A series of N4-benzylamine-N2-isopropyl-quinazoline-2,4-diamine derivatives has been synthesized and tested for antibacterial activity against five bacterial strains. Twelve different substituents on the N4-benzylamine group have been investigated along with replacement of the quinazoline core (with either a benzothiophene or regioisomeric pyridopyrimidine ring systems). In order to develop structure activity relationships, all derivatives were tested for their antibacterial activities against Escherichia coli and Staphylococcus aureus via Kirby–Bauer assays and minimum inhibitory concentration assays. Eight of the most potent compounds against S. aureus and E. coli were also screened against one strain of methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis and Salmonella typhimurium to further examine their antibacterial activities. Lead compound A5 showed good activities with MICs of 3.9 μg mL−1 against E. coli, S. aureus and S. epidermidis and 7.8 μg mL−1 against MRSA. Selected front runners were also screened for their DMPK properties in vitro to assess their potential for further development.

Convenient, practical and economical phosphorylation of thiols has been achieved via halogen- and metal-free K2CO3-promoted aerobic oxidative cross-coupling of trialkyl phosphites, dimethyl phenylphosphonite, or methyl diphenylphosphinite with thiophenols using air as the oxidant at room temperature. This transformation provides a straightforward route to the construction of phosphorus–sulfur bonds with wide functional group compatibility, which affords phosphorothioates in up to 94% yield.

•New turn-on fluorescent probe with high specificity towards DNA G-quadruplex structures.•Simple and small molecular probe integrated from natural product fragments of quinolinium salt and indolyl ring.•Stable imaging signal in live cells staining.A class of small 1-methylquinolinium-based molecular fluorescent probes with high specificity in DNA G-quadruplex structures imaging in live cells was developed through the structural inclusion with an indolyl moiety. The study reveals that the scaffold of 1-methylquinolinium and indole ring is a distinctive combination for molecular design of new probes with effective and sensitive fluorescent signal switch-on functionality, particularly for identifying telomeric DNA, recognizing G-quadruplexes in promoters, and imaging or visualization of DNA G-quadruplex from other DNA structures. In addition, the experimental results demonstrate a rarely investigated factor on the importance of the indolyl moiety and its position when conjugating with a 1-methylquinolinium scaffold though a ethylene bridge in molecular probe design and synthesis; and these factors are determined as the crucial root leading to the excellent fluorescent signal switch-on property for the specific discrimination of DNA G-quadruplexes against other nucleic acids in live human prostate cancer cells (PC-3 cells) experiments. The characteristics of the new probes were comprehensively investigated with fluorescence titration, native PAGE experiments, and CD analysis to validate the selectivity, sensitivity, and stability while interacting with DNA G-quadruplex structures.Download high-res image (227KB)Download full-size image

A new RNA-selective fluorescent dye integrated with a thiazole orange and a p-(methylthio)styryl moiety shows better nucleolus RNA staining and imaging performance in live cells than the commercial stains. It also exhibits excellent photostability, cell tolerance, and counterstain compatibility with 4′,6-diamidino-2-phenylindole for specific RNA–DNA colocalization in bioassays.

•Three terpenoids from A. trifoliatus were found to inhibit the growth and stimulate apoptosis in PC-3 cells.•These terpenoids strongly inhibited NF-κB transcriptional activity and suppressed phosphorylation of STAT3.•These terpenoids also inhibited the expression of survivin.•Triterpenoid 5 strongly inhibited the formation and growth of PC-3 xenograft tumours.•Triterpenoid 5 strongly decreased the expression of phospho-STAT3 and survivin in PC-3 xenograft tumours.Five terpenoids (1–5) from a vegetable plant Acanthopanax trifoliatus (L.) Merr. were investigated for their effects on human prostate cancer cells. The diterpenoid (3) and triterpenoids (4 and 5) were found to inhibit the growth and stimulate apoptosis in PC-3 cells. The effects of these terpenoids on PC-3 cells were associated with strong suppression of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). These terpenoids also inhibited the expression of survivin, a downstream target of NF-κB and STAT3. The in vivo study using a xenograft mouse model showed that 5 strongly inhibited the formation and growth of PC-3 tumours. Moreover, treatment with 5 strongly decreased the expression of phospho-STAT3 and survivin in PC-3 tumours. Our results indicate that 5 has preventive efficacy on the development of PC-3 xenograft tumours. This terpenoid may serve as a candidate for future development as a novel agent for prostate cancer prevention.

