title: Synthesis and evaluation of synthetic retinoid derivatives as inducers of stem cell differentiation.
abstract: All-trans-retinoic acid (ATRA) and its associated analogues are important mediators of cell differentiation and function during the development of the nervous system. It is well known that ATRA can induce the differentiation of neural tissues from human pluripotent stem cells. However, it is not always appreciated that ATRA is highly susceptible to isomerisation when in solution, which can influence the effective concentration of ATRA and subsequently its biological activity. To address this source of variability, synthetic retinoid analogues have been designed and synthesised that retain stability during use and maintain biological function in comparison to ATRA. It is also shown that subtle modifications to the structure of the synthetic retinoid compound impacts significantly on biological activity, as when exposed to cultured human pluripotent stem cells, synthetic retinoid 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid, 4a (para-isomer), induces neural differentiation similarly to ATRA. In contrast, stem cells exposed to synthetic retinoid 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylethynyl)benzoic acid, 4b (meta-isomer), produce very few neurons and large numbers of epithelial-like cells. This type of structure-activity-relationship information for such synthetic retinoid compounds will further the ability to design more targeted systems capable of mediating robust and reproducible tissue differentiation.
authors.affiliation: Department of Biological Sciences, Durham University, Science Laboratories, South Road, Durham, DH1 3LE, UK.
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Christie
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Barnard
authors.forename: Andrei S
authors.initials: AS
authors.lastname: Batsanov
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bridgens
authors.forename: Emily B
authors.initials: EB
authors.lastname: Cartmell
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Collings
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Maltman
authors.forename: Christopher P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Todd B
authors.initials: TB
authors.lastname: Marder
authors.forename: Stefan
authors.initials: S
authors.lastname: Przyborski
authors.forename: Andrew
authors.initials: A
authors.lastname: Whiting
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015195:Drug Design; D047108:Embryonic Development; D006801:Humans; D008027:Light; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects*; D014212:Tretinoin / Q000737:chemistry
chemical_list: D012176:Retinoids; D014212:Tretinoin