Synthesis and mechanism of action of new purine derivatives against triple negative breast cancer.

Triple negative breast cancer (TNBC) is considered to be the most difficult subtype of breast cancer to treat because of its extremely prone to metastasis and the lack of targeted therapy drugs. New purine derivatives were synthesized and evaluated in a series of kinases and cell lines. The most active compounds 3g and 3j were selected based on their antiproliferative activities, then their pharmaceutical activity and mechanism in MDA-MB-231 cells were analyzed. The results in vitro indicated that compounds 3g and 3j can induce MDA-MB-231 cells apoptosis, and inhibit its migration and angiogenesis through influencing protein expression such as Bcl-2, Bax, Bcl-xl, P38, MMP2, MMP9, AKT and EGFR. In vivo results indicate that compounds 3g and 3j can inhibit tumor growth and metastasis and reduce the expression of Ki67 and CD31 protein in TNBC xenograft models. These findings not only broaden our understanding of the anti-TNBC effects and mechanisms of compounds 3g and 3j, but also provide new ideas and reference directions for the treatment of TNBC.

Optimization strategies for conservation of traditional dwellings in Hongcun Village, China, based on decay phenomena analysis.

Hongcun traditional dwellings are representative of Huizhou architecture in China, with distinctive cultural and architectural characteristics in terms of layout, material, decoration and other features. Research on Hongcun traditional dwellings has been a matter of ongoing interest in academic circles in China, but there has been no specific focus on the phenomena of decay affecting these structures, even though research on this aspect has the most direct impact on the conservation of traditional dwellings. In this study, abundant and comprehensive fieldwork was carried out to investigate the building information, materials and especially preservation status of traditional dwellings. Furthermore, the decay phenomena of traditional dwellings were identified and described in detail in the Masonry Components and Wooden Components sections, which are based on the collected information and the relevant guidelines. Moreover, the restoration and actual conservation practices for traditional dwellings, which were specifically both government-led and private projects, were examined. In these analyses, the main problems related to the decay phenomena investigation and intervention are systematically summarized, and corresponding solutions are proposed to ensure that optimized conservation strategies are applied to traditional dwellings in Hongcun village.

Chemoenzymatic synthesis and biological evaluation of ganglioside GM3 and lyso-GM3 as potential agents for cancer therapy.

A highly efficient chemoenzymatic method for synthesizing ganglioside GM3 and lyso-GM3 was reported here. Enzymatic extension of the chemically synthesized lactosyl sphingosine using efficient one-pot multienzyme (OPME) reaction allowed glycosylation to be carried out in aqueous solutions realizing the greening of reactions. Ganglioside GM3 was synthesized through 10 steps with a total yield of 22%. Lyso-GM3 was very useful for kinds of derivatization. The anti-proliferation activity studies demonstrated that these compounds 14-16 with sphingosine exhibited more potency than the corresponding lyso-GM3 with ceramide. All ganglioside GM3 and lyso-GM3 can effectively inhibit the migration of melanoma B16-F10 cells. These chemoenzymaticlly synthesized GM3 and lyso-GM3 exhibited antitumor activities, which can provide valuable sights to search new antitumor agents for cancer therapy.

N-acetylgalactosamine-decorated nanoliposomes for targeted delivery of paclitaxel to hepatocellular carcinoma.

In this study, we designed and developed a novel asialoglycoprotein receptor (ASGPR)-targeted PEGylated paclitaxel (PTX) nanoliposome for hepatocellular carcinoma (HCC). N-acetylgalactosamine with α configuration (Tn) was synthesized and used as the active targeting ligand. Notably, Tn modified nanoliposomes loaded with PTX (Tn-Lipo-PTX) showed a narrow distribution (PDI = 0.18-0.20) with 74 ± 0.36 nm of average sizes. Tn-Lipo-PTX has a high encapsulation efficiency of more than 93.0% and 13% of drug loading (DL). Compared with no targeted Con-Lipo-PTX, Tn-Lipo-PTX showed lower and sustained release characteristic in PBS in vitro. Tn targeting ASGPR was confirmed by HepG-2 cells uptake experiment by fluorescence microscopy analysis. Tn-Lipo-PTX accumulated in HepG-2 cells and this process was inhibited by adding Tn ligand, supporting receptor-mediated endocytosis mechanism. MTT assays was implemented in four cell lines. Tn-Lipo-PTX exhibited superior inhibition against ASGPR on over-expressing HepG-2 (IC50 = 1.93 nM). The cell cycle experiments showed that Tn-Lipo-PTX could efficiently increase the percentage of cells arrest in the G2/M phase. Through western blotting analysis, the ß-tubulin and cyclin B1 expression in the Tn-Lipo-PTX group were significantly higher compared with other groups and the CDK1 was down-regulated compared with PTX group, which indicated that targeting liposome delivery system could not only change periodic proteins expression, but also improve the killing effect of PTX on hepatocarcinoma cell. Tn-installed PEGylated nanoliposomes have a great potential for targeted cancer chemotherapy.

