[Two-stage Inhibition Effects of Burkholderia sp. Y4 Application on Cadmium Uptake and Transport in Wheat].

In order to evaluate the feasibility of using Burkholderia sp. Y4 as a cadmium （Cd）-reducing bacterial agent in contaminated wheat fields， the changes in the rhizosphere soil microbial community and Cd available state， as well as the content and transport characteristics of Cd in the wheat root， basal node， internode， and grain under the treatment of strain Y4 were tested using microbial high-throughput sequencing， step-by-step extraction， subcellular distribution， and occurrence analyses. The results showed that root application of strain Y4 significantly reduced the root and grain Cd content of wheat by 7.7% and 30.3%， respectively， compared with that in the control treatment. The Cd content and Cd transfer factor results in wheat vegetative organs showed that strain Y4 reduced the Cd transfer factor from basal node to internode by 79.3%， and Cd content in the wheat internode stem also decreased by 50.9%. The study of Cd occurrence morphology showed that strain Y4 treatment increased the proportion of residual Cd in roots and basal ganglia， decreased the contents of inorganic and water-soluble Cd in roots， and increased the content of residual Cd in basal ganglia. Further examination of the subcellular distribution of Cd showed that the Cd content in root cell walls and basal ganglia cell fluid increased by 21.3% and 98.2%， respectively， indicating that the Cd fixation ability of root cell walls and basal ganglia cell fluid was improved by the strain Y4 treatment. In the rhizosphere soil， it was found that the microbial community structure was changed by strain Y4 application. Under the Y4 treatment， the relative abundance of Burkholderia increased from 9.6% to 11.5%， whereas that of Acidobacteriota decreased. Additionally， the relative abundance of Gemmatimonadales， Pseudomonadales， and Chitinophagales were also increased by strain Y4 treatment. At the same time， the application of strain Y4 increased the pH value of rhizosphere soil by 8.3%. The contents of exchangeable Cd， carbonate-bound Cd， and iron-manganese oxide-bound Cd in the soil decreased by 44.4%， 21.7%， and 15.9%， respectively， whereas the proportion of residual Cd reached 53.6%. Root application of strain Y4 increased the contents of nitrate nitrogen and ammonium nitrogen in the soil by 22.0% and 21.4%， respectively， and the contents of alkaline nitrogen also increased to a certain extent. In conclusion， the root application of strain Y4 not only improved soil nitrogen availability but also inhibited Cd transport and accumulation from contaminated soil to wheat grains in a "two-stage" manner by reducing Cd availability in rhizosphere soil and improving Cd interception and fixation capacity of wheat roots and basal nodes. Therefore， Burkholderia Y4 has application potential as a Cd-reducing and growth-promoting agent in wheat.

Latest progress in low-intensity pulsed ultrasound for studying exosomes derived from stem/progenitor cells.

Stem cells have self-renewal, replication, and multidirectional differentiation potential, while progenitor cells are undifferentiated, pluripotent or specialized stem cells. Stem/progenitor cells secrete various factors, such as cytokines, exosomes, non-coding RNAs, and proteins, and have a wide range of applications in regenerative medicine. However, therapies based on stem cells and their secreted exosomes present limitations, such as insufficient source materials, mature differentiation, and low transplantation success rates, and methods addressing these problems are urgently required. Ultrasound is gaining increasing attention as an emerging technology. Low-intensity pulsed ultrasound (LIPUS) has mechanical, thermal, and cavitation effects and produces vibrational stimuli that can lead to a series of biochemical changes in organs, tissues, and cells, such as the release of extracellular bodies, cytokines, and other signals. These changes can alter the cellular microenvironment and affect biological behaviors, such as cell differentiation and proliferation. Here, we discuss the effects of LIPUS on the biological functions of stem/progenitor cells, exosomes, and non-coding RNAs, alterations involved in related pathways, various emerging applications, and future perspectives. We review the roles and mechanisms of LIPUS in stem/progenitor cells and exosomes with the aim of providing a deeper understanding of LIPUS and promoting research and development in this field.

