Chemotherapy, as the main treatment for breast cancer, inevitably damages normal tissues due to the lack of targeting. Various nano targeting drug delivery systems (TDDS) have the potential to be developed as anticancer therapeutics. Although mono-ligand-directed liposomes have been used with some success, dual-ligand-directed liposomes exhibit promising advantages. In current work, we synthesized a Y-shaped ligand covalently linking fructose and biotin (Fru-Bio-Chol) to prepare a dual-targeting liposome Fru-Bio-Lip for breast cancer. The targeting ability was evaluated by comparing the Fru-Bio-Lip with the non-modified liposome (Lip), fructose or biotin mono modified liposomes (Fru-Lip and Bio-Lip), and another dual-targeting liposome (Fru + Bio-Lip) physically mixing fructose and biotin mono modified ligands (Fru-Chol and Bio-Chol). The cellular uptake of Fru-Bio-Lip is 3.27-, 1.81-, 2.19-, 1.15-times that of Lip, Fru-Lip, Bio-Lip and Fru + Bio-Lip on 4T1 cells, and 3.11-, 1.80-, 1.89-, 1.15-times on MCF-7 cells. Additionally, the uptake mechanism indicates the uptake of Fru-Bio-Lip is energy-dependently achieved through multiple endocytosis pathway with a dual recognition of fructose and biotin by GLUT(5) and SMVT. The cytotoxicity and apoptosis assay show PTX-Fru-Bio-Lip among liposomes have the strongest proliferation inhibitory effect on breast cancer cells, and the apoptosis rate is 1.7-times that of PTX-Lip. In vivo images indicate Fru-Bio-Lip have the strongest tumour enrichment ability, which is 2.76-, 1.60-, 1.96-, 1.40-times that of Lip, Fru-Lip, Bio-Lip and Fru + Bio-Lip, respectively. Overall, the fructose and biotin covalently modified liposomes improved breast cancer targeting ability, demonstrating great potential as a drug delivery system for breast cancer.

目的 采用金属酶活性位点对比法,发现新的金属β-内酰胺酶(MBL)抑制剂.方法 用自主发展的金属酶活性位点对比法,将MBL活性位点与其他金属酶的活性位点进行对比,从与其相似活性位点所结合的配体中提炼出可能与MBL结合的金属结合药效团骨架,其中,双膦酸骨架具备良好的发展潜力;再用分子对接预测双膦酸骨架与MBL亚型VIM-2的相互作用模式,最后从上市药物中遴选双膦酸类化合物并进行活性验证.结果 利塞膦酸钠、阿伦膦酸钠、米诺膦酸和唑来膦酸等4种药物均对VIM-2亚型表现出了中等强度的抑制活性,其中,阿伦膦酸钠的活性最好,IC50值为25.08 μmol· L-1.结论 金属酶活性位点对比方法可为靶向MBL药物研发提供了新的苗头/先导化合物.

Plasmodium falciparum , the deadliest causal agent of malaria, caused more than half of the 229 million malaria cases worldwide in 2019. The emergence and spreading of frontline drug-resistant Plasmodium strains are challenging to overcome in the battle against malaria and raise urgent demands for novel antimalarial agents. The P . falciparum formate–nitrite transporter (PfFNT) is a potential drug target due to its housekeeping role in lactate efflux during the intraerythrocytic stage. Targeting PfFNT, MMV007839 was identified as a lead compound that kills parasites at submicromolar concentrations. Here, we present 2 cryogenic-electron microscopy (cryo-EM) structures of PfFNT, one with the protein in its apo form and one with it in complex with MMV007839, both at 2.3 Å resolution. Benefiting from the high-resolution structures, our study provides the molecular basis for both the lactate transport of PfFNT and the inhibition mechanism of MMV007839, which facilitates further antimalarial drug design.

A palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides has been developed, which has potential safety advantages over previous carbene coupling reactions using either diazo compounds or their in situ precursors. This reaction affords polysubstituted olefins, and features good substrate tolerance and is suitable for late-stage modification of biologically active molecules. Pd-carbene migratory insertion is supposed to be involved in this coupling reaction.

