Synthetic studies on 1,3-diketones leading to novel curcumin analogs
LE3 .A278 2016
Master of Science
This thesis is divided into four chapters. Chapter 1 presents a short review on the most recent studies on curcumin and its analogs, including the studies from the Jha research group. The diverse medicinal properties of curcumin itself reported in the recent years are reviewed. Although curcumin has shown great potential in treating various diseases, It has not been approved as a clinical drug candidate because of its poor pharmacokinetics. The recent methods developed to solve this problem are briefly described. The biological and other properties of synthetic curcumin analogs (diarylheptanoids and monocarbonyl derivatives) reported in the recent literature are also presented. To build the background and to highlight the purpose of the study reported in this thesis, this review details the past research activities on design, synthesis and bioevaluation of various synthetic curcumin analogs in the Jha research group. Chapter 2 reports the design, synthesis, and characterization of symmetrical diarylheptanoids as a new series of synthetic curcumin analogs. Sixteen novel (E,E)- 2,7-diarylidenedecalin-1,8-diones were successfully synthesized , purified and fully characterized by spectroscopic means. Structure of one compound in the series was unambiguously confirmed by single crystal X-ray crystallography. It is expected that the introduction of a cyclic structure from decalin-1,8-dione to the diarylheptanoid framework of curcumin would result in a better binding of the compounds with the receptor. Evaluation of biological activities of this series of compounds is underway, and the results will be reported in due course. Chapter 3 reports the design, synthesis, and characterization of unsymmetrical diarylheptanoids as another series of synthetic curcumin analogs. Eleven (E,E)-1-benzyl-xiii3-arylidene-5-(3-arylacryloyl)piperidin-4-ones were successfully synthesized, purified and completely characterized by NMR and HRMS data. Because of the presence of a tertiary lkyl basic N atom, the poor pharmacokinetics of these analogs can be overcome by synthesizing the corresponding acid salts (e.g. hydrochloride salt). Also, it is expected that the introduction of a cyclic structure from piperdine-4-one to the diarylheptanoid framework of curcumin would result in a better binding of the compounds with the appropriate receptor. These compounds have also been submitted for biological evaluation in the laboratories of our collaborators. Design, synthesis, and characterization of symmetrical and unsymmetrical ferrocene-based curcumin analogs as nother new series of redox-active synthetic curcumin analogs is presented in Chapter 4 of this thesis. Five ferrocene-based curcumin analogs were successfully synthesized from ferrocenecarboxaldehyde and appropriate β-diketones. These were purified and completely characterized by spectroscopic techniques. It is expected that he introduction of a ferrocene moiety to the diarylheptanoid framework of curcumin would result in enhanced iological activity as shown by other ferrocene containing bioactive molecules.
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