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

Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids

“…Testing the biological activity of novel retinoids is essential for asking whether apparent selectivity in ligand binding translates to retinoid-dependent biological activity . The ligand binding assays supported previous reports 29 that GZ25 exhibits strong biological activity but, for other GZ compounds, the evidence of reduced ability to recruit coactivator raised major questions about likely biological activity. RAR-mediated mechanisms as drivers of biological responses are poorly understood because of the confounding effects of varying RAR specificity of different gene promoters, cellular context and the potential for simultaneous and/or sequential interactions of different RARs.…”

“…To probe the relationships between structure and function of synthetic retinoid-like molecules we have used compounds built around a central 2,4-disubstituted thiazole linker; this thiazole sub-structure imposes a slight twist in the overall shape of the molecule which may mimic the preferred binding conformation of ATRA 23 and may confer selectivity for RARα via interactions with Ser232. 26 , 27 , 28 Members of this synthetic retinoid series (designated GZ, the synthesis of which is reported previously 29 ) have either polyalkoxyalkyl (GZ18), phenyl (GZ24 and the ester GZ22) or 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthyl (GZ25 and the ester GZ23) hydrophobic regions ( Fig. 1 ).…”

Thiazole formation through a modified Gewald reaction

“…The lack of reactivity of substrate 47 can be attributed to the high degree of steric hindrance inhibiting its enolisation. In summary, although our evidence indicates mechanism A is the most likely pathway it should be noted that several benzonitrile derivatives have been shown to successfully result in thiazole formation when reacted with coupling partners such as 2-mercaptopropionic acid, therefore mechanism B could operate under certain conditions [32]. …”

Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes

“…Synthetic retinoids (RAR-Ms) were dissolved in DMSO to give 0.01 M stock solutions. RAR-Ms were designed and synthesized as described previously [31][32][33][34][35][36][37]. The molecular structures of the RAR-Ms are shown in Fig.…”