Circadian rhythms are self-autonomous endogenous clocks synchronized with the rotation of the Earth. With the Earth’s rotation and revolution on its axis, the internal clock undergoes oscillation in the period of ~24 hour and governs day to day activities in most organisms. In humans, it regulates the day to day physiological activities. Today’s modern lifestyle has an impact on health: shift work, jet lag, and irregular eating habits contribute to the misalignment of the endogenous circadian oscillator, thereby, increasing the risk of many metabolic disorders including diabetes, irregular blood pressure, sleep disorders, obesity, depression, and cancer. The primary goal of this research is to design and synthesize therapeutic circadian clock modulators to target clock-related dysfunctions.
This dissertation focusses on designing a library of small molecules which can act on core circadian rhythm proteins. More specifically, the goal is to synthesize different analogs to target cryptochrome. Cryptochrome is an integral part of the mammalian core circadian system and regulates the process of gluconeogenesis, therefore it has been identified as a potential target for type II diabetes. A carbazole scaffold (KL001) was shown to bind at the active site of cryptochrome resulting in a shift in circadian period, and modulation of gluconeogenesis. Herein, a library of the small molecules is synthesized and evaluated based on the structure-activity relationship of KL001.
Just like mammals, most living organisms have developed an endogenous circadian clock. In the latter part of the dissertation, the focus shifts to study of the crucial circadian rhythm proteins of plants. In plants, Light Oxygen Voltage (LOV) domain proteins play an essential role in photoperiodic growth events. LOV domains employ small molecule chemistry to sense blue light in the environment and facilitate plants acclimating their surroundings. In Arabidopsis, the Zeitlupe (ZTL), flavin binding kelch repeat F-box1 (FKF1) and LOV Kelch protein-2 (LKP2) work in concert to measure the day length and to determine flowering time and regulate other circadian processes. Specifically, the focus will be to study the thermal kinetics of LKP2 protein of Arabidopsis thaliana. Furthermore, this study is extended to examine the thermal kinetics of LKP2 protein in an agriculturally important crop Brassica rapa. Finally, a crystal structure of the cryptochrome-like algal protein OtCPF1 is discussed.
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Nagar, Aditi, "Design and Synthesis of Circadian Clock Modulators and The Study of LOV Domain Protein LKP2 in Arabidosis thaliana and Brassica rapa" (2018). Chemistry Theses and Dissertations. 7.