•Dyes with new structural scaffold based on a benzothiazole–benzofuroquinoline core with the incorporation of an amino group.•Application as a G-quadruplex fluorescent probe with excellent selectivity, sensitivity, and stability.•High fluorescent quantum yields when the dyes bound with G-quadruplex DNA.•New fluorescent dyes for living cell staining and imaging.A series of new benzothiazole–benzofuroquinoline conjugates were designed and synthesized to enhance the performance for the application as a G-quadruplex fluorescent probe. All compounds were characterized and the selectivity, sensitivity, and stability of these dyes interacting with G-quadruplex were studied by using fluorescence titration, native PAGE experiments, FRET and CD analysis. Significant enhancement of fluorescent quantum yield was observed when the compound bound with HRAS G-quadruplex. The results indicate that these compounds show much stronger binding affinity and fluorescent response to G-quadruplex than our previously reported benzothiazole–benzofuroquinoline core scaffold (CYTO) due to the incorporation of a specific amino moiety. The application of these new compounds as a fluorescent agent for living cell imaging was also demonstrated.

The flowers of Edgeworthia gardneri are consumed as an herbal tea in Tibet with potential health benefits. To complement the current knowledge regarding the chemical composition and antihyperglycemic activity of the flower of E. gardneri, two new phenolics, gardnerol A and B (1 and 2), along with 19 known phenolics were isolated from the flower of E. gardneri. All isolates were evaluated for their inhibitory activity against α-glucosidase. Compound 5, identified as the major constituent of the flower of E. gardneri, showed a significant α-glucosidase inhibitory activity and acted as a competitive inhibitor. The oral administration of compound 5 at a dose of 300 mg/kg significantly reduced the postprandial blood glucose levels of normal and streptozotocin (STZ)-induced diabetic mice. Furthermore, compound 5 significantly decreased the fasting blood glucose levels in STZ-induced diabetic mice.

In this study, a series of novel ursolic acid (UA) derivatives were designed and synthesized successfully via conjugation of hydrophilic and polar groups at 3-OH and/or 17-COOH position. Molecular docking studies were carried out with the binding of UA and acabose in the active site of α-glucosidase, in order to prove that the hydrophilic/polar moieties can interact with the hydrophobic group of the catalytic pocket and form hydrogen bonds. The bioactivities of these synthesized compounds against α-glucosidase were determined in vitro. Kinetic studies were performed to determine the mechanism of inhibition by compounds 3, 4, 10 and 11. The results indicated that most of the target compounds have significant inhibitory activity, and the compound 3, 4, 10 and 11 were potent inhibitors of α-glucosidase, with the IC50 values of 0.149 ± 0.007, 0.223 ± 0.023, 0.466 ± 0.016 and 0.298 ± 0.021 μM, respectively. These compounds were more potent than parent compound and acarbose. The kinetic inhibition studies revealed that compound 3 and 4 were mix-type inhibitors while compound 10 and 11 were non-competitive inhibitors. Furthermore, the molecular docking studies for these two kinds of compounds suggested that free carboxylic group at either C-3 or C-28 position could remarkably improve inhibitory activity. It is noteworthy that the exploration of relationship between hydrophilic and polar groups of these structures and the hydrophobic group in catalytic pocket is benefited from our rational design of potent α-glucosidase inhibitor.

Silibinin, a major polyphenol in milk thistle, has been reported to have multiple pharmacological activities; therefore, there is an urgent need to well understand how silibinin works on inflammation-associated skin diseases. We herein designed silibinin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated skin inflammation to test its inhibitory effects. It was demonstrated that silibinin, applied topically onto mouse ears following TPA stimulation, effectively down-regulated the expressions of TPA-induced interleukin-1β (IL-1β), interleukin-6 (IL-6), necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. Further mechanistic investigations indicated that silibinin suppressed the expression of IκB kinase (IKK) by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, and thereby suppressing TPA-stimulated nuclear factor-κB (NF-κB) activation. Promisingly, silibinin, used for transdermal application, may be a potent naturally occuring anti-inflammatory agent for the prevention of inflammation-associated skin diseases.

