稠环磺酰胺衍生物的合成与抗菌活性研究

为了寻找抗菌候选化合物,在前期研究基础上,18个稠环磺酰胺衍生物被设计合成,经1H NMR、13C NMR和MS确认结构.采用两倍稀释法对目标物进行体外抗菌活性测试,结果表明:该类衍生物对所测细菌有不同程度的抑制活性,尤以化合物Ⅱi、Ⅱr的抗菌活性最为突出,其中前者对金葡菌(S.aureus)、大肠埃希菌(E.coli...     

Assessment of a gel-type chelating preparation containing 1-hydroxyethylidene-1, 1-bisphosphonate

AIM: To test an aqueous gel containing 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) regarding its interactions with sodium hypochlorite, its calcium binding capacity, and its potential in preventing the formation of a smear layer when used in conjunction with rotary root canal preparation. METHODOLOGY: The experimental aqueous gel consisted of (w/v) 2% alginate, 3% aerosil, 10% Tween 80 and 18% HEBP. Interactions of gel components with hypochlorite were assessed using iodometric titration and monochromatic ultraviolet spectrometry. Two commercial paste-type chelators containing ethylenediaminetetraacetic acid (EDTA) and peroxide (RC-Prep and Glyde) served as controls. Calcium-binding capacities were measured in mixtures with a Ca2+ standard solution buffered at pH 10 using a calcium-selective measuring chain. Finally, root canals of 16 extracted single-rooted premolars per group were instrumented using ProFile instruments dipped in the experimental gel, RC-Prep, or nothing. Additionally, canals were rinsed with 10 mL of a 1% NaOCl solution during/after preparation. Smear scores in instrumented teeth were monitored using scanning electron microscopy. RESULTS: None of the experimental gel components showed short-term interactions with hypochlorite, whilst EDTA, peroxide, RC-Prep and Glyde immediately reduced the hypochlorite in solution. The experimental gel chelated 30 mg Ca2+ g-1, compared with 16 mg Ca2+ g-1 and 11 mg Ca2+ g-1 chelated by RC-Prep and Glyde respectively. Smear scores obtained with the experimental gel were significantly (P<0.05) lower than with RC-Prep in coronal and middle root thirds, whilst no differences were observed in apical root thirds. CONCLUSIONS: Under the conditions of this study, an HEBP gel appeared advantageous over currently available products.     

肝纤维化大鼠血清有机膦酸酯酶的变化

目的:探讨肝纤维化大鼠血清有机磷酸酯酶的变化。方法:用四氯化碳诱导大鼠产生肝纤维化,分别于第4,8,12,14周用荧光分光法测定血清有机膦酸酯酶(PE)水平,并与血清PCⅢ,HA进行比较。结果:于实验第4,8,12,14周,大鼠血清PE水平分别为168.6±40.0,212.9±32.1,271.5±40.6与243.1±83.1IU/L,均明显高于正常大鼠(91.0±25.0IU/L)。与血清PCⅢ及HA呈显著正相关。结论:肝纤维化时血清PE明显升高,且与肝纤维化程度呈正相关,可作为肝纤维化诊断的血清学指标之一。     

阿仑膦酸钠对绝经后妇女骨质疏松症治疗及骨折的预防作用

目的观察阿仑膦酸钠对绝经后妇女骨质疏松症的治疗疗效及骨折的预防作用。方法绝经后骨质疏松妇女165例,随机分为2组:治疗组83例和对照组82例。2组均应用碳酸钙600 mg口服,每晚1次,α-活性维生素D3 0.25μg口服,每日2次。治疗组加阿仑膦酸钠70 mg,每周1次口服。各组用药前及治疗2年后分别检测腰椎及左侧髋部双能X线骨密度检查(BMD)。观察治疗期间骨痛改善情况;随访骨折事件发生率。结果阿仑膦酸钠治疗组治疗2年,腰椎及左侧髋部BMD均有不同程度提高,腰椎BMD上升15.7%,股骨颈BMD值上升20.8%,与治疗前相比有统计学意义(P<0.05)。对照组骨密度则不同程度下降,但无统计学意义(P>0.05),两组相比有统计学意义(P<0.01)。治疗组治疗4周时疼痛缓解有效率达80.7%,治疗3个月时疼痛缓解有效率达89.2%,而对照组分别为24.4%和30.5%,两组之间比较具有统计学意义(P分别为0.021和0.029)。治疗组仅发生1例骨折事件,对照组发生7例骨折事件,两组相比差异有统计学意义(P<0.05)。两组治疗均无明显不良反应。结论阿仑膦酸钠治疗绝经后妇女骨质疏松症疗效肯定,对骨折有明显预防作用。     

