Tuning the Reactivity of Alkoxyl Radicals from Cyclization to 1,2-Silyl Transfer: Stereoselective Synthesis of ß-Substituted Cycloalcohols.

Herein, we report a radical strategy for diastereoselective construction of ß-substituted cyclopentanols and cyclobutanols. The success of the reaction is attributed to the favorable radical 1,2-silyl transfer over the cyclization of alkoxy radicals to the olefins. The reaction shows broad substrate scope and wide functional-group tolerance. The synthetic potential of the methodology was demonstrated in the gram scale reaction and facile synthesis of various spiro compounds.

Synthesis of Stereodefined Trisubstituted Alkenyl Silanes Enabled by Borane Catalysis and Nickel Catalysis.

Regioselective and stereoselective synthesis of trisubstituted alkenyl silanes via hydrosilylation is challenging. Herein, we report the first ß-anti-selective addition of silanes to thioalkynes with B(C6F5)3 as the catalyst. The reaction shows broad substrate scope. The products were proven to be useful intermediates to other trisubstituted alkenyl silanes by Ni-catalyzed stereoretentive cross-coupling reactions of the C-S bond. A mechanism study suggests that nucleophilic attack of thioalkyne to an activated silylium intermediate might be the rate-determining step.

Synthesis of trifluoroalkyl or difluoroalkyl phenanthridine derivatives via cascade reaction using an intramolecular cyano group as a radical acceptor under photoredox catalysis.

In the presence of Ru(phen)3Cl2 or fac-Ir(ppy)3 under visible-light irradiation, the addition of fluorinated radicals to N-arylacrylamides followed by an intramolecular cyano group insertion cascade cyclization process produced trifluoroalkyl or difluoroalkyl phenanthridine derivatives in moderate to good yields. Three easily available fluoroalkylated reagents CF3SO2Cl, BrCF2CO2Et and BrCF2PO(OEt)2 were used as the sources of fluorinated radicals.

Design, synthesis and evaluation of the multidrug resistance-reversing activity of pyridine acid esters of podophyllotoxin in human leukemia cells.

Multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment. To overcome MDR, a serious of pyridine acid esters of podophyllotoxin was synthesized and their antiproliferation activities were evaluated against two human chronic myeloid leukemia cell lines in vitro. Most of them exhibited potent growth inhibition with IC50 values in the nanomolar range as well as markedly reduced resistance factors. The most potent compound, Y8 exhibited an IC50 of 0.046±0.003µM against resistance K562/ADR cells, showing more significant than that of adriamycin and etoposide, respectively. Furthermore, Y8 efficiently triggered cell cycle arrest at S phase and simultaneously induced apoptosis in K562/ADR cells. Meanwhile, Y8 also regulated the expression levels of cell cycle- and apoptosis-related proteins. Additionally, Y8 stimulated the ERK1/2 signalling and reduced the expression of Pgp protein. Finally, on the basis of results obtained using U0126, an ERK1/2 inhibitor, the ERK1/2 signalling pathway was proposed for the multidrug resistance-reversing effect of Y8 in K562/ADR cells. Together, Y8 could be a novel potential MDR reversal agent for the treatment of drug-resistant leukemia.

Aromatic heterocyclic esters of podophyllotoxin exert anti-MDR activity in human leukemia K562/ADR cells via ROS/MAPK signaling pathways.

Currently, multi-drug resistance (MDR) to antineoplastic drugs is a major obstacle to successful treatment of carcinoma. Looking for novel agents with anti-MDR activity is an effectively way to overcome cancer drug resistance. Our previous study showed that podophyllotoxin derivative exhibited potent anti-proliferative effect and down-regulated the expression level of P-gp in K562/ADR cells, which probably was related with the MAPK pathways. However, the relation of P-gp expression and MAPK pathways still remains unclear. In this study, a series of aromatic heterocyclic esters of podophyllotoxin were synthesized and their anticancer effects were evaluated against two human chronic myeloid leukemia cell lines (K562 and K562/ADR), simultaneously, the initial structure-activity relationship was summarized. The most potent compound, Z5, displayed an IC50 value of 0.032 ± 0.006 µM against K562/ADR cells, with a lower resistant factor value of 1.280. Treatment of K562/ADR cells with Z5 caused S cell cycle arrest through reductions in cyclinA, cyclinB1, CDK1 and CDK2 levels. Moreover, Z5 treatment resulted in the induction of apoptosis as characterized by DNA staining, flow cytometry analysis and cleavage of procaspases-3, -8, -9 and PARP. Notably, Z5 significantly inhibited P-gp expression in K562/ADR cells. Additionally, Z5 also caused reactive oxygen species (ROS) generation, which was further demonstrated by preincubation with the antioxidant N-acetylcysteine (NAC). Western blotting revealed that Z5 markedly stimulated the MAPK pathways, including ERK1/2, JNK and P38, however, the mechanisms were prevented by NAC. Finally, the employment of NAC and MAPK inhibitors (U0126, SP600125 and SB203580) remarkably blocked the S phase arrest, apoptosis and down-regulation of P-gp induced by Z5. Taken together, Z5 strongly possessed the potential anti-MDR activity in K562/ADR cells through ROS/MAPK pathways-dependent S phase arrest, apoptosis and down-regulation of P-gp expression.

Synthesis and biological evaluation of a novel artesunate-podophyllotoxin conjugate as anticancer agent.

A novel conjugate of artesunate-podophyllotoxin was prepared and evaluated for its cytotoxicity against diverse normal and multidrug resistance human cancer cell lines by CCK-8 assay. The conjugate exhibited good cytotoxicity on all the cell lines with IC50 values of 0.453±0.156-3.011±0.272µM and reduced the resistant factor. The conjugate was further found to disrupt the microtubule network and induce G2/M cell cycle arrest in multidrug resistance K562/ADR cells. Meanwhile, Hoechst staining analysis suggested that conjugate induced cell death by apoptosis. Furthermore, conjugate could downregulate the levels of P-glycoprotein (P-gp) in P-gp overexpressing K562/ADR cells.

Effect of Sini San freeze-dried powder on sleep-waking cycle in insomnia rats.

OBJECTIVE: To investigate the effects of the Sini San at different doses on each sleeping state [slow-wave sleep 1 (SWS 1), slow-wave sleep 2 (SWS2), rapid-eye-movement (REM), wakefulness (W)] in insomnia rats and to identify its mode of action for improving sleep. METHODS: The insomnia rats were randomly divided into a high-, medium- or low-dose group of Sini San (equal to crude drug 8.8, 4.4, or 2.2 g/kg, respectively) for seven consecutive days. RESULTS: Compared with pre-administration, SWS2 was significantly increased after administration of the low dose. Compared with pre-administration, W was significantly decreased and SWS1, SWS2, and the total sleeping time (TST) were markedly increased after administration of the medium dose. Compared with pre-administration, W was significantly decreased and SWS1, SWS2, rapid-eye-movement sleep, and TST were significantly longer after administration of the high dose. The effects of Sini San on sleep-wake cycle are dose-dependent. CONCLUSION: The results suggest that Sini San extends SWS1 and SWS2, which increases the total sleeping time.