Synthesis and anticancer activity of novel rapamycin C-28 containing triazole moiety compounds.

Rapamycin is an mTOR allosteric inhibitor with multiple functions such as immunosuppressive, anticancer, and lifespan prolonging activities. Its C-43 semi-synthetic derivatives temsirolimus and everolimus have been used as mTOR targeting anticancer drugs in the clinic. Following our previous research on antitumor rapalogs modified on the C-43 position, 13 novel rapamycin triazole hybrids (6a-g, 7a-f) were designed and synthesized on the C-28 position of rapamycin via Huisgen's reaction. Anticancer assays indicated that the targeted derivatives containing phenyl and 4-methylphenyl groups showed an obvious raise in anticancer activity. On the contrary, the compounds with methoxyl, amine, and halogen groups on the benzene ring displayed lower anticancer activity. Compound 6c, as the most active compound, showed a stronger inhibition effect as compared with rapamycin for almost all of the tested cell lines (p < 0.01), except PC-3. Meanwhile, the effect of 6c on inducing apoptosis and cell cycle arrest in A549 cells was more powerful than that of rapamycin. In addition, 6c inhibited the phosphorylation of mTOR and its downstream key kinases 4EBP1 and p70S6K1 in A549 cells, indicating that 6c also effectively inhibits the mTORC1 signaling pathway as rapamycin. On the basis of these findings, 6c may have the potential to be developed as a new mTOR inhibitor against specific cancers.

Design, Synthesis and Biological Evaluation of Novel Rapamycin Benzothiazole Hybrids as mTOR Targeted Anti-cancer Agents.

The immunosuppressant drug rapamycin, was firstly identified as a mammalian target of rapamycin (mTOR) allosteric inhibitor, and its derivatives have been successfully developed as anti-cancer drugs. Therefore, finding rapamycin derivatives with better anti-cancer activity has been proved to be an effective way to discover new targeted anti-cancer drugs. In this paper, structure modification was performed at the C-43 position of rapamycin using bioisosterism and a hybrid approach: a series of novel rapamycin-benzothiazole hybrids 4a-e, 5a-c, and 9a, b have been designed, synthesized and evaluated for their anti-cancer activity against Caski, CNE-2, SGC-7901, PC-3, SK-NEP-1 and A-375 human cancer cell lines. Some of these compounds (4a-e, 9a, b) displayed good to excellent potency against the Caski and SK-NEP-1 cell line as compared with rapamycin. Compound 9b as the most active compound showed IC50 values of 8.3 (Caski) and 9.6 µM (SK-NEP-1), respectively. In addition, research on the mechanism showed that 9b was able to cause G1 phase arrest and induce apoptosis in the Caski cell line. Most importantly, it significantly decreased the phosphorylation of S6 ribosomal protein, p70S6K1 and 4EBP1, which indicated that 9b inhibited the cancer cell growth by blocking the mTOR pathway and may have the potential to become a new mTOR inhibitor.

Synthesis of Rapamycin Derivatives Containing the Triazole Moiety Used as Potential mTOR-Targeted Anticancer Agents.

Rapamycin, a potent antifungal antibiotic, was approved as immunosuppressant, and lately its derivatives have been developed into mTOR targeting anticancer drugs. Structure modification was performed at the C-42 position of rapamycin, and a novel series of rapamycin triazole hybrids (4a-d, 5a-e, 8a-e, and 9a-e) was facilely synthesized via Huisgen's reaction. The anticancer activity of these compounds was evaluated against the Caski, H1299, MGC-803, and H460 human cancer cell lines. Some of the derivatives (8a-e, 9a-e) appeared to have stronger activity than that of rapamycin; however, 4a-d and 5a-e failed to show potential anticancer activity. Compound 9e with a (2,4-dichlorophenylamino)methyl moiety on the triazole ring was the most active anticancer compound, which showed IC50 values of 6.05 (Caski), 7.89 (H1299), 25.88 (MGC-803), and 8.60 µM (H460). In addition, research on the mechanism showed that 9e was able to cause cell morphological changes and to induce apoptosis in the Caski cell line. Most importantly, 9e can decrease the phosphorylation of mTOR and of its downstream key proteins, S6 and P70S6K1, indicating that 9e can effectively inhibit the mTOR signaling pathway. Thus, it may have the potential to become a new mTOR inhibitor against various cancers.

ZnS nanoparticles well dispersed in ethylene glycol: coordination control synthesis and application as nanocomposite optical coatings.