[Effects of Nano-copper Oxide on Physiobiochemical Properties of Brassica chinensis L. and Its Heavy Metal Accumulation Under Cadmium Stress].

To investigate the effects of nano-copper oxide (CuO NPs) on plant growth, physio-biochemical characteristics, and heavy metal content under cadmium stress, a hydroponics experiment was conducted on the effects of single and combined treatments of CuO NPs (0, 10, 20, and 50 mg·L-1) and Cd (0, 1, and 5 µmol·L-1) on the fresh weight, photosynthetic pigment content, MDA content, antioxidant enzyme activity (CAT, POD, SOD, and GR), and Cu and Cd contents in Brassica chinensis L. The results showed that under the single addition of CuO NPs, the fresh weight and activities of CAT, POD, and GR were inhibited as a whole. Photosynthetic pigment content and SOD activity increased first and then decreased with the increase in CuO NPs concentration, whereas MDA content in leaves and roots, and Cu content in subcells of B. chinensis L. increased with the increasing of CuO NPs. As compared with that in the control, CuO NPs promoted the growth of B. chinensis L., and the fresh weight increased by 8.70%-44.87% at 1 µmol·L-1 Cd. When the content of Cd was up to 5 µmol·L-1, a low content (10 mg·L-1) of CuO NPs promoted the growth of B. chinensis L., whereas a high concentration (50 mg·L-1) showed an inhibitory effect. The addition of CuO NPs could increase photosynthetic pigment and MDA contents under different Cd stress, and MDA content in leaves and roots of B. chinensis L. increased by 4.34%-36.27% and 13.43%-131.04%, respectively, than that in the control groups. Under the same concentration of 1 µmol·L-1 Cd, the addition of CuO NPs decreased the activities of CAT and GR, whereas the activity of POD increased. When the content of Cd was up to 5 µmol·L-1, CuO NPs increased the POD activity and inhibited the activity of SOD and GR. The activities of CAT and CAT in the leaves of B. chinensis L. initially showed an increasing and then decreasing trend. CuO NPs and Cd showed antagonistic effects, the maximum reduction of Cd content in leaves and roots of Brassica chinensis L. under 1 µmol·L-1 Cd treatment was 45.64% and 33.39%, and that under 5 µmol·L-1 Cd treatment was 18.25% and 25.35%, respectively. The content of Cu and Cd in subcellular organs of the plants decreased, but the proportion of soluble components increased. These results indicated that CuO NPs at low concentrations promoted plant growth under Cd stress and further inhibited the absorption of Cd but increased the oxidative damage to B. chinensis L.

Facilely tuning the intrinsic catalytic sites of the spinel oxide for peroxymonosulfate activation: From fundamental investigation to pilot-scale demonstration.

Heterogeneous peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs) have shown a great potential for pollutant degradation, but their feasibility for large-scale water treatment application has not been demonstrated. Herein, we develop a facile coprecipitation method for the scalable production (∼10 kg) of the Cu-Fe-Mn spinel oxide (CuFeMnO). Such a catalyst has rich oxygen vacancies and symmetry-breaking sites, which endorse it with a superior PMS-catalytic capacity. We find that the working reactive species and their contributions are highly dependent on the properties of target organic pollutants. For the organics with electron-donating group (e.g., -OH), high-valent metal species are mainly responsible for the pollutant degradation, whereas for the organics with electron-withdrawing group (e.g., -COOH and -NO2), hydroxyl radical (•OH) as the secondary oxidant also plays an important role. We demonstrate that the CuFeMnO-PMS system is able to achieve efficient and stable removal of the pollutants in the secondary effluent from a municipal wastewater plant at both bench and pilot scales. Moreover, we explore the application prospect of this PMS-based AOP process for large-scale wastewater treatment. This work describes an opportunity to scalably prepare robust spinel oxide catalysts for water purification and is beneficial to the practical applications of the heterogeneous PMS-AOPs.

