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Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
Örebro University, Department of Natural Sciences. (Biofysikalisk kemi)
Örebro University, Department of Natural Sciences. (Biofysikalisk kemi)
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. Vol. 434, no 1-3, p. 101-106
Keywords [en]
5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
National Category
Theoretical Chemistry Physical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-4092DOI: 10.1016/j.cplett.2006.11.084ISI: 000243820100020Scopus ID: 2-s2.0-33846018089OAI: oai:DiVA.org:oru-4092DiVA, id: diva2:138391
Available from: 2007-06-25 Created: 2007-06-25 Last updated: 2017-10-17Bibliographically approved
In thesis
1. A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
Open this publication in new window or tab >>A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
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.

Publisher
p. 37
Series
Licentiate Thesises in Life Science, ISSN 1653-9516 ; 5
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4627 (URN)
Presentation
2008-03-06, 00:00 (English)
Opponent
Supervisors
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-10-18
2. 5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Open this publication in new window or tab >>5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 76
Series
Örebro Studies in Life Science ; 6
Keywords
5-Aminolevulinic acid, tautomerization, PDT, DFT, MM, QM/MM, Porphobilinogen synthase, Uroporphyrinogen III decarboxylase, membrane penetration, enzyme mechanism
National Category
Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-9951 (URN)978-91-7668-718-5 (ISBN)
Public defence
2010-04-28, Hörsal M, Musikhögskolan, Örebro Universitet, Örebro, 10:15 (English)
Opponent
Supervisors
Available from: 2010-03-17 Created: 2010-03-10 Last updated: 2017-10-17Bibliographically approved

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Erdtman, EdvinEriksson, Leif A.

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