Synthesis of KS15 derivatives as CRY-mediated circadian clock modulators

Abstract

Physiological and metabolic processes such as hormonal changes, metabolism, and sleep/wake cycles are attributed to the circadian clock. The autonomous circadian rhythms are orchestrated by transcriptional and translational feedback loops, which is constituted by the clock genes and proteins. Small molecules have been playing prominent roles in understanding the molecular clock machinery. KS15, a novel cryptochrome (CRY) inhibitor, is an ethoxypropanoic acid directly binding to CRY1/2 thereby modulating the molecular circadian clockwork. In spite of the physiological and clinical importance of circadian rhythms, only a part of the structural and functional properties of KS15 has been studied. Considering small-molecules modulating CRY provide unique chemical tools to understand the molecular circadian clock machinery along with numerous applications, it is of importance to have their derivatives evaluated. Hence, we undertook a systematic derivatization of KS15 and evaluation of the derivatives to further understand the depth of chemical perturbation on circadian clock machinery. Herewith, we would like to report our studies on the design, synthesis, and evaluation of KS15 derivatives. Examples will be discussed including varied alternative patterns of 2-ethoxypropanoic acid moiety, varied functional groups at the hydrophobic benzene ring, and conformationally restricted oxazolines and oxazoles in comparison of the oxime linker of KS15 on their molecular clock modulating activities. We believe the derivatization and functional studies based on the KS15 derivatives will pave the way for the development of novel therapeutics with circadian nature.