[Variations in Cadmium Accumulation and Transport and Ionomic Traits Among Different Winter Wheat Varieties].

A field trial was conducted to identify the key factors affecting intraspecific variation in the cadmium (Cd) content in the grain of winter wheat. Three wheat cultivars with low Cd accumulation and two wheat cultivars with high Cd accumulation were planted. The Cd accumulation and transport and ionomic traits were examined in different organs of the tested wheat cultivars. Additionally, correlation analysis and principal component analysis were used to identify the key plant organs, translocation pathways, and elements that determine the intraspecific variation in the Cd content in wheat grain. The results showed that the bioaccumulation factors of Cd in glume, rachis, internode 1, and node 1, as well as the transport factors of Cd from rachis to grain, from rachis to glume, from internode 1 to rachis, and from node 1 to internode 1, were significantly correlated with Cd bioaccumulation factors in grain. The above-mentioned bioaccumulation factors and transport factors of Cd made a great contribution to the principal components that could discriminate between the wheat cultivars with low and high Cd accumulation and were significantly different among cultivars. Therefore, glume, rachis, internode 1, and node 1 were the key organs affecting the genotype differences in Cd content in wheat grain, and Cd translocation from rachis to grain, from rachis to glume, from internode 1 to rachis, and from node 1 to internode 1 were the key pathways controlling the variety differences in Cd accumulation in wheat grain. The analysis of wheat ionome showed that the bioaccumulation factors of Mg and Mn in the key organs and the transport factors of Mo, Cr, and Pb in the key transport pathways were significantly correlated with the bioaccumulation factor of Cd in wheat grain and contributed greatly to the differentiation between the wheat cultivars with low and high Cd accumulation in the principal component analyses. Thus, in the above-mentioned key organs and transport pathways, Mg, Mn, Mo, Cr, and Pb were the key elements affecting the genotype differences in Cd content in wheat grain.

Evaluation of Xpert GBS assay and Xpert GBS LB assay for detection of Streptococcus agalactiae.

BACKGROUND: Group B Streptococcal (GBS) infection is the primary agent of neonatal morbidity and mortality. Rapid and simple methods to detect GBS are Xpert GBS and GBS LB assays based on real-time polymerase chain reaction (PCR). However, since the diagnostic accuracy of the two techniques in diagnosing GBS remains unclear, we designed this study to appraise the diagnostic accuracy of the aforementioned. METHODS: A systematic search of all literature published before July 16, 2020 was conducted using Embase, PubMed, Web of Science, and Cochrane Library. The study quality was evaluated through Review Manager 5.3. Accordingly, data extracted in the included studies were analyzed using Meta-DiSc 1.4 and Stata 12.0 software. The diagnosis odds ratio (DOR) and bivariate boxplot were utilized to evaluate the heterogeneity. Publication bias was appraised by using Deeks' funnel plot. RESULTS: A total of 13 studies were adopted and only 19 sets of data met the criteria. The sensitivity and specificity of Xpert GBS were 0.91 (95% CI 0.89-0.92) and 0.93 (95% CI 0.92-0.94). The area under the curve (AUC) was 0.9806. The sensitivity and specificity results of Xpert GBS LB were 0.96 (95% CI 0.95-0.98) and 0.94 (95% CI 0.92-0.95), respectively. The AUC was 0.9950. No publication bias was found. CONCLUSIONS: The Xpert GBS and GBS LB assays are valuable alternative methods with high sensitivity and specificity. However, determining whether they can be used as clinical diagnostic standards for GBS is essential for the future.

Genome-Wide Identification and Analysis of Enhancer-Regulated microRNAs Across 31 Human Cancers.

Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner, and dysregulation of target genes could lead to various diseases, such as cancer. Recent studies have shown that enhancers can regulate microRNAs (miRNAs) and participate in their biological synthesis. However, the network of enhancer-regulated miRNAs across multiple cancers is still unclear. Here, a total of 2,418 proximal enhancer-miRNA interactions and 1,280 distal enhancer-miRNA interactions were identified through the integration of genomic distance, co-expression, and 3D genome data in 31 cancers. The results showed that both proximal and distal interactions exhibited a significant cancer type-specific feature trend at the tissue level rather than at the single-cell level, and there was a noteworthy positive correlation between the expression of the miRNA and the number of enhancers regulating the same miRNA in most cancers. Furthermore, we found that there was a high correlation between the formation of enhancer-miRNA pairs and the expression of enhancer RNAs (eRNAs) whether in distal or proximal regulation. The characteristics analysis showed that miRes (enhancers that regulated miRNAs) and non-miRes presented significant differences in sequence conservation, guanine-cytosine (GC) content, and histone modification signatures. Notably, GC content, H3K4me1, and H3K36me3 were present differently between distal and proximal regulation, suggesting that they might participate in chromosome looping of enhancer-miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391-1186507 ∼ miR-200a was highly relevant to the survival of thyroid cancer patients and a cis-eQTL SNP on the enhancer affected the expression of the TNFRSF18 gene as a tumor suppressor.

Van der Waals Heterostructured MOF-on-MOF Thin Films: Cascading Functionality to Realize Advanced Chemiresistive Sensing.

Heterostructured metal-organic framework (MOF)-on-MOF thin films have the potential to cascade the various properties of different MOF layers in a sequence to produce functions that cannot be achieved by single MOF layers. An integration method that relies on van der Waals interactions, and which overcomes the lattice-matching limits of reported methods, has been developed. The method deposits molecular sieving Cu-TCPP (TCPP=5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin) layers onto semiconductive Cu-HHTP (HHTP=2,3,6,7,10,11-hexahydrotriphenylene) layers to obtain highly oriented MOF-on-MOF thin films. For the first time, the properties in different MOF layers were cascaded in sequence to synergistically produce an enhanced device function. Cu-TCPP-on-Cu-HHTP demonstrated excellent selectivity and the highest response to benzene of the reported recoverable chemiresistive sensing materials that are active at room temperature. This method allows integration of MOFs with cascading properties into advanced functional materials.

Hot food and beverage consumption and the risk of esophageal squamous cell carcinoma: A case-control study in a northwest area in China.

BACKGROUND: This study was trying to investigate the association of hot food and beverage consumption and the risk of esophageal squamous cell carcinoma in Hotan, a northwest area of China with high risk of esophageal squmous cell carcinoma. METHODS: A population-based case-control study was designed. For the study, 167 patients diagnosed with esophageal squamous cell carcinoma were selected from Hotan during 2014 to 2015, and 167 community-based controls were selected from the same area, matched with age and sex. Information involved of temperature of food and beverage intake was obtained by face-to-face interview. Logistic regression analyses were performed to investigate the association between temperature of food and beverage intake and the risk of esophageal squamous cell carcinoma. RESULTS: The temperature of the food and beverage consumed by the esophageal squamous cell carcinoma patients was significantly higher than the controls. High temperature of tea, water, and food intake significantly increased the risk of esophageal squamous cell carcinoma by more than 2-fold, with adjusted odds ratio 2.23 (1.45-2.90), 2.13 (1.53-2.66), and 2.98 (1.89-4.12). CONCLUSIONS: Intake of food and beverage with high temperature was positively associated with the incidence of esophageal squamous cell carcinoma in Northwestern China.

[Application of ICP-mS and AFS to detecting heavy metals in phosphorus fertilizers].

