Photoinduced halogen-bonding enabled synthesis of oxindoles and isoindolinones from aryl iodides.

We report the use of halogen bonding (XB) for the generation of aryl radicals from aryl halides under blue light irradiation and applied it in radical generation/1,5-hydrogen-atom transfer/radical cyclization cascade reactions for the synthesis of oxindoles and isoindolinones. On the basis of experimental studies, we propose that DBU can serve as a suitable XB acceptor with aryl halides for the formation of a photoactive electron donor and acceptor complex.

Catalytic charge transfer complex enabled difluoromethylation of enamides with difluoromethyltriphenylphosphonium bromide.

A catalytic charge transfer complex strategy that enabled difluoromethylation and ethoxycarbonylmonofluoromethylation of enamides with phosphonium bromine salts has been reported. This strategy also provides a convenient approach for the synthesis of functionalized oxindoles and 1,1-diphenylethylenes with easily available phosphonium bromine salts and a catalytic amount of iodine anion.

Self-assembled dehydropeptide nanocarrier as a delivery system for antitumor drug temozolomide.

Stable molecular conformation and intermolecular forces are essential for peptide self-assembly. In this study, one novel dehydropeptide (DDP) monomer (Boc-(Z)Cα,ß-ΔPhe-Gly-NHMe, DDP 1) was prepared; its conformation was confirmed to be more stable than the normal peptide 2 by nuclear magnetic resonance (NMR) and X-ray crystal diffraction experiments. DDP 1 was self-assembled to one novel dehydropeptide nanomaterial (DDPN 1). Fourier transform infrared (FTIR) spectroscopy results showed that hydrogen bonding was the main driving force of self-assembly. Electron microscope images displayed that the DDPN 1 fibers were longer and more stable than peptide 2 nanomaterials. Results of cell activity and enzyme hydrolysis proved that DDPN 1 had excellent biocompatibility and resistance to the enzymatic hydrolysis of protease K. Therefore, the DDPN 1 was used to load the antitumor drug temozolomide (TMZ). Due to intermolecular hydrogen bonds formed between TMZ and DDPN 1, TMZ-loaded DDPN 1 had a high percent entrapment efficiency (EE) of 83.72 ± 4.30% (n = 8) and a percent drug loading efficiency (LE) of 6.70 ± 0.34% (n = 8), and the half-life of TMZ-loaded DDPN 1 was 2.5-3 times longer than that of TMZ at pH 7. The in vitro cell viability results revealed that TMZ-loaded DDPN 1 exhibited higher antitumor activity (IC50 = 552.1 µM) against U118-MG than that of TMZ (IC50 = 1980.1 µM), possibly because that U118-MG cells uptook more TMZ from TMZ-loaded DDPN 1 than from free TMZ directly. This study is expected to inspire the design of biocompatible nanocarriers applied for anti-enzymatic hydrolysis in drug delivery systems.

Novel artemisinin derivatives with potent anticancer activities and the anti-colorectal cancer effect by the mitochondria-mediated pathway.

Many artemisinin derivatives have good inhibitory effects on malignant tumors. In this work, a novel series of artemisinin derivatives containing piperazine and fluorine groups were designed and synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies. The in vitro cytotoxicity against various cancer cell lines was evaluated. Among the derivatives, compound 12h was found to exhibit not only the best activity against HCT-116 cells (IC50 = 0.12 ± 0.05 µM), but also low toxicity against normal cell line L02 (IC50 = 12.46 ± 0.10 µM). The mechanisms study revealed that compound 12h caused the cell cycle arrest in G1 phase, induced apoptosis in a concentration-dependent manner, significantly reduced mitochondrial membrane potential, increased intracellular ROS and Ca2+ levels, up-regulated the expression of Bax, cleaved caspase-9, cleaved caspase-3, and down-regulated the expression of Bcl-2 protein. A series of analyses confirmed that 12h can inhibit HCT-116 cells migration and induce apoptosis by a mechanism of the mitochondria-mediated pathway in the HCT-116 cell line. The present work indicates that compound 12h may merit further investigation as a potential therapeutic agent for colorectal cancer.

Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents.

Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 µM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.

