A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).

In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.

Five new sesquiterpene polyol esters were isolated from the root bark of Celastrus angulatus by bioassay-guided fractionation. Their structures were determined by spectral data interpretation as 1alpha,2alpha,6beta,8beta,13-pentaacetoxy-9beta-benzoyloxy-4beta-hydroxy-beta-dihydroagarofuran (1), 1alpha,2alpha,6beta-triacetoxy-8alpha-(beta-furancarbonyloxy)-9beta-benzoyloxy-13-isobutanoyloxy-4beta-hydroxy-beta-dihydroagarofuran (2), 1alpha,2alpha,6beta-triacetoxy-8beta-isobutanoyloxy-9beta-(beta-furancarbonyloxy)-13-(alpha-methyl)butanoyloxy-4beta-hydroxy-beta-dihydroagarofuran (3), 1alpha,2alpha,6beta-triacetoxy-8alpha,13-diisobutanoyloxy-9beta-benzoyloxy-4beta-hydroxy-beta-dihydroagarofuran (4), and 1alpha,2alpha,6beta-triacetoxy-8alpha-isobutanoyloxy-9beta-benzoyloxy-13-(alpha-methyl)butanoyloxy-4beta-hydroxy-beta-dihydroagarofuran (5). Compounds 1-5 exhibited insecticidal activity against the larval of Mythimna separata.

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Four streptothricin-group antibiotics (1ϳ4) were isolated from the fermentation broth of Streptomyces qinlingensis sp. nov. Along with the known antibiotics streptothricins F (1) and D (3), two new members of this class (2, 4) were identified as 12-carbamoyl derivatives of 1 and 3, respectively, mainly by analysis of the IR, HR-MS and NMR spectral data. The antibacterial activities of 1ϳ4 against Escherichia coli (MICs 3.1, 25.0, 3.1 and 12.5 m g/ml), Bacillus subtilis (MICs 6.3, 25.0, 3.1 and 50 m g/ml), Staphylococcus aureus (MICs 12.5, Ͼ100.0, 6.3, Ͼ100.0 mg/ml), Bacillus cereus (MICs 25.0, 50.0, 25.0 and 50.0 mg/ml) and Pseudomonas aeruginosa (MICs 50.0, Ͼ100.0, 50.0, Ͼ100.0mg/ml) were assayed by micro-broth dilution. The results based on MIC data indicated that 2 and 4 exhibited significantly less potent antibacterial activities when compared to that of 1 and 3.