Diverse rearranged phragmalin-type limonoids from the leaves of Swietenia macrophylla and their hypoglycemic activity

Swietenia macrophylla King (Meliaceae), a valuable tree species, is extensively cultivated in tropical regions, holding significant economic value. The seeds and leaves of S. macrophylla, obtained as a by-product of wood processing, have been demonstrated to possess hypoglycemic and lipid-lowering effects. To further explore their potential applications, eighteen new phragmalin-type limonoids (1-18), alongside thirteen known analogues (19-31), were isolated from the leaves of Swietenia macrophylla. Swietelactones A (1) and B (2) represent a pair of C-1 ' heterotropic isomers characterized by a rare spiro[5,5]undecane moiety and a distinctive C-15 ethyl chain. Swietelactone C (3) is notable as the first identified 2,3-seco phragmalin limonoid, presumably formed via Baeyer-Villiger oxidation. Swietelactones D (4) and E (5) exhibit a stereoscopic configuration that deviates from the typical structure of limonoids, representing the first instance of a 9 beta-H limonoid. Compounds 3, 8-13, 16, 17, 20, 21, 23, 24 demonstrated inhibitory effects on hepatic glucose production in mouse primary hepatocytes (MPH) models and triglyceride production in Hep G2 cells at a concentration of 40 mu M. Moreover, compound 21 was found to initiate a cascade reaction, suppressing the expression of PCK1, a crucial gluconeogenic enzyme. This inhibition occurs through the downregulation of PKA-alpha protein and its downstream phosphorylated CREB protein, ultimately reducing hepatic glucose production. This research may offer valuable insights supporting the potential medical application of S. macrophylla as a natural hypoglycemic agent.