RESUMO
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.
Assuntos
Axônios/efeitos dos fármacos , Álcoois Graxos/síntese química , Álcoois Graxos/farmacologia , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Animais , Álcoois Graxos/química , Hidroquinonas/química , CamundongosRESUMO
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.
Assuntos
Axônios/efeitos dos fármacos , Hidroquinonas/farmacologia , Antioxidantes/farmacologiaRESUMO
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.
Assuntos
Álcoois/síntese química , Álcoois Graxos/síntese química , Sequestradores de Radicais Livres/síntese química , Indóis/síntese química , Neurônios/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Álcoois/química , Álcoois/farmacologia , Animais , Benzotiazóis , Diferenciação Celular/efeitos dos fármacos , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Radicais Livres/química , Técnicas In Vitro , Indóis/química , Indóis/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Neurônios/citologia , Oligonucleotídeos Antissenso/farmacologia , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Receptor Notch1 , Receptor Notch2 , Receptor Notch4 , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Receptores Notch , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/citologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
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.
