) are the most widely used sensitizers in oncologic PDT and are indicated for a variety of cancers 102,103). In vitro and in vivo studies reported for these sensitizers and for the new generation of bacteriochlorin... 

Weak electron acceptors with low triplet energies18 should be used as sensitizers. Tetraphenylporphin (34.0 keal/mol). metalloporphyrins (e.g.. zinc tetraphenylporphin), and hematoporphyrin (37.2 keal/mol) are suitable. Rose bengal (39.2-42.2 keal/mol) can be cm-... 

Reactions with steroidal monoolefins Photooxygenation of A2-3-methyl-5with methanolic sodium iodide, gives the two allylic alcohols (2) and (3). Similar oxidation of the isomeric A2-2-methyl-5a-cholestene yields the... 

E. Reddi, M.A.J. Rodgers, J.D. Spikes, G. Jori (1984). The effect of medium polarity on the hematoporphyrin-sensitized photooxidation of L-tryptophan. Photochem. Photobiol, 40,415-421. 

The effect was used to detect traces of oxygen [103, 104) produced in the photosynthetic process. TTypaflavine, benzoflavine, Euchrysine 3R, Rheonine 3 A, Rhoduline Yellow, safranine, chlorophyll, and hematoporphyrin adsorbed on silica gel or aluminium oxide were the dyes that were most efficiently quenched. Unfortunately, most dyes are photolabile, and traces of water or ammonia strongly interfere. Hydrogen, nitrogen, methane, ethylene, and carbon dioxide are without influence. The method is suitable for the extremely sensitive determination of oxygen at partial pressures between O.S and 0.006 kPa and is characterized by a fast response tim but requires several seconds for regeneration. 

J. Moan, H.B. Steen, K. Fehren, T. Christensen (1981). Uptake of hematoporphyrin derivative and sensitizer photoinactivation of C3H cells with different oncogenic potential. Cancer Lett., 14, 291-296. 

With these possibilities in mind we attempted the photo-oxygenation of norbornene. With either methylene blue or hematoporphyrin as sensitizer and methanol or pyridine as solvent, we obtained no evidence of any reaction by infrared or NMR spectrum, by gas chromatography, or by spot test for hydroperoxide (potassium iodide/starch in 2-propanol/ acetic acid) or peroxide (hydriodic acid/starch in 2-propanol). While the half-life of reaction of cyclohexene was only about one day under our reaction conditions, no evidence of reaction of norbornene was obtained in a period of one month. Assay of norbornene by gas chromatography with benzene as internal standard failed to show any depletion of norbornene over the attempted reaction interval. 

Moan and coworkers have reported a series of hematoporphyrin dialkyl ethers 1 (Scheme 2) and observed that the sensitizing efficiency increased with decreasing polarity. Hematoporphyrin diamyl ether was more efficient than HpD and was slightly less effective than Photofrin. Pandey et al. also observed that the di-phytyl ether derivative of hematoporphyrin 2 was nearly as active as Photofrin in vivo. However, the related phytyl ester derivatives 3 and protoporphyrin 4 did not show any photosensitizing activity. A few years later, Woodbum et al. and Reiss and coworkers reported a series of hematoporphyrin derivatives substituted at the 3 and 8 positions (lUPAC nomenclatiue) of the macrocycle with ether, thioether, ester and amino functions 5. Some of these analogues were found to be biologicaly active. 

Hematoporphyrin IX (HPIX) was the first porphyrin isolated from natural materials, obtained by the sulfiuic acid treatment of blood. HPIX, and some derivatives, are commercially available and have been reported to offer a wide variety of uses. They are used as sensitizes in cancer physiotherapy. These compoimds are selectively concentrated by neoplastic tissues, and accordmgly the tumors can be distinguished by selective fluorescence imder UV light. 

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