Many human diseases, such as obesity and diabetes, show annual increases in prevalence and often involve intestinal microbes. One such probiotic bacterium, Akkermansia muciniphila, which was discovered a decade ago, has been reported to influence glucose homeostasis and to contribute to gut health. Amuc_1100, a functionally uncharacterized protein of A. muciniphila, was found to be a key active component in reducing the body weight of mice. Here, the crystal structure of Amuc_1100 (residues 31-317), referred to as Amuc_1100*, is reported at 2.1 Å resolution. Amuc_1100* has a similar fold to three proteins related to pilus formation, PilO, PilN and EpsL, indicating a similar function. Biochemical investigations further confirmed a monomeric state for the soluble region of Amuc_1100, which differs from the dimeric states of PilO, PilN and EpsL. This study provides a structural basis for the elucidation of the molecular mechanism of Amuc_1100.

Magnetic targeting, which utilizes a magnetic field to specifically deliver therapeutic agents to the targeted regions, can greatly improve the treatment efficiency. Herein, ibuprofen-loaded brain targeting magnetic nanoparticles (AA-Ibu-PEG-DA@MNPs) modified with ascorbic acid (AA) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to the brain through Na[Formula: see text]-dependent vitamin C transporter 2 (SVCT 2 ) and glucose transporter 1 (GLUT 1 ). The brain targeting magnetic nanoparticles, AA-Ibu-PEG-DA@MNPs, have a particle size of 82.5[Formula: see text]nm, 2% drug loading capacity and limited cytotoxicity against bEnd.3 cells. What’s more, the nanoparticles maintained the magnetic property with a saturation magnetization level at 52.17[Formula: see text]emu/g and could release ibuprofen when incubated in different mediums, including various buffers, mice plasma and brain homogenate. The results indicate that the magnetic nanoparticles may have the potential to be a promising approach to selectively deliver drugs into the brain. This study may be conducive to the field of CNS drugs delivery.

目的 设计并合成一系列吡啶并[2,3-b]吡嗪类成纤维细胞生长因子受体(FGFR)抑制剂,同时对其抗胃癌活性进行初步评价.方法 以5-溴吡啶-2-胺为起始原料,经9步反应合成了13个未见报道的化合物,并通过MTT法评价其抗胃癌活性.结果与结论 目标化合物的结构经NMR和HRMS确证,其中多个化合物对胃癌SNU-16细胞系具有良好的抑制活性,具有进行更深入的构效研究价值,有望成为一种潜在的新增FGFR抑制剂.

OBJECTIVE To synthesize the heptamethine indocyanine dyes with the terminal group-glycine methyl ester (PLGAS-1),and to study its effect as a contrast agent for photoacoustic imaging.METHODS 3-Bromo-propionic acid by chlorination was reacted with glycine methyl ester hydrochloride to get 3-bromo-propionamide methyl ester(XBXA-3).XBXA-3 was coupled with 2,3,3-trimethyl-3H-indole to obtain quaternary ammonium salt (JAY-1),then JAY-1 was condensated with 2-chloro-3-hydroxy-methylene cyclohexene aldehyde to get the PLGAS-1.And its maximum absorption and emission wave length were detected.In vitro phantom model was establised to compare photoacoustic imaging of PLGAS-1,ICG and Gold nanorods (CTAB-7-760).RESULTS PLGAS-1 was synthesized and its structures was characterized.Its maximum absorption and emission wavelengths were in the near-infrared region.Photoacoustic imaging in vitro showed that photoacoustic signal amplitude of PLGAS-1 was obviously higher than that of ICG and CTAB-7-760 under the same conditions and it had a good linear relationship between photoacoustic signal amplitude and concentration.CONCLUSION PLGAS-1 can provide a guideline for the study of novel photoacoustic imaging contrast agents.