The study of the preparation and application of ZnS nanoparticles (NPs) has been one of the most prominent hotspots in the domain of semiconductor NPs. The ZnS NPs usually exist in two crystallographic forms: zinc blende (cubic) and wurtzite (hexagonal). However, controlled preparation of ZnS NPs with specified crystallographic forms is still a difficult problem. Herein, zinc blende type ZnS NPs have been prepared by coordination control with diethanolamine (DEA) in ethylene glycol (EG). The prepared ZnS NPs can be well dispersed in EG without precipitation. The effect of DEA on the crystal form of the ZnS NPs was studied. We conclude that in EG, when no strong coordinating agent exists for the zinc ion, hexagonal crystal ZnS nanoparticles may be obtained, while coordinating agents such as acetate and DEA coordinated with the zinc(II) ion can inhibit the formation of the hexagonal ZnS crystal nucleus and the more stable zinc blende can be obtained. Moreover, transparent nanocomposite coatings of ZnS in PU matrix were prepared. This demonstrates that the incorporation of ZnS NPs can improve the refractive index of the optical coatings.

FIM-A, a phosphorus-containing sirolimus, inhibits the angiogenesis and proliferation of osteosarcomas.

The mTOR pathway is a central control of cell growth, proliferation, metabolism, and survival, and is deregulated in most cancers. Cancer cells are addicted to increased activity of mTOR kinase-mediated signaling pathways, leading to numerous inhibitors of mTOR signaling in preclinic and clinical trials for cancer therapy. Phosphorus-containing sirolimus (FIM-A), which targets mTOR signaling, inhibits cancer cell growth in vitro. Here we report that FIM-A reduces the angiogenesis and proliferation of osteosarcoma both in vitro and in vivo. In cultured osteosarcoma cell lines, FIM-A inhibited cell proliferation and arrested cells in the G1 phase of the cell cycle, accompanied with reduction of VEGF and HIF-1alpha. With in vivo mouse osteosarcoma xenografts, FIM-A treatment resulted in the inhibition of mTORC1 signaling as demonstrated by the decreased phosphorylation of p70S6K1 and 4E-BP1. Consistent with this finding, FIM-A significantly decreased the average tumor volume, nuclei staining of PCNA, and the number of intratumoral microvessels. Our data demonstrated that targeting mTORC1 by FIM-A inhibited the growth of osteosarcoma in vitro and in vivo, providing the basis for further development of FIM-A as a therapy for osteosarcoma patients.

41-Azido-41-de-oxy-rapamycin.

The title compound, C(51)H(78)N(4)O(12), is a derivative of rapamycin, a triene macrolide anti-biotic mol-ecule isolated from Streptomyces hygroscopicus. The macrocyclic ring structure has 15 chiral centres, with one of the substituent hy-droxy groups giving an intra-molecular hydrogen bond to a ketone O-atom acceptor. The mol-ecules also form inter-molecular hy-droxy-ketone O-H⋯O hydrogen-bonding associations, giving one-dimensional chains extending along (010). The crystal has 108 Å(3) solvent-accessible voids.

40-De-oxy-40(S)-iodo-rapamycin.

The title compound, C(51)H(78)INO(12), contains a 29-membered ring incorporating amide, lactone and ester groups. It contains a total of 15 stereogenic centres. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, forming C(8) chains propagating in [100]. A weak intra-molecular O-H⋯O inter-action also occurs.

Benzocyclobutene-functionalized hyperbranched polysiloxane for low-k materials with good thermostability.

Although hyperbranched polysiloxanes have been extensively studied, they have limited practical applications because of their low glass transition temperatures. In this study, we synthesized benzocyclobutene-functionalized hyperbranched polysiloxane (HB-BCB) via the Piers-Rubinsztajn reaction. The synthesized material was cured and crosslinking occurred at temperatures greater than 200 °C, forming a low-k thermoset resin with high thermostability. The structure of the resin was characterized using nuclear magnetic resonance (NMR) spectroscopy, viz. 1H NMR and 13C NMR spectroscopy. 29Si NMR spectroscopy was used to calculate the degree of branching. Differential scanning calorimetry, dynamic mechanical analysis, and thermogravimetric analysis revealed that the cured resin possesses good high-temperature mechanical properties and exhibits a high thermal decomposition temperature (Td5 = 512 °C). In addition, the cured resin has a low dielectric constant (k = 2.70 at 1 MHz) and low dissipation factor (2.13 × 10-3 at 1 MHz). Thus, the prepared resin can function as a low-k material with excellent high-temperature performance. These findings indicate that the performance of crosslinked siloxane is significantly attributed to the introduction of BCB groups and the formation of the highly crosslinked structure.

Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway.

Liver fibrosis is a progression of chronic liver disease, which lacks effective therapies in the world. Attractively, more and more evidences show that natural products are safe and effective in the prevention and treatment of hepatic fibrosis. Artesunate, a water-soluble hemisuccinate derivative of artemisinin, exerts various pharmacological activities such as anti-inflammatory, anti-tumor and immunomodulating abilities. However, the effects of artesunate on hepatic fibrosis are little-known. Here our study was performed to investigate the effect of artesunate on carbon tetrachloride (CCl4)-induced mouse liver fibrosis and elucidate whether artesunate could alleviate liver fibrosis by regulating ferritinophagy- mediated ferroptosis in hepatic stellate cells (HSCs). Firstly, our results demonstrated that artesunate treatment could induce activated HSC ferroptosis in fibrotic livers. Moreover, primary HSCs isolated from different animal groups were cultured to detect biomarkers of ferroptosis including iron, lipid peroxidation, glutathione (GSH) and prostaglandin endoperoxide synthase 2 (ptgs2) levels. The results revealed that artesunate remarkably promoted ferroptosis of activated HSCs. Furthermore, consistent with the experimental results in vivo, the data in vitro still indicated that artesunate treatment markedly induced ferroptosis in activated HSCs, which mainly embodied as declined cell vitality, increased cell death rate, accumulated iron, elevated lipid peroxides and reduced antioxidant capacity. Conversely, inhibition of ferroptosis by deferoxamine (DFO) completely abolished artesunate-induced anti-fibrosis effect. Surprisingly, artesunate also evidently triggered ferritinophagy accompanied by up-regulation of LC3 (microtubule-associated protein light chain 3), Atg3, Atg5, Atg6/beclin1, Atg12 (autophagy related genes) and down-regulation of p62, FTH1 (ferritin heavy chain), NCOA4 (nuclear receptor co-activator 4) in activated HSCs. Nevertheless, depletion of ferritinophagy by specific inhibitor lysosomal lumen alkalizer-chloroquine (CQ) inhibited artesunate-induced ferroptosis and anti-fibrosis function. These results suggested that ferritinophagy-mediated HSC ferroptosis was responsible for artesunate-induced anti-fibrosis efficacy, which provided new clues for further pharmacological study of artesunate.

Removable Large-Area Ultrasmooth Silver Nanowire Transparent Composite Electrode.

In this work, a composite silver nanowire (AgNW) transparent electrode that is large-area ultrasmooth without conductivity or transmittance scarifice, removable but with good resistance to both water and organic solvent, is reported. Via a simple low-temperature solution process without complicated transfer steps or additional pressure pressing, a new kind of AgNWs composite with biocompatible and patternable chitosan polymer complex demonstrates a quite low root-mean-square roughness ∼7 nm at a largest reported scan size of 50 µm × 50 µm, which is among the best flat surface. After long-term exposure to both water and organic solvent, it still shows strong adhesion, unchanged transparency, and no obvious conductivity reduction, suggesting a good stability staying on the substrate. Meanwhile, the polymer and silver nanowire in the composite electrode can be damaged via the same process through concentrated acid or base etching to leave off the substrate, allowing a simple patterning technology. Besides, the imported insulating polymer does not lower down the opto-electrical performance, and a high figure of merit close to 300 is obtained for the composite electrode, significantly outperforming the optoelectronic performance of indium-tin oxide (ITO) coated plastics (∼100) and comparable to ITO-coated glass. It shows great advantage to replace ITO as a promising transparent electrode.

Annealing-free and strongly adhesive silver nanowire networks with long-term reliability by introduction of a nonconductive and biocompatible polymer binder.

