Aminolevulinic acid esters

Tunstall, R.G., Barnett, A.A., Schofield, J., Griffiths, J., Vernon, D.I., Brown, S.B., and Roberts, D.J. (2002) Porphyrin accumulation induced by 5-aminolevulinic acid esters in tumor cells growing in vitro and in vivo, Br. J. Cancer, 87 246-250. 

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...

Washbrook, R. and Riley, PA. (1997) Comparison of 8-aminolevulinic acid and its methyl ester as an inducer of porphyrin synthesis in cultured cells, Br. J. Cancer, 75 1417-1420. 

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. 

Cottier L, Descotes G, Eymard L, Rapp K (1995) Syntheses of y-oxo acids or y-oxo esters by photooxygenation of furanic compounds and reduction under ultrasound application to the synthesis of 5-aminolevulinic acid hydrochloride. Synthesis 303-306... 

In plants treated with these herbicides, damage is light dependent and closely correlated with the level of PPIX that accumulates. PPIX accumulation is apparently largely extraplastidic. Treatment with the porphyrin precursor 5-aminolevulinic acid (ALA), in combination with the heme and chlorophyll pathway inhibitor 2,2 -dypyridyl (DP), results in the accumulation of toxic levels of primarily Mg-PPIX monomethyl ester. DP deregulates porphyrin synthesis and ALA provides additional substrate. DP and other chlorophyll synthesis modulators in combination with ALA can increase the selectivity as well as enhance the efficacy of ALA as a herbicide. Exogenously applied porphyrins are far less effective as herbicides than treatment with compounds that cause plants to accumulate their own porphyrins. 

A typical reaction that uses an amino acid derivative involves initial conversion to an enolate anion. This nucleophilic species is then reacted with an alkyl halide or a carbonyl derivative. An example that produces a new amino acid is the reaction of the ethyl ester of n-benzyl glycine with lithium diisopropylamide to give the enolate. Subsequent reaction with the mixed anhydride shown below proceeded with displacement of acetate to give /.22J.13 Acid hydrolysis generated a P-keto amino acid, which decarboxylated under the reaction conditions to give 4-oxo-5-aminopen-tanoic acid 1.156, also known as 5-aminolevulinic acid). 

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