Phosphonate production by marine microbes: Exploring new sources and potential function

Phosphonates are organophosphorus metabolites with a characteristic C-P bond. They are ubiquitous in the marine environment, their degradation broadly supports ecosystem productivity, and they are key components of the marine phosphorus (P) cycle. However, the microbial producers that sustain the large oceanic inventory of phosphonates as well as the physiological and ecological roles of phosphonates are enigmatic. Here, we show that phosphonate synthesis genes are rare but widely distributed among diverse bacteria and archaea, including Prochlorococcus and SAR11, the two major groups of bacteria in the ocean. In addition, we show that Prochlorococcus can allocate over 40% of its total cellular P-quota toward phosphonate production. However, we find no evidence that Prochlorococcus uses phosphonates for surplus P storage, and nearly all producer genomes lack the genes necessary to degrade and assimilate phosphonates. Instead, we postulate that phosphonates are associated with cell-surface glycoproteins, suggesting that phosphonates mediate ecological interactions between the cell and its surrounding environment. Our findings indicate that the oligotrophic surface ocean phosphonate pool is sustained by a relatively small fraction of the bacterioplankton cells allocating a significant portion of their P quotas toward secondary metabolism and away from growth and reproduction.

Phosphorus (P) is an essential nutrient for all life. Phytoplankton and bacterioplankton (bacteria and archaea) in the surface ocean use P primarily for growth, reproduction, and as an energy currency such that almost all cellular P is associated with rapidly cycled compounds, including nucleic acids, ATP, and phospholipids (1). For example, in the North Pacific subtropical gyre, RNA synthesis accounts for over half of phosphate uptake in phytoplankton communities (2). In times of P scarcity, some marine microbes can modulate their cellular P requirements by recycling RNA from ribosomes (3), substituting phospholipids with other non-P lipids (4), or drawing upon internal stores of P accumulated during periods of P abundance (5, 6). The balance between microbial, physiological processes that require P and those that conserve or internally recycle P has significant downstream consequences for ecological stoichiometry and the marine P biogeochemical cycle (7).Nevertheless, in nutrient-impoverished midocean gyres, microbial demand for P is often so high that environmental phosphate concentrations are consumed to low-nanomolar levels. Under these conditions, up to half of the microbial P demand is met through the uptake and metabolism of P-containing dissolved organic matter (8). Dissolved organic P (DOP) is a complex, poorly characterized mixture of high– and low–molecular weight (HMW and LMW) phosphate and phosphonate esters released via exudation and cell death. Marine DOP consists primarily of monomeric and polymeric phosphate esters originating from well-known primary metabolites (e.g., nucleotides, nucleic acids, phospholipids, phosphoglycans, phosphoproteins, and vitamins) that are synthesized by all marine microbes. The presence of phosphate esters in DOP is easily explained.However, a large fraction of HMWDOP, between 20 and 25%, occurs as phosphonates (9)—an enigmatic class of compounds with a direct carbon to P (C-P) bond—that are not products of the primary cellular metabolism (Fig. 1) (10). Phosphonates were initially believed to be rare and unusual compounds with little environmental relevance (11). However, recent studies have indicated that many marine microbes have the potential to degrade and use phosphonates as a nutritional P source (Fig. 1) (12–14). This has been experimentally confirmed (15–17), showing that degradation of phosphonates in HMWDOP is an important source of marine methane, thereby contributing to the supersaturation of methane in oxic oligotrophic waters (18)—the so-called “marine methane paradox” (19).Open in a separate windowFig. 1.Phosphonate production and consumption in the marine environment. (A) This schematic emphasizes reaction pathways (e.g., to methylphosphonate [Mpn]) (18) that are most relevant for planktonic ecosystems in the oligotrophic surface ocean. Branch points to additional natural products are indicated where possible. For a comprehensive overview please refer to ref. 10. The isomerization of phosphoenolpyruvate (PEP) via PEP mutase (PepM, red and gray boxes) produces the phosphonopyruvate (PnPy) precursor from which effectively all known phosphonate compounds are derived. The pepM gene is a robust genomic marker for phosphonate production potential due to this functional conservation. Mpn, a well-known substrate for aerobic marine methane production (18), is produced by 1) the decarboxylation of PnPy to phosphonoacetaldehyde (PnAa) via phosphonopyruvate decarboxylase (Ppd), 2) the dehydrogenation of PnAa to 2-hydroxyethylphosphonic acid (2-HEP) via phosphonoacetaldehyde dehydrogenase (Pdh), and finally 3) transformation of 2-HEP by Mpn synthase (MpnS). (B) Phosphonate degradation via cleavage of the C-P bond proceeds through at least three mechanisms: hydrolytic (2-AEP, named for the representative 2-aminoethylphosphonate degradation pathway via PhnWX), radical (C-P lyase), and oxidative (PhnYZ). The proposed HpnWXZ pathway (greyed) is likely oxidative but is rare in the genomes we examined.Although it is now recognized that phosphonates support a significant fraction of microbial P demand in the ocean, only two bacterioplankton species have been experimentally confirmed as phosphonate producers: Trichodesmium erythraeum, a nitrogen-fixing cyanobacterium (20), and Nitrosopumilus maritimus from the Marine Group I (MGI) Thaumarchaeota (21). These two groups by themselves can only account for a small fraction of the total inventory of phosphonates observed in surface ocean DOP (SI Appendix, SI Results) (20).Most of our understanding of the distribution of the phosphonate synthesis trait in the wild is derived from genomics approaches using phosphonate biosynthesis genes as biomarkers (21–23). The enzyme phosphonenolpyruvate mutase (PepM) is required to form the initial C-P bond in the phosphonopyruvate precursor from which all other known phosphonate biosynthetic products are derived (Fig. 1). This makes the pepM gene a key biomarker for phosphonate biosynthetic potential. Metagenomic studies have estimated that 8 to 16% of all surface bacterioplankton may be phosphonate producers, including the abundant marine groups Prochlorococcus and SAR11 (21, 22). However, none of these organisms have been experimentally shown to produce phosphonate, and little is known about the functional roles that phosphonates play in Prochlorococcus and SAR11 ecology (10).Here, we first expand on earlier metagenomic studies and incorporate thousands of randomly sampled single-cell genomes from across the tropical and subtropical surface ocean to identify potential phosphonate producers and to quantify their potential contribution to the phosphonate pool. The single-cell genomes allowed us to determine whether individual cells are capable of both producing and consuming phosphonates. The expanded dataset also allowed us to explore the frequencies of phosphonate production and consumption traits among closely related groups and identify associations of these traits with environmental variables. Further, we identified a cultured strain of Prochlorococcus that has the full phosphonate biosynthetic pathway and demonstrate that it produces high–molecular weight phosphonate compounds. Finally, we identified the macromolecular cellular components with which the phosphonates are associated giving us clues as to their functional roles in ocean ecosystems.     

