Structure, Self-Assembly, and Phase Behavior of Neuroactive -Acyl GABAs: Doxorubicin Encapsulation in NPGABA/DPPC Liposomes and Release Studies. | LitMetric
N-Acylated amino acids and neurotransmitters in mammals exert significant biological effects on the nervous system, immune responses, and vasculature. -Acyl derivatives of γ-aminobutyric acid (-acyl GABA), which belong to both classes mentioned above, are prominent among them. In this work, a homologous series of -acyl GABAs bearing saturated -acyl chains (C8-C18) have been synthesized and characterized with respect to self-assembly, thermotropic phase behavior, and supramolecular organization. Differential scanning calorimetric studies revealed that the transition enthalpies and entropies of -acyl GABAs are linearly dependent on the acyl chain length. The crystal structure of -tridecanoyl GABA showed that the molecules are packed in bilayers with the acyl chains aligned parallel to the bilayer normal and that the carboxyl groups from opposite layers associate to form dimeric structures involving strong O-H···O hydrogen bonds. In addition, N-H···O and C-H···O hydrogen bonds between amide moieties of adjacent molecules within each layer stabilize the molecular packing. Powder X-ray diffraction studies showed odd-even alternation in the spacings, suggesting that the odd chain and even chain compounds pack differently. Equimolar mixtures of -palmitoyl GABA and dipalmitoylphosphatidylcholine (DPPC) were found to form stable unilamellar vesicles with diameters of ∼300-340 nm, which could encapsulate doxorubicin, an anticancer drug, with higher efficiency and better release characteristics than DPPC liposomes at physiologically relevant pH. These liposomes exhibit faster release of doxorubicin at acidic pH (<7.0), indicating their potential utility as drug carriers in cancer chemotherapy.
N-Acylated amino acids and neurotransmitters in mammals exert significant biological effects on the nervous system, immune responses, and vasculature. -Acyl derivatives of γ-aminobutyric acid (-acyl GABA), which belong to both classes mentioned above, are prominent among them. In this work, a homologous series of -acyl GABAs bearing saturated -acyl chains (C8-C18) have been synthesized and characterized with respect to self-assembly, thermotropic phase behavior, and supramolecular organization.
We determined that compounds in which γ-aminobutyric acid (GABA) and linear saturated fatty acids of various lengths are amide-bonded, as found in the human brain, have the ability to gelate organic solvents. We also synthesized compounds of these GABA derivatives attached to 1,5-anhydro-d-glucitol (1,5-AG) or d-glucopyranose (Glc) via ester linkages, and these compounds were also found to be able to gelate organic solvents. From the comparative experiments of gelation using various lengths of -linear saturated fatty acyl-GABAs and their ester derivatives, it was determined that the compound of -tetradecanoic acyl-GABA bonded to 1,5-AG via ester linkage (CGABA-AG) had a particularly high gel hardness and could gelate various organic solvents.
Derived from arachidonic acid (AA), the endogenous cannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) is a substrate for α/β hydrolase domain-12 (ABHD12). Loss-of-function mutations of ABHD12 are associated with the neurodegenerative disorder polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC). ABHD12 knockout (KO) mice show PHARC-like behaviors in older adulthood.