Efficient chemoenzymatic synthesis of fluorinated sialyl Thomsen-Friedenreich antigens and investigation of their characteristics.

A set of fluorinated sialyl-T derivatives were efficiently synthesized using one-pot multi-enzyme (OPME) chemoenzymatic approach. The P. multocida α2-3-sialyltransferase (PmST1) involved in the synthesis showed extremely flexible donor and acceptor substrate specificities. These sialosides have been successfully investigated with stability towards Clostridium perfringens sialidase substrate specificity assay using 1H NMR spectroscopy. Hydrolysis studies monitored by 1H NMR clearly demonstrated that the fluorine substitution obviously reduced hydrolysis rate of Clostridium perfringens sialidase. To further investigate the fluorine influence, structure-dependent variation of sialoside-lectin binding was observed for MAL and different sialoside-immobilized surfaces. Subtle changes on the ligand of carbohydrate-binding protein were distinguished by SPR. These fluorinated sialyl-T derivatives obtained are valuable probes for further biological studies or antitumor drug design.

Synthesis of 2'-paclitaxel 2-deoxy-2-fluoro-glucopyranosyl carbonate for specific targeted delivery to cancer cells.

A novel 2-fluorodeoxyglucose conjugated derivative of paclitaxel was efficiently synthesized using a linker between 2'-OH of paclitaxel and C1-hydroxyl group of 2-fluorodeoxyglucose. In preparation of the prodrug, allyl carbonates were selected as the protective group and the efficient one-step removal of allyloxycarbonyl groups at the end of the synthesis using palladium chemistry gave the target molecule in good yield. The prodrug not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also demonstrated enhanced cytotoxicity and selectivity for cancer cells and less toxicity toward normal HUVEC cells.

Recent advances in the development of cyclin-dependent kinase 7 inhibitors.

Cyclin dependent kinase 7 (CDK7) plays a double role as it activates several other cyclin dependent kinases and participates to the initiation of transcription. This kinase is overexpressed in various types of tumors. Relatively few selective CDK7 inhibitors have been up to now disclosed. Most of these inhibitors belong to two chemical families: pyrazolopyrimidines and pyrazolotriazines on one side and pyrimidines on another side. They also differ by their molecular mechanism of action. Some are acting as competitive inhibitors and some others are covalent inhibitors. With these tools, the understanding of the potential therapeutic interest of CDK7 inhibitors in cancer is rapidly growing. They display antiproliferative activity against various types of tumors and leukemia and synergies have been identified. Two inhibitors are undergoing clinical testing. The most potent compounds inhibit a large number of cell-lines with IC50 < 200 nM.

Synthesis and immunogenicity of the Mycobacterium tuberculosis arabinomannan-CRM197 conjugate.

Lipoarabinomannan (LAM) is a major structural surface component of Mycobacterium tuberculosis. This study describes the synthesis of the well-defined lipoarabinomannan (LAM) specific dodecasaccharide-protein conjugate and immunological studies. Arabinomannan (AM) dodecasaccharide has been efficiently synthesized and covalently conjugated to carrier proteins, including cross reactive mutant (CRM197) diphtheria toxoid and bovine serum albumin (BSA) for novel neoglycoconjugates, creating a potent T-dependent conjugate vaccine. Preliminary mice immunization studies on the neoglycoconjugate revealed that it could give rise to a strong IgG antibody titer in mice at 4.0 µg dose with an aluminum phosphate adjuvant. AM-CRM197 shows potential as an excellent candidate for a new carbohydrate-based vaccine that would be capable of eliciting a protective immune response against tuberculosis.