In Vitro Evaluation of a Series of N-Dodecanoyl-l-Amino Acid Methyl Esters as Dermal Penetration Enhancers

Fincher, Timothy K.; Yoo, Sun Dong; Player, Mark R.; Sowell, J. Walter; Michniak, B. B.

doi:10.1021/js9600787

Cited by 18 publications

(10 citation statements)

References 27 publications

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“…Corresponding compounds have been explored in the past as dermal penetration enhancers (Fincher et al . ) and, by us, as cytoprotective antioxidants in cell culture (Moosmann and Behl ). Model compounds were synthesized for six of the most enriched amino acids in integral membrane proteins, which collectively make up 57% of all amino acids in the transmembrane domains found in the human proteome (data not shown).…”

Section: Resultsmentioning

confidence: 95%

“…Amino acid‐lipid hybrid molecules (aminoacyllipids) were prepared essentially as described (Fincher et al . ; Moosmann and Behl ), using a Schotten‐Baumann procedure to couple the corresponding amine precursors and fatty acid acyl halides by base catalysis in tetrahydrofuran or dimethylformamide. Identity and purity were confirmed by analytical TLC, 1 H‐NMR spectroscopy, and, for some compounds, by HPLC and mass spectrometry (MALDI‐MS or electrospray‐ionization mass spectrometry).…”

Section: Methodsmentioning

confidence: 99%

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Membrane protein oxidation determines neuronal degeneration

Hajieva

Bayatti

Granold

et al. 2015

Journal of Neurochemistry

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Oxidative stress is an early hallmark in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, the critical biochemical effector mechanisms of oxidative neurotoxicity have remained surprisingly elusive. In screening various peroxides and potential substrates of oxidation for their effect on neuronal survival, we observed that intramembrane compounds were significantly more active than aqueous or amphiphilic compounds. To better understand this result, we synthesized a series of competitive and site-specific membrane protein oxidation inhibitors termed aminoacyllipids, whose structures were designed on the basis of amino acids frequently found at the protein-lipid interface of synaptic membrane proteins. Investigating the aminoacyllipids in primary neuronal culture, we found that the targeted protection of transmembrane tyrosine and tryptophan residues was sufficient to prevent neurotoxicity evoked by hydroperoxides, kainic acid, glutathione-depleting drugs, and certain amyloidogenic peptides, but ineffective against non-oxidative inducers of apoptosis such as sphingosine or Akt kinase inhibitors. Thus, the oxidative component of different neurotoxins appears to converge on neuronal membrane proteins, irrespective of the primary mechanism of cellular oxidant generation. Our results indicate the existence of a oneelectron redox cycle based on membrane protein aromatic surface amino acids, whose disturbance or overload leads to excessive membrane protein oxidation and neuronal death. However, comparative investigations of postmortem biomarker oxidation also have inherent limitations. In general, a chemical rationale for the observed structural specificity, if detected, can rarely be assigned. Moreover, it is usually impossible to assess through mere comparison the causal role of an oxidative event in disease progression. A causal Received March 18, 2014; revised manuscript received October 10, 2014; accepted October 24, 2014. Address correspondence and reprint requests to Parvana Hajieva and Christian Behl, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany. E-mail: hajieva@uni-mainz.de and cbehl@uni-mainz.de 1 Present address: Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, UK.Abbreviations used: 6-DCFA, 6-carboxy-2 0 ,7 0 -dichlorodihydrofluorescein diacetate bisacetoxymethyl ester; BSO, buthionine sulfoximine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

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Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Membrane protein oxidation determines neuronal degeneration

Hajieva

Bayatti

Granold

et al. 2015

Journal of Neurochemistry

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“…Natural AAs were from Sigma-Aldrich, and N-acetylated natural AA derivatives were from Bachem. N-dodecanoylated natural AA derivatives were synthesized from free amine precursors as described (42).…”

Section: Methodsmentioning

confidence: 99%

Modern diversification of the amino acid repertoire driven by oxygen

Granold

Hajieva

Toşa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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All extant life employs the same 20 amino acids for protein biosynthesis. Studies on the number of amino acids necessary to produce a foldable and catalytically active polypeptide have shown that a basis set of 7–13 amino acids is sufficient to build major structural elements of modern proteins. Hence, the reasons for the evolutionary selection of the current 20 amino acids out of a much larger available pool have remained elusive. Here, we have analyzed the quantum chemistry of all proteinogenic and various prebiotic amino acids. We find that the energetic HOMO–LUMO gap, a correlate of chemical reactivity, becomes incrementally closer in modern amino acids, reaching the level of specialized redox cofactors in the late amino acids tryptophan and selenocysteine. We show that the arising prediction of a higher reactivity of the more recently added amino acids is correct as regards various free radicals, particularly oxygen-derived peroxyl radicals. Moreover, we demonstrate an immediate survival benefit conferred by the enhanced redox reactivity of the modern amino acids tyrosine and tryptophan in oxidatively stressed cells. Our data indicate that in demanding building blocks with more versatile redox chemistry, biospheric molecular oxygen triggered the selective fixation of the last amino acids in the genetic code. Thus, functional rather than structural amino acid properties were decisive during the finalization of the universal genetic code.

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“…In a recent study, enhancers based on 10 different α-amino acids were compared [130]. The polar head consisted of an amino acid methyl ester; the dodecanoyl moiety attached to the amino acid nitrogen formed the hydrophobic part.…”

Section: N-dodecanoyl-l-amino Acid Methyl Estersmentioning

confidence: 99%

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

Vávrová

Zbytovská²,

Hrabálek³

2005

CMC

112

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Transdermal drug delivery offers numerous advantages over conventional routes of administration; however, poor permeation of most drugs across the skin barrier constitutes a serious limitation of this methodology. One of the approaches used to enlarge the number of transdermally-applicable drugs uses permeation enhancers. These compounds promote drug permeation through the skin by a reversible decrease of the barrier resistance. Enhancers can act on the stratum corneum intracellular keratin, influence desmosomes, modify the intercellular lipid domains or alter the solvent nature of the stratum corneum. Even though, hundreds of substances have been identified as permeation enhancers to date, yet our understanding of the structure-activity relationships is limited. In general, enhancers can be divided into two large groups: small polar solvents, e.g. ethanol, propylene glycol, dimethylsulfoxide and amphiphilic compounds containing a polar head and a hydrophobic chain, e.g. fatty acids and alcohols, 1-dodecylazepan-2-one (Azone), 2-nonyl-1,3-dioxolane (SEPA 009), and dodecyl-2-dimethylaminopropanoate (DDAIP). In this review we have focused on structure-activity relationships of amphiphilic permeation enhancers, including the properties of the hydrophobic chains, e.g. length, unsaturation, and branching, as well as the polar heads characteristics, e.g. hydrogen bonding ability, lipophilicity, and size. We present over 180 examples of enhancers with different polar head to illustrate the structural requirements and the possible role of the polar head. We have given an overview of the methods used for investigation of the mechanisms of permeation enhancement, namely differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, X-ray diffraction and future perspectives in this field. Furthermore, biodegradability and chirality of the enhancers are discussed.

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In Vitro Evaluation of a Series of N-Dodecanoyl-l-Amino Acid Methyl Esters as Dermal Penetration Enhancers

Cited by 18 publications

References 27 publications

Membrane protein oxidation determines neuronal degeneration

Membrane protein oxidation determines neuronal degeneration

Modern diversification of the amino acid repertoire driven by oxygen

Amphiphilic Transdermal Permeation Enhancers: Structure-Activity Relationships

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