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A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
Örebro University, Department of Natural Sciences. (Biofysikalisk kemi)
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5ALA) is a widely used prodrug in Photodynamic therapy (PDT). The target molecule in 5ALA-PDT is Protoporphyrin IX (PpIX), which is synthesized endogenously via the heme pathway in the cell. In this thesis; the structural and energetic properties of 5ALA, its methyl-, ethyl- and hexyl esters, four different 5ALA enols, and hydrated 5ALA have been investigated using Quantum Mechanical (QM) first principles calculations. The vacuum proton affinity (PA) of 5ALA is found to be in good agreement with other similar compounds. The keto-enol tautomerization mechanism of 5ALA has been studied, and a self-catalysis mechanism has been proposed to be the most probable. Molecular Dynamics (MD) simulations of a lipid bilayer have been performed to study the membrane permeability of 5ALA and its esters. In the simulations the molecules were inserted in the middle of the membrane, equilibrated, and then simulated in 20 ns. It has been found that there are some differences in penetration between the molecules studied. The methyl ester of 5ALA is diverging from the others by having its barrier not in the middle of the membrane, as the others have.

Place, publisher, year, edition, pages
2008. , p. 37
Series
Licentiate Thesises in Life Science, ISSN 1653-9516 ; 5
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-4627OAI: oai:DiVA.org:oru-4627DiVA, id: diva2:138926
Presentation
2008-03-06, 00:00 (English)
Opponent
Supervisors
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-10-18
List of papers
1. Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
2007 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, no 1-3, p. 101-106Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2007
Keyword
5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
National Category
Theoretical Chemistry Physical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
Available from: 2007-06-25 Created: 2007-06-25 Last updated: 2017-10-17Bibliographically approved
2. Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
2008 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, p. 4367-4374Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

Place, publisher, year, edition, pages
Washington DC: American Chemical Society, 2008
Keyword
Aminolevulinic Acid/*chemistry, Carboxylic Acids/chemistry, Catalysis, Isomerism, Protons, Quantum Theory, Thermodynamics, Water/chemistry
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Physical Chemistry Theoretical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-10-17Bibliographically approved
3. Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
Open this publication in new window or tab >>Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 178-182Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2008
Keyword
Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Physical Chemistry Theoretical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2018-01-13Bibliographically approved

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