Magnolol is a major active constituent of Magnolia officinalis which is a natural traditional Chinese medicine. Inspired by magnolol which shows a wide diversity of bioactivities, a series of magnolol derivatives containing nonsteroidal anti-inflammatory drugs (NSAIDs) were designed, synthesized and screened for their anti-inflammatory activities by using a TPA-induced mouse ear edema model. These results indicated that in comparison with magnolol and ketoprofen, topical application of A10 (magnolol derivative containing ketoprofen) prior to TPA treatment markedly suppressed the expressions of IL-1β, IL-6 and TNF-α, respectively. Further mechanical investigations demonstrated that A10 inhibited IKK and IκBα phosphorylation, thereby suppressing the activation of p65. Accordingly, A10 may be a potent anti-inflammatory agent capable of preventing inflammation-associated edema.

The insertion of arynes into the O–H bond of aliphatic carboxylic acids promoted by sodium carboxylates is described. The reactions led to the formation of aryl carboxylates in good yields with good chemoselectivities under mild conditions.

(5S,8S,10aR)-tert-butyl 5-(tert-butoxycarbonylamino)-2,6-dioxooctahydro-1H-pyrrolo[2,1-d][1,5]oxazocine-8-carboxylate 5, containing an original proline-like moiety, was prepared through Yamaguchi lactonization. However, it was observed that this 8 + 5 bicyclic lactone was spontaneously rearranged to the corresponding 7 + 5 bicyclic lactam under acid conditions, used to remove the Boc/tBu protecting groups. Both core structures were confirmed by one-dimensional and two-dimensional NMR, as well as HRMS. The new proline-like moieties are unknown up to now, and the 7 + 5 bicyclic lactam, much more stable than its precursor, may represent a valuable template to develop constrained non-peptide mimetics.

Sixty-one curcumin-related compounds were synthesized and evaluated for their anticancer activity toward cultured prostate cancer PC-3 cells, pancreas cancer Panc-1 cells and colon cancer HT-29 cells. Inhibitory effects of these compounds on the growth of PC-3, Panc-1 and HT-29 cells were determined by the MTT assay. Compounds E10, F10, FN1 and FN2 exhibited exceptionally potent inhibitory effects on the growth of cultured PC-3, Panc-1 and HT-29 cells. The IC50 for these compounds was lower than 1 μM in all three cell lines. E10 was 72-, 46- and 117-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. F10 was 69-, 34- and 72-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. FN1 and FN2 had about the same inhibitory effect as E10 and F10 toward Panc-1 cells but were less active than E10 and F10 toward PC-3 and HT-29 cells. The active compounds were potent stimulators of apoptosis. The present study indicates that E10, F10, FN1 and FN2 may have useful anticancer activity.Graphical abstractWe report here on the synthesis and inhibitory effects of 61 curcumin-related compounds on the growth of cultured human prostate, pancreas and colon cancer cells. E10, F10, FN1 and FN2 were many-fold more active than curcumin.Highlights► Curcumin has been widely studied as an inhibitor of carcinogenesis. ► Sixty-one curcumin-related compounds were tested for effects on growth of cultured cancer cells. ► Many curcumin-related compounds inhibited the growth of prostate, pancreas and colon cancer cells. ► The most active curcumin-related compound was 46- to 117-fold more active than curcumin. ► Active curcumin-related compounds stimulated apoptosis in prostate cancer cells.

A new RNA-selective fluorescent dye integrated with a thiazole orange and a p-(methylthio)styryl moiety shows better nucleolus RNA staining and imaging performance in live cells than the commercial stains. It also exhibits excellent photostability, cell tolerance, and counterstain compatibility with 4′,6-diamidino-2-phenylindole for specific RNA–DNA colocalization in bioassays.