Kai-Bo Wang

Peganumine A, a β-Carboline Dimer with a New Octacyclic Scaffold from Peganum harmala

Peganumine A (1), a new dimeric β-carboline alkaloid characterized by a unique 3,9-diazatetracyclo[6.5.2.0(1,9).0(3,8)]pentadec-2-one scaffold, was isolated from the seeds of Peganum harmala. The structure including the absolute configuration was determined by spectroscopic data, X-ray crystallography, ECD calculation, and CD exciton chirality approaches. Compound 1 showed moderate cytotoxic activity against MCF-7, PC-3, and HepG2 cells and selective effects on HL-60 cells with an IC50 value of 5.8 μM.

Two Pairs of Enantiomeric Alkaloid Dimers from Macleaya cordata

Two pairs of enantiomeric alkaloid dimers, (±)-macleayins A (1) and B (2), representing a novel dimerization pattern of two different types of alkaloids via a C-C σ-bond, were isolated from the aerial parts of Macleaya cordata. The enantiomeric separation was achieved by chiral chromatography. Their structures and stereochemistry were determined by the analysis of extensive spectroscopic data, electronic circular dichroism calculation, and single-crystal X-ray diffraction data. (-)-Macleayin A exhibits modest cytotoxic activity against HL-60 cell line with the IC50 value of 3.51 μM.

Pegaharmalines A and B, two novel β-carboline alkaloids with unprecedented carbon skeletons from Peganum harmala

Pegaharmalines A (1) and B (2), two novel β-carboline alkaloids with unprecedented carbon skeletons, were isolated from the seeds of Peganum harmala. Their structures were determined by spectroscopic methods and the absolute configuration of 1 was elucidated by CD analysis. 1 and 2 exhibited significant cytotoxicities on HL-60 cells with IC50 values of 9.4 and 13.6 μM, respectively.

Butenolide derivatives from the plant endophytic fungus Aspergillus terreus

Three new butenolides containing 5-hydroxyfuran-2(5H)-one core, asperteretal A (1), asperteretal B (2), and asperteretal C (3), together with seven known butenolides (4-10), were obtained from an endophytic fungus Aspergillus terreus PR-P-2 isolated from the plant Camellia sinensis var. assamica. The structures of compounds 1-3 were elucidated on the basis of detailed spectroscopic analysis including UV, IR, HRESIMS, 1D and 2D NMR, and ECD spectra. Compounds 1, 3, 5 and 6-8 showed potent inhibitory effects on NO production in RAW 264.7 lipopolysaccharide-induced macrophages, and compounds 5 and 8 also exhibited moderate cytotoxicity against HL-60 cell line.

Structure-based virtual screening and ADME/T-based profiling for low molecular weight chemical starting points as p21-activated kinase 4 inhibitors

A structure-based virtual screening approach to targeting p21-activated kinase 4 (PAK4) was performed to identify good chemical starting points for medicinal chemistry. A pre-filtrated database was screened against two designed PAK4 pharmacophores, and the pharmacophore search hits were docked into a PAK4 crystal structure. Twenty-seven compounds were then selected for in vitro PAK4 inhibition assay, and results showed three compounds exhibiting a micro-molar IC50 in a dose–response assay. Interactive modes of the three compounds were studied and showed good binding modes in the PAK4 active site. Calculated ADME/T properties of the three hits were also analyzed and showed good drug-like properties. The results of in vitro PAK4 inhibition assay, interactive mode study and ADME/T prediction revealed that the three compounds have potential PAK4 inhibitory activities and can be further optimized and developed as lead compounds.

Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala

Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5-8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC50 value of 15.41 μM.

Antiproliferative Dimeric Aporphinoid Alkaloids from the Roots of Thalictrum cultratum

Inspired by the intriguing structures and bioactivities of dimeric alkaloids, 11 new thalifaberine-type aporphine-benzylisoquinoline alkaloids, thalicultratines A-K, a tetrahydroprotoberberine-aporphine alkaloid, thalicultratine L, and five known ones were isolated from the roots of Thalictrum cultratum. Their structures were defined on the basis of NMR and HRESIMS data. The antiproliferative activities of compounds 1-17 were evaluated against human leukemia HL-60 and prostate cancer PC-3 cells. Most alkaloids showed potent cytotoxicity against selected cancer cells. Preliminary SARs are discussed. The most active new compound (3), with an IC50 value of 1.06 μM against HL-60 cells, was selected for mechanism of action studies. The results revealed that compound 3 induced apoptosis and arrested the HL-60 cell cycle at the S phase with the loss of mitochondria membrane potential. The nuclear morphological Hoechst 33258 staining assay was also carried out, and the results confirmed apoptosis.

Paenibacillin A, a new 2(1H)-pyrazinone ring-containing natural product from the endophytic bacterium Paenibacillus sp. Xy-2

A new 2(1H)-pyrazinone ring-containing natural product, paenibacillin A (1), together with five known diketopiperazine derivatives 2–6 and two known isoflavones 7–8, was isolated from the culture of an endophytic bacterium Paenibacillus sp. Xy-2. The structure of compound 1 was elucidated by extensive spectral methods, including UV, IR, HR-ESI-MS, 1D and 2D NMR and ECD experiments. Compound 1 exhibited moderate cytotoxicity against HL-60 cell line with IC50 value of 50.48 μM.

Trametramide A, a new pyridone alkaloid from the fungus Trametes trogii TGC-P-3.

(30 cm×3.5 cm) over RP18 silica and eluted with gradients of H2OMeOH (1:0, 1 L), (4:1, 1 L), (7:3, 1 L), (3:2, 2 L), (1:1, 2 L), (2:3, 2 L), (3:7, 2 L), (1:4, 2 L), and (0:1, 2 L) to get 15 fractions (1–15). Fraction 2 (147mg) was chromatographed on a silica gel (85 cm×2 cm) using CHCl3/MeOH/H2O (32:8:1 and 30:10:1) to obtain compound 1 (2.7mg). Compounds 3 (22.8mg), 5 (15.5mg), and 7 (26mg) were obtained from fraction 9 (600mg) by CC on silica gel (90 cm×3.5 cm) by using CHCl3/MeOH/H2O mixtures (32:8:1 and 30:10:1)]. Fraction 5 (615mg) was subjected to CC [silica gel (85 cm×2.5 cm), using mixtures of CHCl3/MeOH/H2O (32:8:1 and 30:10:1)] to purify 6 (10mg), 8 (149mg), and 9 (50mg). Fraction 8 (408mg) was subjected to CC [silica gel (90 cm×2.5 cm), eluted by CHCl3/MeOH/H2Omixtures (32:8:1 and 30:10:1)] to afford yellowish brown needles of 2 (113.3mg). Compound 4 (10mg) was obtained by CC [silica gel (90 cm×2 cm), eluted by CHCl3/MeOH/ H2O mixtures (32:8:1 and 30:10:1)] of fraction 10 (240mg). (7R,8S,8′S)-4,9,4′-trihydroxy-3,3′-dimethoxy-4′-sulfonyl-7,9′-epoxylignan (1): White amorphous powder; [α] D +12 (c=0.1, MeOH); UV (MeOH) λmax 204, 277nm; IRνmax cm :1602, 1512, 1457, 1417, 1264, 1123, 1048, 3418, 2934; HRESIMS m/z 439.1026 [M H] (calcd for C20H23O9S, 439.1063); H and C NMR data (DMSO-d6) see Table 1.