ABSTRACT
Following the promising activity of Q2FA15 on axonal growth, two new series of N/O-substituted QFAs were synthesized, based on a SN2-type reaction. O-alkylated QFA bearing 14 carbon atoms on the side chain (n=14) shows a very potent activity on axonal growth though lowered when compared to Q2FA15. While O-alkylation allows good retention of the biological activity, N-alkylation abolishes it nonetheless. A solid-phase-supported synthesis of Q2FA15 allowing the conception of new hybrid compounds is also described.
Subject(s)
Axons/drug effects , Fatty Alcohols/chemical synthesis , Fatty Alcohols/pharmacology , Hydroquinones/chemical synthesis , Hydroquinones/pharmacology , Animals , Fatty Alcohols/chemistry , Hydroquinones/chemistry , MiceABSTRACT
The synthesis of three series of quinol fatty alcohols (QFAs) and their biological activities on the promotion of axonal growth are described. Interestingly, the 15-(2,5-dimethoxyphenyl)pentadecan-1-ol, the QFA bearing 15 carbon atoms on the side chain (n=15), shows the most potent promotion of axonal growth in the presence of both permissive and non-permissive naturally occurring substrates such as Sema3A and myelin proteins.
Subject(s)
Axons/drug effects , Hydroquinones/pharmacology , Antioxidants/pharmacologyABSTRACT
In a search for inducers of neuronal differentiation to treat neurodegenerative diseases such as Alzheimer's disease, a series of indole fatty alcohols (IFAs) were prepared. 13c (n = 18) was able to promote the differentiation of neural stem cell derived neurospheres into neurons at a concentration of 10 nM. Analysis of the expression of the Notch pathway genes in neurospheres treated during the differentiation phase with 13c (n = 18) revealed a significant decrease in the transcription of the Notch 4 receptor.
Subject(s)
Alcohols/chemical synthesis , Fatty Alcohols/chemical synthesis , Free Radical Scavengers/chemical synthesis , Indoles/chemical synthesis , Neurons/drug effects , Stem Cells/drug effects , Alcohols/chemistry , Alcohols/pharmacology , Animals , Benzothiazoles , Cell Differentiation/drug effects , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Free Radicals/chemistry , In Vitro Techniques , Indoles/chemistry , Indoles/pharmacology , Membrane Proteins/genetics , Membrane Proteins/physiology , Mice , Neurons/cytology , Oligonucleotides, Antisense/pharmacology , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Receptor, Notch1 , Receptor, Notch2 , Receptor, Notch4 , Receptors, Cell Surface/biosynthesis , Receptors, Cell Surface/genetics , Receptors, Notch , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/cytology , Structure-Activity Relationship , Sulfonic Acids/chemistry , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transcription, GeneticABSTRACT
One of the reasons for the lack of nerve regeneration in the CNS is the formation of a glial scar over-expressing multiple inhibitory factors including myelin-associated proteins and members of the Semaphorin family. Innovative therapeutic strategies must stimulate axon extension across the lesion site despite this inhibitory molecular barrier. We recently developed a synthetic neurotrophic compound combining an omega-alkanol with a retinol-like cycle (3-(15-hydroxy-pentadecyl)-2,4,4,-trimethyl-cyclohexen-2-one (tCFA15)). Here, we demonstrate that tCFA15 is able to promote cortical axon outgrowth in vitro even in the presence of the inhibitory Semaphorin 3A and myelin extracts. This growth-promoting effect is selectively observed in axons and requires multiple growth-associated intracellular pathways. Our results illustrate the potential use of synthetic neurotrophic compounds to promote nerve regeneration by counteracting the axonal growth inhibition triggered by glial scar-associated inhibitory factors.
