Hemato-porphyrine derivate

Table 1 provides a fairly comprehensive listing of trivial names still in regular use in the porphyrin and chlorophyll area. The uro-, copro- and etio-porphyrins are examples of primary type isomer systems, while proto-, meso-, deutero- and hemato-porphyrins derive from the situation where 15 isomers exist. Phyllo-, pyrro- and rhodo-porphyrins, all being chlorophyll degradation products, are examples of the situation where there are four different kinds of porphyrin substituent. It transpires that, in biologically important porphyrin derivatives, the isomer chosen by Nature is Type-Ill (for the primary system), Type-IX (with three types of substituent) and Type-XV (with four). As can be seen in Schemes 1 and 2, primary type-III is related to type-IX in Scheme 2, and type-IX is in turn related to type-XV in the yet more complicated four-substituent system. 

Some of the key properties of a photosensitizer are high efficiency of singlet-oxygen generation, strong absorption in the red and particularly near-IR (660-800 nm), preferential affinity for tumor rather than healthy tissue, and rapid clearance from the body. Porphyrin and phthalocyanine dyes fit these criteria best, and much work has been done on these dye types [76], Photofrin, a hemato-porphyrin derivative, was the first photosensitizer to be approved for clinical use. It is a complex mixture of monomeric porphyrins (protoporphyrin, hematopor-phyrin (84), and hydroxyethylvinyldeuteroporphyrin) and oligomers of these porphyrins. 

Moan, J. and Sommer, S. (1985) Oxygen dependence of the photosensitizing effect of hemato-porphyrin derivative in NHIK 3025 cells, Cancer Res., 45 1608-1610. 

Early studies with PDT employed complex mixtures of poorly defined porphyrins known as hemato-porphyrin derivative (photofrin I) or a partially purified mixture known as porfimer sodium (PHOTOFRIN II) that was administered parenterally with subsequent irradiation using polychromatic light sources. The major problem with this approach was the prolonged period (4-6 weeks) of photosensitivity caused by skin retention of the porphyrin formulations. This led to a search for compounds that could be administered topically and that were eliminated more readily from the skin. The porphyrin precursor S-aminolevulinic acid (ALA) is converted to various porphyrins, particularly protoporphyrin (proto), in tissues including the skin (see below). Protoporphyrin subsequently is eliminated rapidly from the body, thereby minimizing the period of skin photosensitivity to a few hours. Topically applied ALA HCl (20% wA>) and, more recently, the methyl ester of ALA have been used successfully for the PDT of various types of nonmelanoma skin cancers and premalignant lesions. 

Recently, a method for diagnostics and treatment of cancer has been developed that is based on photoexcitation of the fluorescing substance hemato-porphyrin derivative (HPD) [15.154,15.155]. A solution of this substance is injected into the veins and is distributed in the whole body after a few hours. While HPD is released by normal cells after 2-4 days, it is kept by cancer cells for a longer time [15.156]. If a tissue containing HPD is irradiated by a UV laser, it emits a characteristic fluorescence spectrum, which can be used for a diagnostic of cancer cells. Figure 15.29 shows the emission spectrum of a tissue with and without HPD, and also the fluorescence of pure HPD in... 

Gibson, S.L. and Hilf, R., Photosensitization of mitochondrial cytochrome c oxidase by hemato-porphyrin derivative and related porphyrins in vitro and in vivo. Cancer Res., 43, 4191,1983. 

The synthesis of porphyrins from monopyrrolic, dipyrrolic, tripyrrolic and tctrapyrrolic precursors requires, even for an experienced porphyrin chemist, a substantial amount of time and effort to accomplish. As an alternative to these total synthetic routes, nature provides a source of prefabricated porphyrins. Among the several porphyrins which can be isolated from natural material,s the red blood pigment heme, protoporphyrin dimethyl ester81 b and hemato-porphyrin, both derived from heme, are the only compounds which can be obtained in sufficient amounts. Heme is available in almost unlimited amounts from slaughter-house waste. From 1 L of blood ca. 1 g of heme can be isolated.81 b Currently, heme is offered commercially by chemical retailers at a relatively low price so that is cheaper to buy hemin than to perform a self-isolation in the laboratory. 

Using a typical poly (vinyl chloride) (PVC)-based membrane with different ionophores - Zn-bis(2,4,4-trimethylpen-tyl) dithiophosphinic acid complex [450], protoporphyrin IX dimethyl ester [451], porphyrin derivative [452] and hemato-porphyrin IX [453], tetra(2-aminophenyl) porphyrin [454], cryptands [455, 456], 12-crown-4 [457], benzo-substituted macro-cyclic diamide [458], 5,6,14,15-dibenzo-l, 4-dioxa-8,l 2, diazacyclopentadecane-5,14-diene [459], and (A-[(ethyl-l-pyrrolidinyl-2 -methyl) ] methoxy-2-sulfamoyl-5 -benza-mide [460] - the sensors for zinc ions were prepared and investigated. The armed macrocycle, 5,7,7,12,14,14-hexamethyl-1,4,8,11 -tetraazacyclo tetradeca-4,11 -diene dihydrogen perchlorate was used for the preparation of polystyrene-based Zn(II)-sensitive electrode [461]. 

Another of the dicarboxylic porphyrins, present in highest concentration of the three, was a porphyrin which may be derived from hemato-porphyrin by a dehydration of one of the a-hydroxyethyl side chains. The third dicarboxylic porphyrin was protoporphyrin, which may be derived from the monovinyl porphyrin by a dehydration of the second hydroxyethyl group. The hematoporphyrin and the monovinyl compound appear to be the direct precursors of protoporphyrin. 

It should be noted here that there is a very wide latitude in the quality of the commercially available materials. Recently reported experiences with ferric hematoporphyrin derivatives are quite typical. In general, esters are better than the unesterified bases. For the blood-derived materials the usual order of quality goes deutero, hemato, and meso, with protoporphyrin the worst. For a well-defined preparation of natural porphyrins, it is always best to purify the starting material and to characterize it ° satisfactorily before carrying out any chemical modifications. 

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