N-Heterocyclic carbene-catalyzed [3 + 2] annulation of bromoenals with 3-aminooxindoles: highly enantioselective synthesis of spirocyclic oxindolo-γ-lactams.

The chiral N-heterocyclic carbene-catalyzed [3 + 2] annulation of α-bromoenals and 3-aminooxindoles was developed, giving the corresponding spirocyclic oxindolo-γ-lactams in good yields with high diastereoselectivities and enantioselectivities.

Enantioselective N-heterocyclic carbene-catalyzed synthesis of trifluoromethyldihydropyridinones.

The enantioselective N-heterocyclic carbene-catalyzed [4 + 2] cyclocondensation of α-chloroaldehydes and trifluoromethyl N-Boc azadienes was developed, giving the corresponding 3,4-disubstituted-6-trifluoromethyldihydropyridin-2(1H)-ones in good yields with exclusive cis-selectivities and excellent enantioselectivities.

Design of novel CSA analogues as potential safeners and fungicides.

Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues.

Enantioselective N-heterocyclic carbene-catalyzed synthesis of indenopyrones.

The chiral N-heterocyclic carbene-catalyzed [4 + 2] cyclization of α-chloroaldehydes and arylidene indanediones was developed, giving the corresponding indenopyrones in good yields with high diastereoselectivities and enantioselectivities.

Synthesis, larvicidal activities and antifungal activities of novel chlorantraniliprole derivatives and their target in the ryanodine receptor.

In order to identify novel chlorantraniliprole derivatives as potential insecticides or fungicides, 25 analogues of chlorantraniliprole were synthesized. The insecticidal activities against oriental armyworm and the antifungal activities against five typical fungi of these derivatives were tested. Compounds 2u, 2x and 2y exhibited good activities against oriental armyworm, especially compounds 2u and 2x which showed higher larvicidal activities than indoxacarb. Moreover, all of the tested compounds exhibited activities against five typical fungi. The Ki values of all synthesized compounds were calculated using AutoDock4. The relationship between the Ki values and the results of insecticidal activities against oriental armyworm further indicated that the membrane-spanning domain protein of the ryanodine receptor might contain chlorantraniliprole binding sites.

[Research progress of small peptidomimetics].

The study of peptide drugs has been an important direction in research and development of new drugs. However, lots of natural macromolecular peptides are limited in clinical use by their metabolic instability and low bioavailability. In recent years, the active small peptidomimetics open up a new hotspot of peptide drug development with the characteristics of low molecular weight, high bioactivity and structural modification. Many peptidomimetics are on the market or on the clinical study. This paper elaborated the small peptidomimetics approved by American Food and Drug Administration (FDA) from 2005 to 2014, and reviewed their researching status with source, synthetic method, chemical structure, marketing time, indication, clinical efficacy and safety. Research prospects in this field were discussed.

Novel chlorantraniliprole derivatives as potential insecticides and probe to chlorantraniliprole binding site on ryanodine receptor.

The lepidopteran pests such as diamondback moth are the regularly harmful pests of crops in the world, which brings enormous losses in crop production. Chlorantraniliprole is an anthranilic diamide insecticide registered for the control of lepidopteran pests with high insecticidal activity, however with uncertain binding site action target of chlorantraniliprole on ryanodine receptor, a series of new chlorantraniliprole derivatives were synthesized and the insecticidal activities of these compounds against diamondback moth were evaluated with chlorantraniliprole and indoxacarb as control. All compounds except 8h, 8p and 8t exhibited varying degree of activities against diamondback moth. Especially, compounds 8c, 8i, 8k and 8l displayed good insecticidal activities against diamondback moth and the activities are even better than that of indoxacarb during 72 h period. The Ki values of all synthesized compounds were calculated through autodocking program respectively. The relationship between calculation value of molecular docking and results of insecticidal activities indicated that the proposed specific receptor, the membrane-spanning domain protein of diamondback moth ryanodine receptor in our study might have chlorantraniliprole binding sites.

Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum.

A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably, worm reduction rate of R-3 was 60.0% at a single oral dose of 200mg/kg against juvenile stage of Schistosoma japonicum. The target compounds displayed in vivo antischistosomal activity against both Schistosoma japonicum and Schistosoma mansoni. Furthermore, all R-isomers displayed stronger antischistosomal activity than S-isomers in vivo, indicating R-isomers were the active enantiomers, while S-isomers were less active ones. This structure activity relationship (SAR) could have important implications in further drug development for schistosomiasis.

