| Nigrasin I (1), an isoprenylated flavone isolated from Morus nigra Linn, is proved to possess the ability to increase the sensitivity of insulin and promote the glucose transport by promoting adipogenesis and the expression of glucose transporter 4 (GLUT 4). Additionally, it can inhibit pancreatic lipase (PL) to some extent. Therefore, Nigrasin I has great potential to be developed into a dual targeting drug candidate with antidiabetic and anti-obesity activities.Natural sources of 1 are very limited due to its extremely low contents in M. nigra, which affected the further biological evaluation for 1. Besides, the chemical synthesis of Nigrasin I has not yet been reported. In this thesis, its total synthesis and the syntheses of its analogues are pursued, with the aims of addressing the issue of its availability for further bioactivity assay and studying the structure activity relationship (SAR). Therefore, it is of great significance to establish the synthetic route of Nigrasin I both in developing the synthetic methodology of natural isoprenylated flavonoids and in discovering novel dual targeting drug candidates for metabolic diseases.After thorough investigation into three synthetic routes, the total synthesis of Nigrasin I was accomplished in 22% overall yield via 11 steps with cheap and commercially available 1-(2,4,6-trihydroxyphenyl)ethanone as the starting material. Besides, another bioactive natural product Kuwanon C was also synthesized in 21% overall yield through a key intermedidate from the route to Nigrasin I. During the synthetic process, the establishment of some new reaction conditions of Claisen rearrangement and debenzylation, has improved the efficiency of synthesis considerably. Totally 42 novel compounds were synthesized, whose structures were confirmed by 1H NMR,13C NMR and MS, and 36 of them were analogues of target molecule which were available for bioassay.Bioactivities of some compounds that were obtained at the early age of exploring the synthesis of Nigrasin I were tested, including the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) and NF-kB pathway. The bioassay data of the former indicated that all of those compounds demonstrated comparable or even better inhibitory activity than the positive control oleanolic acid. The SAR information can be summarized on the basis of those preliminary bioassay results:(1) The reverse prenyl side chain at 8-position has a positive effect on the inhibitory activity.(2) The prenyl side chain at 3-position is not crucial to the inhibitory activity.(3) The exposure of hydroxyl at 7-position is crucial to the inhibitory activity.(4) The protection of the two hydroxyls in ring B was beneficial to the activity, and the sterically hindered protecting groups like benzyl and benzoyl proved to be better than substituents like methyl and acetyl in improving bioactivity.The bioassay data of inhibitory activity against NF-κB indicated that only compounds 91 and 64 demonstrated inhibitory activity to some extent, whereas others were inactive. Accordingly, the SAR information can be summarized as fellows:The isoprenylization of 7-hydroxyl is crucial to the inhibitory activity, whereas the side chains at 3- and 8-positions are unnecessary to the activity.Besides, the activity assay of promoting adipogenesis and inhibiting pancreatic lipase is in progress.The SAR information obtained will undoubtedly be helpful in the further study of this series of compounds. |
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