Development and applications of photo-triggered theranostic agents

Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases.     

叠氮膦酸酯类化合物的合成及生物活性研究

首次合成了未见文献报道的O,O二(β叠氮乙基)α对甲苯磺酰胺基α取代苄基膦酸酯系列化合物。用1HNMR、元素分析、IR分别对其进行了结构鉴定,同时对此类化合物的生物活性进行了测试     

Inhibition of thymidine phosphorylase (PD-ECGF) from SD-lymphoma by phosphonomethoxyalkyl thymines

A series of thymine phosphonomethoxyalkyl derivatives were evaluated for their ability to inhibit thymidine phosphorylase (dThdPase) purified from rat spontaneous T-cell lymphoma. A kinetic study of thymidine phosphorolysis catalyzed by dThdPase was performed with thymidine and/or inorganic phosphate as substrates. Data show that the substantial inhibitory effect of these acyclic nucleotide analogues is decreasing in the order of (R)-FPMPT>(S)-FPMPT>or=(R)-HPMPT>(S)-PMPT>(S)-HPMPT>PMET>or=(R)-PMPT. The inhibitory potency (K(i)/(dThd)K(m)) of the most efficient inhibitors from this series against T-cell lymphoma enzyme is 0.0026 for (R)-FPMPT and 0.0048 for (S)-FPMPT. The studied compounds do not inhibit Escherichia coli and human enzyme and possess lower inhibitory potency against rat liver thymidine phosphorylase.     

Exclusive recognition of sarcosine in water and urine by a cavitand-functionalized silicon surface

A supramolecular approach for the specific detection of sarcosine, recently linked to the occurrence of aggressive prostate cancer forms, has been developed. A hybrid active surface was prepared by the covalent anchoring on Si substrates of a tetraphosphonate cavitand as supramolecular receptor and it was proven able to recognize sarcosine from its nonmethylated precursor, glycine, in water and urine. The entire complexation process has been investigated in the solid state, in solution, and at the solid-liquid interface to determine and weight all the factors responsible of the observed specificity. The final outcome is a Si-based active surface capable of binding exclusively sarcosine. The complete selectivity of the cavitand-decorated surface under these stringent conditions represents a critical step forward in the use of these materials for the specific detection of sarcosine and related metabolites in biological fluids.