In order to investigate heavy metals in phosphorus fertilizers in China, 159 samples of phosphorus fertilizers including imported fertilizers and domestic fertilizers were collected from fertilizer markets, and the contents of heavy metals were determined by ICP-MS and AFS after microwave digestion. The results showed that the phosphorous fertilizers contained certain amount of heavy metals, and there was great variability in the contents of heavy metals. The mean contents of Cd, Cu, Zn, Cr, Pb, Ni, As and Hg were 0. 77, 35.6, 102.7, 24. 1, 16.6, 15.4, 19.4 and 0. 08 mg kg-1 fertilizer, respectively; based on the calculation of P2O5, the mean contents of above heavy metals were 4. 48, 258. 4, 767. 4, 190. 0, 151.3, 134. 5, 155. 8 and 8. 79 mg kg-1 P2 O5, respectively. The contents of heavy metals Cd, Cr, Pb, As and Hg in the tested samples accord with the ecological index of arsenic, cadmium, lead, chromium and mercury for fertilizers (GB/T 23349-2009), with the exception of Cd in one imported sample of diammonium phosphate and As in one sample of mono-ammonium phosphate. Analyzing the contents of heavy metals in imported fertilizers, the Cd contents in imported fertilizers was ranged from 0. 02 to 27. 2 mg kg-1 fertilizer, the mean and median Cd contents in imported fertilizers were 3. 20 and 0. 41 mg kg-1 fertilizer, respectively. And the Cu, Cr and Hg contents in the imported fertilizers were higher than that of domestic fertilizers, the mean contents of Cu, Cr and Hg in imported fertilizers were 39. 4, 26. 6 and 0. 47 mg kg-1 fertilizer, respectively.

Total synthesis of camptothecin and SN-38.

A new practical and concise total synthesis of enantiopure camptothecin and SN-38 (14% overall yield, 99.9% ee and 99.9% purity) was described, starting from inexpensive and readily available materials. The development of column chromatography-free purification was achieved in all steps, which offers an economic industrial process to the camptothecin-family alkaloids.

[Comparison of sedative effect of dexmedetomidine and midazolam for post-operative patients undergoing mechanical ventilation in surgical intensive care unit].

OBJECTIVE: To study sedative effect and safety of dexmedetomidine and midazolam for post-operative patients undergoing mechanical ventilation(MV) in surgical intensive care unit(SICU). METHODS: Two hundred cases of post-operative patients undergoing MV with tracheal intubation in SICU were enrolled and divided into two groups by random numerical table method. They were treated either with midazolam (98 cases) or dexmedetomidine (102 cases). In both groups fentanyl was given intravenously continually for analgesia. The amount of fentanyl was adjusted according to Prince-Henry analgesic score to keep on 1-2 analgesic score; the dose of sedation was regulated by Riker sedative and restless score (SAS) maintain 2-4 sedative score. During the course, parameters of the ventilator, electrocardiogram, heart rate(HR), blood pressure, respiratory rate, pulse oxygen saturation (SpO(2)), blood gas analysis were observed and registered continuously. The amount of the drug, duration of MV, and incidence of side-effects such as hypotension, bradycardia, delirium, nausea, etc. were recorded in two groups. RESULTS: In all the patients in two groups taking dexmedetomidine or midazolam expected sedative and analgesia scores were obtained. In the group with dexmedetomidine, the patients were aroused easier with adequate sedation, and when compared with the group with midazolam, dose of fentanyl (µg× kg(-1)×h(-1) ) was significantly smaller (0.23±0.13 vs. 0.41±0.12, P<0.01), duration of MV (hours) was clearly shorter (7.20±6.29 vs. 12.44±8.96, P<0.01), the rates of hypotension (27.45% vs. 11.22%) and bradycardia (24.51% vs. 10.20%) were significantly higher (both P<0.05), the rate of delirium was clearly lower (3.92% vs. 31.63%, P<0.01), the rate of nausea showed a slight decrease (9.80% vs. 11.22%, P>0.05). The patients in the group with dexmedetomidine were divided into two subgroups of hypotension and non-hypotension. The quantity of blood loss during operation (ml/kg), amount of fluid infusion during operation (ml× kg(-1)×h(-1) ), blood lactic acid concentration (mmol/L) on the day of surgical operation and the 1st day post-operative showed no significant difference between these subgroups (quantity of blood loss on the day of surgical operation: 12.79±12.13 vs. 13.52±11.62; amount of fluid infusion during surgical operation: 11.91±4.59 vs. 13.09±7.05;blood lactic acid concentration on the day of operation: 1.88±1.07 vs. 1.71±0.87, blood lactic acid concentration on the 1st day post-operative:1.43±0.98 vs. 1.37±0.79, all P>0.05). CONCLUSION: Sedative effect of dexmedetomidine is satisfactory for patients undergoing MV after operation, with the property of easier arousal, lower delirium rate, and it helps to shorten the duration of MV with reduction the dosage of fentanyl by 50%. However, it is necessary to enhance observation in order to prevent and control hypotension and bradycardia.

Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes.

BACKGROUND: Methionine aminopeptidase is a potential target of future antibacterial and anticancer drugs. Structural analysis of complexes of the enzyme with its inhibitors provides valuable information for structure-based drug design efforts. RESULTS: Five new X-ray structures of such enzyme-inhibitor complexes were obtained. Analysis of these and other three similar structures reveals the adaptability of a surface-exposed loop bearing Y62, H63, G64 and Y65 (the YHGY loop) that is an integral part of the substrate and inhibitor binding pocket. This adaptability is important for accommodating inhibitors with variations in size. When compared with the human isozymes, this loop either becomes buried in the human type I enzyme due to an N-terminal extension that covers its position or is replaced by a unique insert in the human type II enzyme. CONCLUSION: The adaptability of the YHGY loop in E. coli methionine aminopeptidase, and likely in other bacterial methionine aminopeptidases, enables the enzyme active pocket to accommodate inhibitors of differing size. The differences in this adaptable loop between the bacterial and human methionine aminopeptidases is a structural feature that can be exploited to design inhibitors of bacterial methionine aminopeptidases as therapeutic agents with minimal inhibition of the corresponding human enzymes.

Inhibition of monometalated methionine aminopeptidase: inhibitor discovery and crystallographic analysis.

Two divalent metal ions are commonly seen in the active-site cavity of methionine aminopeptidase, and at least one of the metal ions is directly involved in catalysis. Although ample structural and functional information is available for dimetalated enzyme, methionine aminopeptidase likely functions as a monometalated enzyme under physiological conditions. Information on structure, as well as catalysis and inhibition, of the monometalated enzyme is lacking. By improving conditions of high-throughput screening, we identified a unique inhibitor with specificity toward the monometalated enzyme. Kinetic characterization indicates a mutual exclusivity in binding between the inhibitor and the second metal ion at the active site. This is confirmed by X-ray structure, and this inhibitor coordinates with the first metal ion and occupies the space normally occupied by the second metal ion. Kinetic and structural analyses of the inhibition by this and other inhibitors provide insight in designing effective inhibitors of methionine aminopeptidase.

[Effects of brain stem and spinal cord by isoflurane inhibiting nociceptive reflex].

OBJECTIVE: To explore the effect positions of the volatile anesthetic inhibiting the nociceptive reflex in the central nervous system. METHODS: Thirty adult SD rats were randomly and equally divided into two groups that the lip and hind paw of rats were held by clamp. The minimum alveolar concentration (MAC) was determined by clamping two places: one was to clamp the hind paw of rats, of which the nervous reflex is controlled via the spinal cord; the another group was to clamp the lip of rats, of which the nervous reflex is controlled through the brain stem. RESULTS: The isoflurane MAC was 1.44% +/- 0.09% in clamping the hind paw group, while 1.29% +/- 0.11% for clamping the lip group (P < 0.05). CONCLUSION: Both brain stem and spinal cord are the effect positions of volatile anesthetics (especially isoflurane).