Indole croconium(ICR) was synthesized by condensation reaction of croconic acid with 2,3,3-trimethylindolenine.The structure was confirmed by 1H NMR and MS.The preliminary study of ICR as a photoacoustic imaging contrast agent was investigated.The results showed that ICR exhibited a sharp and strong absorption in the near infrared region, the maximum absorption wavelength was 755 nm and emission wavelength was 775 nm, and the molar absorption coefficient was 4.14×105 L·mol-1·cm-1.The photoacoustic imaging effect of ICR was far better than that of the indocyanine green(ICG).Photoacoustic intensity of ICR was 520 000 times of that of ICG at the concentration of 21.6 μmol·L-1.

An efficient synthesis of bis(indolyl)methanes from aldehydes with indoles through graphene oxide -catalyzed Friedel-Crafts alkylation is developed. The reaction proceeds in water by using graphene oxide as the single catalyst to provide the desired products in good to excellent yields. Also, this methodology has a broad substrate scope, and is environment friendly and cost economic.

3,3-(亚乙二氧基)雌甾-5(10),9(11)-二烯-17-酮经乙炔加成,与苯硫氯反应,脱苯亚磺酰基,去甲基重排,羰基保护制得3,3∶20,20-二(亚乙二氧基)-17α-羟基-19-去甲孕甾-5(10),9(11)-二烯(7),7以六氟丙酮为催化剂环氧化制得3,3∶20,20-二(亚乙二氧基)-17α-羟基-5α,10α-环氧-19-去甲孕甾-9(11)-烯,然后经格氏加成、去保护、乙酰化合成醋酸乌利司他,总收率23.1％,纯度99.8％.优化后工艺生产成本低,生产周期短,操作简便.

Osteoarthritis is no doubt a difficult disease to manage. Targeted delivery of drugs to bone may not only enhance the treatment efficacy, but also reduces the quantity of drug administered. In this paper, we have synthesized two series of NSAID-Glu oligopeptide conjugates built up by the therapeutic moiety (naproxen and ibuprofen) and the targeting moieties (Glutamic oligopeptides) via amide linkage, as novel potential bone-targeting NSAIDs prodrugs. Preliminary studies indicated that these prodrugs exhibited outstanding hydroxyapatite affinity, furthermore, NSAIDs-glutamic hexa-peptide conjugates were found more potent in hydroxyapatite binding. The adequate chemical stability of the conjugates in different buffers, indicated that the conjugates might become a promising approach of selective delivery of drugs to bone tissues. These results may be conducive to the study of bone targeting drugs delivery.

目的 设计并合成苯骈呋喃类衍生物,并研究其促骨形成作用.方法 以苯甲醚为原料,经7步反应得到目标产物,并研究目标产物的促骨形成作用.结果 目标化合物的结构经1 HNMR、MS确证.结论 目标化合物Ⅱa具有较好的促骨形成作用.

Improving the cell penetration and enhancing the cell selectivity of drugs have been approved for overcoming the major drawbacks of chemotherapeutic agents: the toxicity to normal cells and the drug resistance in tumors. In this paper, lysine dendrimers (G1–G3) were chosen as novel cell‐penetrating carriers for anti‐cancer drugs based on the internalization mechanism of cell‐penetrating peptides and the characteristics of dendritic peptides. After labeling with fluorescein isothiocyanate (FITC), the cell‐penetrable capacity of lysine dendrimers was certified by flow cytometric analysis. In a preliminary biological evaluation, the conjugates of lysine dendrimers and 5‐fluorouracil showed the expected advantages: stable drug release, low toxicity to normal cells, and moderate inhibition of tumor cells. These results imply that cell‐penetrable lysine dendrimers could be potential carriers in drug delivery of anti‐cancer medicine.

