Total Synthesis Of Norartocarpin As A Natural Pancreatic Lipase Inhibitor

Norartocarpin (1),an isoprenylated flavone isolated from Artocarpus nitidus TREC. and Artocarpus hypargyreus HANCE, is first proved to be a promising candidate as a pancreatic lipase (PL) inhibitor by our research group. The activity of norartocarpin is comparable with that of olistat,a marketed PL inhibitor. Moreover, while controlling the weight of Zucker rats, norartocarpin did not significantly affect the appetite, which demonstrated its lower side effects.Due to the potent inhibitory activity against PL of norartocarpin, its total synthesis was pursued, with the aims of providing enough sample for further pharmacological study and obtaining more analogues of norartocarpin to investigate the structure activity relationship (SAR). Therefore, it is of great significance to establish the synthetic route of norartocarpin both in developing the synthetic methodology of natural isoprenylated flavonoids and in discovering novel drug candidates of intellectual property.After thoroughly investigating into three synthetic routes, the total synthesis of norartocarpin was achieved in0.41%overall yield via14steps with cheap and commercially available1,3,5-trimethoxybenzene as the starting material. By the same synthetic routes, another natural active product artocarpin could be attained. The total synthesis of norartocarpin and artocarpin were first completed and it should be of great values to the research and development of natural isoprenylated flavonoids resource.Totally48novel compounds were synthesized, whose structures were identified by1H NMR,13C NMR and MS spectra, and30of them were analogues of target molecule which were available for the bioassay.The inhibitory activities against PL of norartocarpin and its analogues as well as some novel synthetic intermediates were tested with olistat as the positive control. The bioassay data indicated that the target molecule (1) demonstrated remarkable inhibitory activity, whereas others were inactive. Accordingly, the following SAR information can be summarized on the basis of these preliminary bioassay results:(1) The flavone skeleton was crucial to the inhibitory activity against PL as all compounds without the flavone skeleton showed no activity.(2) The analogue99with substitution at C-6by3-methylbutanoyl was inactive, indicating that the3-methyl-l-butenyl group at C-6was also necessary to the activity.(3) Four OH groups on A and B rings were required to be exposed for the activity because the analogues with protection of OH by CH3, PMB or Bn (78、88a-b、89a-b、90a、92、93.98a、105and106) behaved without bioactivity.The SAR information will be helpful in further structural modifications of norartocarpin.During the synthesis of target molecule, a series of interesting chemical reaction features were observed and studied, which provided valuable experimental information on the synthesis and chemical properties of this type of isoprenylated flavonoids.