[Security evaluation of bupivacaine, ropivacaine combined with fentanyl in postoperative continuous epidural analgesia].

OBJECTIVE: To investigate the effects, side-effects and security of bupivacaine, ropivacaine combined with fentanyl in postoperative continuous epidural analgesia. METHODS: A total of 1 600 postoperative continuous epidural analgesia patients receiving different agents in SICU were divided into two groups: 0.1% bupivacaine +5 microg/ml fentanyl group (group B, n = 920) and 0.2% ropivacaine +2 microg/ml fentanyl group (group R, n = 680). The effects (visual analog-scale score and content to analgesia), side effects were analyzed retrospectively in the two groups. RESULTS: Compared with group B, patients in group R had higher analgesia contentment (P < 0.05), but no difference in visual analog-scale score was found in the two groups. The incidences of urinary retention, nausea and vomiting, skin itching in group B were significantly higher than those in group R (P < 0.05). In each group, patients over sixty had higher ratio of hypotension than those under sixty (P < 0.05); The female patients had a higher incidence of nausea and vomiting than male patients (P < 0.05); The incidence of debility and numbness of lower limbs in patients with lumbar segments epidural analgesia was higher than those with thoracic analgesia (P < 0.05). CONCLUSIONS: 0.1% bupivacaine +5 microg/ml fentanyl and 0.2% ropivacaine +2 microg/ml fentanyl can provide adequate pain relief in postoperative continuous epidural analgesia, and 0.2% ropivacaine +2 microg/ml fentanyl comes with less side effects. The incidence of complication is related with analgesics, age, gender and the position of epidural puncture.

Metalloform-selective inhibition: synthesis and structure-activity analysis of Mn(II)-form-selective inhibitors of Escherichia coli methionine aminopeptidase.

Methionine aminopeptidase (MetAP) is a promising target for development of novel antibacterial, antifungal and anticancer agents. However, its physiologically relevant metal ion remains to be defined, and its inhibitors need to inhibit the in vivo metalloform. Based on the Mn(II)-form-selective inhibitors discovered by high throughput screening as leads, a series of analogs of 5-phenylfuran-2-carboxylic acid was prepared and subsequently evaluated on Co(II)-, Mn(II)-, Ni(II)-, and Fe(II)-forms of Escherichia coli MetAP, in order to define the structural elements responsible for their inhibitory potency and metalloform selectivity. Various substitutions on the phenyl ring changed their potency on the Mn(II)-form but not their metalloform selectivity. We conclude that the preferential coordination of the carboxyl group to Mn(II) ions is the major determinant for their superb selectivity toward the Mn(II)-form. Changing the carboxylate to hydroxamate alters its ability to bind and discriminate different metal ions, and the hydroxamate derivative becomes non-selective among the metalloforms tested.

Identification of potent type I MetAPs inhibitors by simple bioisosteric replacement. Part 2: SAR studies of 5-heteroalkyl substituted TCAT derivatives.

Systematic SAR studies on the thiazole ring 5-substituent of TCAT derivatives revealed that the introduction of a beta-alkoxy or an amino group enhanced the inhibitory activity significantly. The present compounds are representative of specific Co(II)-MetAP1 inhibitors. Before the physiologically relevant metal ions for MetAPs are established, these small molecular compounds could be used as tools for detailed biological studies.

Identification of potent type I MetAP inhibitors by simple bioisosteric replacement. Part 1: Synthesis and preliminary SAR studies of thiazole-4-carboxylic acid thiazol-2-ylamide derivatives.

A series of thiazole-4-carboxylic acid thiazol-2-ylamide (TCAT, 4) derivatives were designed and synthesized according to simple bioisosteric replacement from previously reported pyridine-2-carboxylic acid thiazol-2-ylamide (PCAT) MetAP inhibitors. The preliminary SAR studies demonstrated that these TCAT series of compounds showed different activity and selectivity compared with those of the corresponding PCAT compounds. These findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.