A novel brain targeting l-ascorbic acid derivatives with "lock-in" function were designed and synthesized as prodrugs to achieve the effective delivery of ibuprofen to brain by glucose transporter 1 (GLUT1) and the Na(+)-dependent vitamin C transporter SVCT2. Ibuprofen-loaded four prodrugs were tested in the animals. Results from the in vivo distribution study after i.v. administration of these four prodrugs and naked ibuprofen indicated that four prodrugs exhibited excellent transport ability across the BBB and significantly increased the level of ibuprofen in brain. Among them, prodrugs 4 showed higher brain concentration. Both biodistribution data and pharmacokinetic parameters suggested that l-ascorbic acid thiamine disulfide delivery system was a promising carrier to enhance CNS drug's delivery ability into brain.

目的为了研究非天然氨基酸的合成,推广其在现代制药工业中的应用,设计并合成了环苏氨酸（丝氨酸）洐生化的甘氨酸Ni（Ⅱ）螯合物。方法以苏氨酸（丝氨酸）为原料,通过与甲醛成环,（Boc）2O保护氨基,再与2-氨基-二苯甲酮成酰胺,脱Boc上的苄基后,最后与Gly和Ni（Ⅱ）在碱性环境下形成平面正方形螯合物。结果和结论目标化合物Ⅱa d 及Ⅲ经1HNMR、MS确证结构。

An effective liver-targeted delivery system was successfully developed by designing ligand-mediated nanoparticles composed of glycyrrhetinic acid (GA)-conjugated block copolymers (glycyrrhetinic acid-modified poly(ethylene glycol)-poly(β-benzyl-l-asparate, GA-PEG-PBLA) synthesized via ring-opening polymerization of the β-benzyl-l-asparate N-carboxyanhydride (BLA-NCA) monomer initiated by GA-modified polyethylene glycol (PEG). Chemical structures of the synthesized polymers were confirmed by 1H nuclear magnetic resonance (1H NMR) and Fourier transform infrared assay (FTIR) and molecular weight determined by gel permeation chromatography (GPC). The copolymers were processed into nanoparticles for delivery of paclitaxel (PTX). In this work, the PTX-loaded nanoparticles were prepared by the emulsion-solvent evaporation method, and the physicochemical properties and cytotoxicity were investigated. The particle sizes of nanoparticles determined by dynamic light scattering measurements were around 70 nm. Transmission electron microscopy showed that the nanoparticles were spherical in shape. The results of in vitro release tests showed that the release profiles of PTX-loaded nanoparticles had a sustained drug release pattern, and PTX release from nanoparticles at pH 5.8 was much faster than that at pH 7.4. The drug release profiles were also fitted for mathematical models to analyze the release mechanism, and the Korsmeyer-Peppas model was found to be the best fit model, indicating a combined effect of diffusion and erosion mechanisms for drug release. The cytotoxicity based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against human hepatic carcinoma HepG2 cells indicated that the GA-PEG-PBLA nanoparticles had low cytotoxicity and good biocompatibility. These results indicated that the GA-PEG-PBLA nanoparticles could be a novel candidate for liver-targeted delivery of poorly water-soluble anticancer drugs.

目的 改进成纤维细胞生长因子受体拮抗剂LY2874455的合成方法.方法 以3,5-二氯吡啶、1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-4-甲醛(16)和1-乙酰基-1H-吲唑-5-基乙酸酯为原料经Wittig反应、Heck加成、水解、缩合及脱保护基等步骤得到目标产物LY2874455.结果与结论 目标化合物和中间体的结构经1 H-NMR和MS谱确证.改进后的合成路线中关键中间体(E)-1-(四氢-2H-吡喃-2-基)-3-(2-(1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑-4-基)乙烯基)-1H-吲唑-5-醇的收率为45％(以16计).

In the search for better antioxidants with more satisfactory lipophilicity, a series of Janus dendrimers that consisted of gallic acid and alkyl chains as the peripheral groups, were designed and synthesized. These dendrimers take advantage of a dendritic display to carry multi-antioxidants and multi-lipophilic moieties simultaneously. Consequently, the resulting dendrimers, which showed satisfactory lipophilicity and better antioxidant activity than the gallic acid monomer, are potential novel lipophilized antioxidant agents.