As a promising candidate to replace the brittle and expensive transparent indium tin oxide (ITO) conductor, the use of silver nanowire (AgNW) networks still involves issues such as high-temperature post-treatments and poor substrate adhesion for industrial application. Here a room-temperature soldering and one-step solution method is developed to achieve high-performance Ag nanowire transparent conductive films (TCFs). A nonconductive binder is prepared from poly(dopamine) and alginic acid which contains abundant catechol and carboxylic acid functional groups. The drying of the binder on the Ag nanowire percolation networks induces tighter contact among the nanowires and strong adhesion to the substrate, simultaneously enhancing the electrical and mechanical properties without a high-temperature annealing process. As a result, a highly conductive and bendable AgNW film is demonstrated on a low-cost polyethylene glycol terephthalate (PET) substrate, showing an 89% optical transmittance at λ = 550 nm and a sheet resistance of 16.3 Ohm sq(-1). Its optical and electrical performances are superior to those obtained from the reported indium tin oxide (ITO) films. Moreover, the AgNW film exhibits strong adhesion to the substrate, maintaining its conductivity after 100 tape tests, and it still resists the tape test even after exposure to solvent for several hours. Most importantly, the film shows good reliability during long-term 85 °C/85% RH (relative humidity) aging, which has been rarely investigated although it is a critical requirement for industrial application. The advanced and wide-ranging features of the prepared AgNW film greatly contribute to its use as a transparent electrode in multifunctional flexible electronic devices.

Site-selective growth of patterned silver grid networks as flexible transparent conductive film by using poly(dopamine) at room temperature.

Metal transparent conductive films (TCFs) have received increasing attention in various flexible electronics. However, there are two crucial issues that need to be addressed: (1) strong adhesion between metal TCFs and the flexible substrates and (2) high conductivity with short treatment time and low process temperature, simultaneous with high transparency. In this paper, a site-selective electroless plating combination with poly(dopamine) modification is demonstrated to fabricate a new high performance transparent conductor composed of a periodic two-dimensional silver network on a heat sensitive flexible substrate at room temperature. The TCF reveals an extremely high ratio of DC to optical conductivity (σ(DC)/σ(Op)) value in the range of 350-1000 for various fabricated silver grid films. It also exhibits particularly strong adhesion, which can resist ultrasonic treatment in water or organic solvent for several hours. Its reliability (stable for at least 1440 h during 85 °C/85% RH aging) meets the essential requirements for microelectronic applications. Using this method, we obtain silver grid film on a flexible polyethylene terephthalate substrate with optical transmittance of 91% and sheet resistance of 8 Ohm sq(-1), which is comparable to or better than the commercially available indium tin oxide.

Copper nanoparticles: aqueous phase synthesis and conductive films fabrication at low sintering temperature.

Conductive copper nanoinks can be used as a low-cost replacement for silver and gold nanoinks that are used in inkjet printing of conductive patterns. We describe a high-throughput, simple, and convenient method for the preparation of copper nanoparticles in aqueous solution at room temperature. Copper acetate is used as the precursor, hydrazine as the reducing agent, and short chain carboxylic acids as capping agents. The concentration of the carboxylic acid plays a key role in the preparation of such copper nanoparticles. Stable copper nanoparticles with a diameter of less than 10 nm and a narrow size distribution were prepared when high concentrations of lactic acid, citric acid, or alanine were used. Thermogravimetric analysis results showed that any lactic acid or glycolic acid adsorbed on the surface of the copper nanoparticles can be removed at a relatively low temperature, especially, glycolic acid, which can be removed from the surface at about 125 °C. Highly conductive copper films prepared using lactic acid and glycolic acid as capping agents were obtained by drop coating a copper nanoparticle paste onto a glass slide followed by low temperature sintering. The electrical resistivity of the copper film using glycolic acid as the capping agent was 25.5 ± 8.0 and 34.8 ± 9.0 µΩ·cm after annealing at 150 and 200 °C for 60 min under nitrogen, respectively. When lactic acid was used as the capping agent, the electrical resistivity of the copper films was 21.0 ± 7.0 and 9.1 ± 2.0 µΩ·cm after annealing at 150 and 200 °C for 60 min under nitrogen, respectively, with the latter being about five times greater than the resistivity of bulk copper (1.7 µΩ·cm).

Facile approach in fabricating superhydrophobic and superoleophilic surface for water and oil mixture separation.

Metal copper mesh with superhydrophobic and superoleophilic surface had been successfully fabricated via a facile solution-immersion process. The hierarchical structure was prepared on the commercial copper mesh surface by etching with the nitric acid. After being modified by 1-hexadecanethiol (HDT), the as-prepared mesh indicated both superhydrophobic and superoleophilic property simultaneously. This as-prepared metal mesh could then be applied for oil and water mixture separation. The unusual wettability of the as-prepared mesh was stable in corrosive conditions, such as acidic, basic, and salt solutions. The solution-immersion method was simple, time-saving, and inexpensive and therefore exhibited great potential application.