5-Aminolevulinic acid derivatives

Fotinos N, Campo MA, Popowycz F, Gurny R, Lange N (2006) 5-Aminolevulinic acid derivatives in photomedicine characteristics, application and perspectives. Photochemistry and Photobiology 82 994-1015. 

B.B. Noodt, K. Berg, T. Stokke, Q. Peng, J.M. Nesland (1996). Apoptosis and necrosis induced with light and 5-aminolevulinic acid-derived protoporphyrin IX. Br. J. Cancer, 74, 22-29. 

Q. Peng, J. Moan, T. Warloe, V. lani, H.B. Steen, A. Bjorseth, J.M. Nesland (1996). Build-up of esterified aminolevulinic-acid-derivative-induced porphyrin fluorescence in normal mouse skin. J. Photochem. Photobiol. B Biol., 34, 95-96. 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

Fig. 2 Examples of photosensitizers presently approved for clinical applications or in clinical studies. mTHPC, tetra (meso-hydroxy) phenyl chlorin BPD-MA, benzoporphyrin derivative Photofrin is a mixture of several compounds where dimers or trimers of the indicated structure are assumed to be of major importance PpIX, protoporphyrin IX - accumulating upon treatment with 5-aminolevulinic acid or its ester derivatives, NPe6, HPPH, Hexyl pyropheophorbide TPPS2a, disulfonated (adjacent) tetraphenylporphin AlPcS2a, disulfonated (adjacent) aluminum phthalocyanine. Areas with ionic side groups are indicated in shadow...

Aminolevulinic acid hydrobromide (233) gave 2,5-bis(2-carboxyethyl)pyrazine (235) (Et2N, 3-A molecularsieve, air, 20°C, 3 days 50%) 542 the intermediate 3,6-dihydro derivative (234) could be isolated as its HgCl2 complex.244... 

This brief survey of natural products derived from the 3-deoxy-D-oro6iTk>-heptulosonic acid 7-phosphate pathway illustrates the economy of fimda-mental biosynthetic pathways. The relative economy and simplicity of the biological degradative and energy-yielding reactions is paralleled in the biosynthetic reactions. For example, 3-deoxy-D-oroW o-heptulosonic acid 7-phosphate is a precursor of a host of aromatic products mevalonic acid is the progenitor of the terpenoids and steroids, and 5-aminolevulinic acid of the porphyrins. 

The fluorimetric determination of -aminolevulinic acid is based on derivati-zation with acetylacetone and formaldehyde. The fluorescent derivative was separated at ambient temperature from other reaction components on a Unisil NQ C18 column (4.6 mm x 250 mm). The mobile phase was composed of methanol-water-glacial acetic acid (600 400 10, v/v). Detection is by fluorescence (excitation, 370 nm emission, 460 nm). 

Kloek, J., Akkermans, W., and Beijersbergen van Henegouwen, G.M.J. (1998) Derivatives of 5-aminolevulinic acid for photodynamic therapy enzymatic conversion into protoporphyrin, Photochem. Photobiol., 67 150-154. 

Uehlinger, P., Zellweger, M., Wagnieres, G., Juillerat-JeannereL L., van den Bergh, H., and Lange, N. (2000) 5-Aminolevulinic acid and its derivatives physical chemical properties and protoporphyrin IX formation in cultured cells, J. Photochem. Photobiol. B Biol., 54 72-80. 

The shared structural core of tetrapyrroles intuitively implies a common biosynthetic pathway. This is indeed the case. All tetrapyrroles derive from a common precursor molecule, 5-aminolevulinic acid (ALA), and the following biosynthetic steps up to uroporphyrinogen III are all conserved. The major branching point occurs... 

Figure 18 Origin of the molecular framework of cobalamin. Adenosylcobalamin is derived from aminolevulinic acid, SAM, cobalt, glutamine, threonine, ATP, NaMN, and FMN. The diagram is color coded for easy interpretation.

All of the nitrogen in heme is derived from glycine and all of the carbons are derived from succinate and glycine. Thus, the process by which heme is synthesized is also called the succinate-glycine pathway. The first step in the process is catalyzed by a pyridoxal phosphate-containing enzyme, 5-aminolevulinic acid synthetase (ALA synthetase)... 

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. 

Z. Malik, M. Djaldetti (1979). 5-Aminolevulinic acid stimulation of derivative, and hemoglobin synthesis by uninduced friend erythroleukemic cells. Cell Differ., 8, 223-233. 

ALA, Aminolevulinic acid ALT, aspartate aminotransferase HpD, hematoporphyrin derivative mTHPC, 5,10,15,20-tetra(m-hydroxyphenyl)chlorin SCC, Squamous cell carcinoma TOP, tracheo esophageal fistula Tl, cancer involving the mucosa and/or submucosa T2, cancer invading into muscularis propria but not through this layer. Indicates number of tumors. 

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