Structurally Diverse Phenolic Amides from the Fruits of Lycium barbarum with Potent α-Glucosidase, Dipeptidyl Peptidase-4 Inhibitory, and PPAR-γ Agonistic Activities.

A total of nine new phenolic amides (1-9), including four pairs of enantiomeric mixtures (3-5 and 8), along with ten known analogues (10-19) were identified from the fruits of Lycium barbarum using bioassay-guided chromatographic fractionation. Their structures were elucidated by comprehensive spectroscopic and spectrometric analyses, chiral HPLC analyses, and quantum NMR, and electronic circular dichroism calculations. Compounds 5-7 are the first example of feruloyl tyramine dimers fused through a cyclobutane ring. The activity results indicated that compounds 1, 11, and 13-17 exhibited remarkable inhibition against α-glucosidase with IC50 of 1.11-33.53 µM, 5-150 times stronger than acarbose (IC50 = 169.78 µM). Meanwhile, compounds 4a, 4b, 5a, 5b, 13, and 14 exerted moderate agonistic activities for peroxisome proliferator-activated receptor (PPAR-γ), with EC50 values of 10.09-44.26 µM. Especially,compound 14 also presented inhibitory activity on dipeptidyl peptidase-4 (DPPIV), with an IC50 value of 47.13 µM. Furthermore, the banding manner of compounds 14 and 17 with the active site of α-glucosidase, DPPIV, and PPAR-γ was explored by employing molecular docking analysis.

Monomeric and dimeric guaianolide sesquiterpenoids with hypoglycemic activity from Achillea alpina.

Three new monomeric (1-3) and two newdimeric guaianolides (4 and 5), along with three known analogues (6-8) were isolated from the aerial part of Achillea alpina L. Compounds 1-3 were three novel 1,10-seco-guaianolides, while 4 and 5 were two novel 1,10-seco-guaianolides involved heterodimeric [4 + 2] adducts. The new structures were elucidated by analysis of spectroscopic data and quantum chemical calculations. All isolates were evaluated for their hypoglycemic activity with a glucose consumption model in palmitic acid (PA)-induced HepG2-insulin resistance (IR) cells, and compound 1 showed the most promising activity. A mechanistic study revealed that compound 1 appeared to mediate hypoglycemic activity via inhibition of the ROS/TXNIP/NLRP3/caspase-1 pathway.

LSD1 inhibitors from the roots of Pueraria lobata.

One new 6a,11a-dehydropterocarpan derivative, 6-O-methyl-anhydrotuberosin (1), one new 6a-hydroxypterocarpan, (6aR,11aR,11bR)-hydroxytuberosone (7), and seven known compounds including two 6a,11a-dehydropterocarpans (2 and 4), two coumestans (3 and 5), one isoflavonoid (6) and two other phenolic compounds (8 and 9) were isolated from the roots of Pueraria lobata. The structures of the isolated compounds were elucidated with spectroscopic and spectrometric methods (1 D and 2DNMR, HRESIMS). Compounds 1, 2, 4-5 showed potent LSD1 inhibitory activities with IC50 values ranging from 1.73 to 4.99 µM. Furthermore, compound 2 showed potent cytotoxicity against gastric cancer cell lines MGC-803 and BGC-823, and lung cancer cell lines H1299 and H460.

1,10-seco guaianolide-type sesquiterpenoids from Chrysanthemum indicum.

ABSTACTA chemical investigation of the whole plant of traditional Chinese medicine, Chrysanthemum indicum L., led to the discovery of six guaianolide-type sesquiterpenoids 1-6 with a 1,10-splited skeleton. The structure of the new compound 1 was established by extensive analysis of UV, IR, MS, NMR and ECD data. Compounds 3-6 are mutually stereoisomers with four chiral centers and their absolute configurations were determined by comparison of ECD spectra. The anti-inflammatory effects of these isolates on lipopolysaccharide (LPS)-induced nitric oxide (NO) were investigated in RAW 264.7 cells. Results showed that most of the compounds displayed NO production inhibitory activities with IC50 values ranged from 3.54 to 8.17 µM.

Unusual constituents from the medicinal mushroom Ganoderma lingzhi.

Extensive studies have revealed that triterpenoids, meroterpenoids, and polysaccharides are the main constituents of the well-known traditional Chinese medicinal mushroom Ganoderma. In this study, we report seven previously undescribed sesquiterpenoids, including six gymnomitranes (1-6) and a novel type of sesquiterpenoid (8), together with a polyketide (7) and a known steroid (9) from the fruiting bodies of Ganoderma lingzhi, a fungus used as traditional medicine and food supplement in East Asia for ages. The structures of 1-8 were deduced by analysis of spectroscopic data, X-ray single crystal diffractions and TDDFT/ECD calculations. Compound 8 possessed an unusual 14(7→6)-cuparane scaffold. Compound 9 exhibited weak cytotoxicity against the five human cancer cell lines HL-60, MCF-7, SW480, A549, and SMMC-7721 with IC50 values of 18.0-32.3 µM. A simple structure-activity-relationship (SAR) investigation by acetylating the 5-OH of 9 (9a) suggested that the 5-OH is essential for its cytotoxicity. Additionally, the biosynthetic pathways for compounds 2 and 8 are discussed.

Chemical Space of FLT3 Inhibitors as Potential Anti-AML Drugs.

BACKGROUND: FLT3 is a member of receptor tyrosine kinase III family, mainly expressed in hematopoietic cells. The aberrant expression and function of FLT3 are strongly related to leukemia, especially acute myeloid leukemia. Its varieties of amino-acid residues mutations, such as FLT3-ITDs and -TKDs, can induce constant proliferation of hematological tumor cells with poor prognosis. Hence FLT3 serves as a promising target in AML chemotherapy. OBJECTIVE: This review focused on the progress of FLT3 inhibitors study including those that have entered clinical trials or were reported in numerous patents all over the world. Thus, we provided a useful reference for the development of new anti-leukemia drugs. METHOD: Through a comprehensive retrospective study, FLT3 inhibitors in several patent applications were identified and classified into five categories, including quinolone-related, indole-related, ureas, pyrimidines and other compounds. RESULTS: For each category of compounds, the structural feature, SAR, biological activity and current research status were thoroughly reviewed and analyzed. CONCLUSION: Although some of those compounds expressed potent bioactivities and have reached the advanced clinical trials for the treatment of leukemia, there are still several problems need to be faced before they enter the market eventually, especially the drug resistance issue. The improvement of therapeutic potency for FLT3 inhibitors might depend on the useful combination therapy and further refinement of the intrinsic properties of FLT3 inhibitors.