Synthesis and applications of 2,4-disubstituted thiazoles derivatives as small molecule modulators of cellular development

Zhou, G.-L.; Tams, D.M.; Marder, T.B.; Valentine, R.; Whiting, A.; Przyborski, S.A.

doi:10.1039/c3ob00005b

Synthesis and applications of 2,4-disubstituted thiazoles derivatives as small molecule modulators of cellular development Thumbnail

Authors

G.-L. Zhou

D.M. Tams

T.B. Marder

R. Valentine

Professor Andrew Whiting andy.whiting@durham.ac.uk
Professor

Professor Stefan Przyborski stefan.przyborski@durham.ac.uk
Acting Executive Dean

Abstract

Understanding how the structure of molecules relates to their function and biological activity is essential in the development of new analogues with targeted activity. This is especially relevant in mediating developmental processes in mammalian cells and the regulation of stem cell differentiation. In this study, thiazole-containing small molecules were synthesised and investigated for their ability to induce the differentiation of human pluripotent stem cells and their derivatives. Analyses of cell morphology, cell viability, expression of cell surface markers and ability to induce cell differentiation and regulate neurite formation identified the analogue with the longest and most bulky hydrophobic side chain as possessing comparable or enhanced activity to all-trans-retinoic acid (ATRA). Interestingly, a shorter, less bulky, known thiazole compound reported to be isoform selective for the retinoic acid receptor β2 (RARβ2) agonist did not mediate differentiation under the conditions tested; however, activity could be restored by adjusting the structure to a longer, more bulky molecule. These data provide further insight into the complexity of compound design in terms of developing small molecules with specific biological activities to control the development and differentiation of mammalian cells.

Citation

Zhou, G., Tams, D., Marder, T., Valentine, R., Whiting, A., & Przyborski, S. (2013). Synthesis and applications of 2,4-disubstituted thiazoles derivatives as small molecule modulators of cellular development. Organic and Biomolecular Chemistry, 11(14), 2323-2334. https://doi.org/10.1039/c3ob00005b

Journal Article Type	Article
Publication Date	Apr 14, 2013
Deposit Date	Nov 22, 2013
Publicly Available Date	May 22, 2014
Journal	Organic and Biomolecular Chemistry
Print ISSN	1477-0520
Electronic ISSN	1477-0539
Publisher	Royal Society of Chemistry
Peer Reviewed	Peer Reviewed
Volume	11
Issue	14
Pages	2323-2334
DOI	https://doi.org/10.1039/c3ob00005b