Small change, big difference: A promising praziquantel derivative designated P96 with broad-spectrum antischistosomal activity for chemotherapy of schistosomiasis japonica.

BACKGROUND: Praziquantel (PZQ) has been the first line antischistosomal drug for all species of Schistosoma, and the only available drug for schistosomiasis japonica, without any alternative drugs since the 1980s. However, PZQ cannot prevent reinfection, and cannot cure schistosomiasis thoroughly because of its poor activity against juvenile schistosomes. In addition, reliance on a single drug is extremely dangerous, the development and spread of resistance to PZQ is becoming a great concern. Therefore, development of novel drug candidates for treatment and control of schistosomiasis is urgently needed. METHODOLOGYS/PRINCIPAL FINDINGS: One of the PZQ derivative christened P96 with the substitution of cyclohexyl by cyclopentyl was synthesized by School of Pharmaceutical Sciences of Shandong University. We investigated the in vitro and in vivo activities of P96 against different developmental stages of S. japonicum. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of P96 in vitro. Both mouse and rabbit models were employed to evaluate schistosomicidal efficacy of P96 in vivo. Besides calculation of worm reduction rate and egg reduction rate, quantitative real-time PCR was used to evaluate the in vivo antischistosomal activity of P96 at molecular level. In vitro, after 24h exposure, P96 demonstrated the highest activities against both juvenile and adult worm of S. japonicum in comparison to PZQ. The antischistosomal efficacy was concentration-dependent, with P96 at 50µM demonstrating the most evident schistosomicidal effect. Scanning electron microscopy demonstrated that P96 caused more severe damages to schistosomula and adult worm tegument compared to PZQ. In vivo, our results showed that P96 was effective against S. japonicum at all developmental stages. Notably, its efficacy against young stage worms was significantly improved compared to PZQ. Moreover, P96 retained the high activity comparable to PZQ against the adult worm of S. japonicum. CONCLUSIONS: P96 is a promising drug candidate for chemotherapy of schistosomiasis japonica, which has broad spectrum of action against various developmental stage, potentially addressing the deficiency of PZQ. It might be promoted as a drug candidate for use either alone or in combination with PZQ for the treatment of schistosomiasis.

Hepatic Aquaporin 10 Expression Is Downregulated by Activated NFκB Signaling in Human Obstructive Cholestasis.

Background and Aims: Recent studies reported that the hepatic expression of AQP8 and AQP9 was downregulated in bile duct-ligated (BDL) rats and that overexpression of human AQP1 in the rat liver attenuated cholestasis. However, the hepatic expression of AQP10 and its regulatory mechanism in human cholestasis remain unclear. Methods: Serum and liver samples were collected from 34 patients with obstructive cholestasis and from 12 control patients. Eight-week-old male C57BL/6J mice were intravenously injected with an adeno-associated virus 8 (AAV8) encoding human AQP10 driven by a hepatocyte-specific Alb promotor (AAV8-Alb promotor-hAQP10) for functional studies. Constructs of the AQP10 promoter and PLC/PRF/5-ASBT cell lines were used for regulatory mechanism studies. Results: AQP10 was significantly downregulated in patients with obstructive cholestasis and negatively associated with the serum levels of total bile acid (TBA). The hepatocyte-specific overexpression of hAQP10 significantly attenuated the cholestatic liver injury and intrahepatic bile acids (BA) accumulation in BDL mice. Conjugated BAs, such as TCA and inflammatory factor TNFα, significantly repressed AQP10 expression. Furthermore, NFκB p65/p50 directly bound to the AQP10 promotor and decreased its activity in PLC/RPF/5-ASBT cells and in the livers of patients with obstructive cholestasis. However, these changes were diminished by BAY 11-7082 (a specific inhibitor of NFκB signaling). Conclusion: We are the first to report that AQP10 was significantly decreased in patients with obstructive cholestasis. AQP10 overexpression significantly attenuated cholestatic liver injury in BDL mice. Therefore, overexpression of hAQP10 in the liver may be a valuable strategy for cholestasis intervention.

