Nine naturally occurring prenylated isoflavones and three nonnatural analogues were synthesized for the first time. The 12 newly synthesized and 11 previously synthesized isoflavones were tested for their activity as modulators of Saccharomyces cerevisiae α-glucosidase. Out of the 23 prenylated isoflavones tested in total, 4',7-dihydroxy-3',5'-diprenylisoflavone ( 26 ) and 8-prenyldaidzein ( 28 ), both secondary plant metabolites originally isolated from Psoralea corylifolia , were found to be the most potent inhibitors of S. cerevisiae α-glucosidase, with IC 50 values of 7.8 ± 2.3 μM and 14.6 ± 5.1 μM, respectively. Kinetic analysis revealed that 26 acts through a noncompetitive mechanism and 28 through an uncompetitive mechanism of inhibition. Surprisingly, a few of the compounds tested, in particular isoflavones with a 6,7- and 3',4'-dioxy substitution pattern, were found to be activators of S. cerevisiae α-glucosidase. The most notable effects in this regard were observed for predurallone ( 21c ), a secondary plant metabolite originally isolated from Millettia dura , and its nonnatural analogue 7-methylpredurallone ( 22c ). At a concentration of 50 μM, both compounds enhanced the activity of S. cerevisiae α-glucosidase by 53.7 ± 8.8% and 41.5 ± 8.2%, respectively. To the best of our knowledge, these are the first examples of small molecule activators of this enzyme.

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Type 2 diabetes mellitus (T2DM) and cancers are two globally prevalent diseases which can increase the incidence of each other. Intestinal α-glucosidase and β-glucuronidase are key targets for glycaemic control and chemotherapy detoxification, respectively. This study first found that the leaf methanol extract of Millettia pachycarpa displayed dual inhibition to the two enzymes. The dually active constituents were then isolated and identified as two prenylated isoflavones of 6,8-diprenylorobol and 6,8-diprenylgenistein. Diprenylorobol exhibits competitive inhibition to both the two enzymes with K i values of 21.6 μM (α-glucosidase) and 1.41 μM (β-glucuronidase). Diprenylgenistein is an uncompetitive inhibitor of α-glucosidase ( K i = 11.4 μM) but a competitive inhibitor of β-glucuronidase ( K i = 1.69 μM). Molecular docking studies showed that both the two isoflavones tightly bind into the active pockets via various hydrogen bonds and hydrophobic interactions. In summary, the current study identifies two promising dual inhibitors of α-glucosidase and β-glucuronidase from the leaves of Millettia pachycarpa .

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In this study, we reported millepachine (MIL), a novel chalcone compound for the first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 µM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL's antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently inhibited tumor growth. Treatment of mice with MIL (20mg/kg intravenous [i.v.]) caused more than 65% tumor inhibition without cardiac damage compared with 47.57% tumor reduction by 5mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug.

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