Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis.
Abdellah EzzanadRicardo Gómez-OlivaFelipe Escobar-MontañoMónica Díez-SalgueroNoelia Geribaldi-DoldanSamuel Dominguez-GarciaJosé Manuel Botubol-AresCarolina de Los ReyesRosa Durán-PatrónPedro Nunez-AbadesAntonio José Macías-SánchezCarmen CastroRosario Hernández-GalánPublished in: Journal of medicinal chemistry (2021)
A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC-HRMS screening of the latex of Euphorbia resinifera. Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFGα) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGFα release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGFα assay and at inducing neural progenitor cell proliferation in vitro, also leading to enhanced neurogenesis in vivo when administered intranasally to mice.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- signaling pathway
- cerebral ischemia
- neural stem cells
- ms ms
- spinal cord injury
- high resolution mass spectrometry
- type diabetes
- metabolic syndrome
- high throughput
- subarachnoid hemorrhage
- drug delivery
- adipose tissue
- multiple sclerosis
- childhood cancer
- resting state
- risk assessment
- mass spectrometry
- high fat diet induced
- insulin resistance
- anti inflammatory
- blood brain barrier
- ultra high performance liquid chromatography
- tandem mass spectrometry