Interface assembly of specific recognition gripper wrapping on activated collagen fiber for synergistic capture effect of iodine.

Efficient capture of radioactive iodine (129I, 131I) is of great significance in spent fuel treatment. In this paper, a new adsorbent named Catechin@ACF was successfully prepared through interface assembly of specific recognition gripper with plant polyphenols (catechin) on activated collagen fiber (ACF), and the catechin membrane with specific grip on iodine was successfully constructed on the surface of ACF. The results showed that the adsorbent assembled catechin membrane was rich in aromatic rings, hydroxyl groups and imine adsorption sites, and possessed specific recognition and capture characteristics of iodine. Moreover, the as-prepared Catechin@ACF showed excellent capture capacity for iodine vapor and iodine in organic solution with the maximum capture capacity of 2122.68 mg/g and 258.29 mg/g, respectively. In iodine-cyclohexane solution, the adsorption process was in according with the Pseudo first order kinetic and Langmuir isothermal model. In addition, the specific recognition and capture mechanism analysis indicated that the aromatic rings, phenolic hydroxyl groups and imine groups in the catechin membrane were the specific and effective grippers for iodine, and finally iodine formed a stable conjugated system with the adsorbent in the form of I- and I3-. Therefore, the as-prepared specific iodine capturer Catechin@ACF was expected to play a vital role in the capture of radioactive iodine in spent fuel off-gas because of its specific recognition, high capture capacity, large-scale preparation, and environment-friendly.

Oxidized Bletilla rhizome polysaccharide-based aerogel with synergistic antibiosis and hemostasis for wound healing.

Uncontrolled bleeding and infection following trauma remain a clinical challenge. Here, we developed a synergistic hemostatic and antibacterial aerogel dressing based on oxidized Bletilla rhizome polysaccharide Schiff Base (ORBPS) and polyvinyl alcohol (PVA) by using a combined freeze-drying/cross-linking process. Bletilla rhizome polysaccharide (RBP) was extracted by water extraction and alcohol precipitation. RBP contained mannose and glucose in the molar ratio of 2:1 and its molecular weight was 8.2 × 105 g/mol. ORBPS was prepared via Schiff base reaction between silver sulfadiazine and oxidized RBP (ORBP), and verified by FTIR and NMR spectra. The resultant ORBPS/PVA aerogel exhibited excellent antibacterial and hemostatic capabilities. The aerogel also showed good liquid absorption capacity and biocompatibility. Full-thickness skin defect experiments indicated the aerogel enhanced wound healing by reducing inflammation, promoting angiogenesis, and accelerating epithelialization. Therefore, ORBPS/PVA aerogel may be a potential hemostasis and anti-infection wound dressing.

Novel nitrogen mustard-artemisinin hybrids with potent anti-leukemia action through DNA damage and activation of GPx.

The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is crucial. In this study, we designed and synthesized several hybrids and obtained a new lead molecule 5a, with a strong therapeutic effect on leukemia. The results indicated that most hybrids effectively inhibited the growth of leukemia cells, HCT-116, and A549 cancer cells with an IC50 of <10 µM. Among these hybrids, 5a and 4h showed significant anticancer activity against CCRF-CEM, with IC50 values of 0.895 µM and 0.555 µM, respectively. Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Upon investigating the mechanism of action, we found that 5a downregulated Bcl-2 and caused DNA double-stranded breaks (DSBs) to induce several genotoxic stress responses. The results of the flow cytometry assay showed that 5a was a non-specific molecule in the cell cycle. Furthermore, 5a did not affect total ROS levels but significantly improved the activity of glutathione peroxidase (GPx). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia.

Diversity oriented design of various benzophenone derivatives and their in vitro antifungal and antibacterial activities.

A series of new substituted benzophenone derivatives was designed, synthesized and screened for their antifungal and antibacterial activities. The bioassays indicated that most of the synthesized compounds showed some antifungal activity against the tested phytopathogenic fungi, but lower antibacterial activities towards the five vibrios isolated from marine sources. The preliminary structure activity relationship (SAR) of the compounds was also discussed.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR.

BACKGROUND: Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). METHODS: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. RESULTS: It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. CONCLUSION: The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.