https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45054 Escherichia coli and Pseudomonas aeruginosa, with a clear delineation of the outer and inner membrane as well as the peptidoglycan layer. We suggest that the use of ultrathin cryo-sectioning can be used to better visualize and understand drug interaction mechanisms on the bacterial cell membrane.]]> Wed 26 Oct 2022 11:36:12 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44078 6] and the protic ionic liquid ethanolammonium nitrate (ETAN) failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate. Analysis of the structure activity relationship data suggested the presence of a bulky moiety originating from the isocyanide (cyclohexyl and benzyl) enhanced cytotoxicity. Removal of the acetylenic H-atom from the ethanoic acid moiety was detrimental to cytotoxicity. The most active analogues produced, N-(2-cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl-N-(3,5-dimethoxyphenyl)propiolamide, returned average GI₅₀ values of ≤1 μM across the cancer cell lines evaluated. Combined, these data suggest that analogues of this nature are interesting potential anti-cancer development leads.]]> Wed 26 Oct 2022 10:31:27 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3326 Wed 24 Jul 2013 22:21:31 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:42541 Wed 24 Aug 2022 16:53:29 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37670 Wed 22 Mar 2023 17:08:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27267 Wed 17 Nov 2021 16:32:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46366 in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.]]> Wed 16 Nov 2022 08:57:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38143 Wed 15 Feb 2023 11:16:01 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19862 t-butyl based palladium catalyst CatCart™ FC1032™. Deactivated aryl bromides and activated aryl chlorides were cross-coupled with 5-formyl-2-furanylboronic in the presence of (Bu)₄N⁺OAc⁻ using the bis-triphenylphosphine CatCart™ PdCl₂(PPh₃)₂-DVB. Initial evidence indicates the latter method may serve as a universal approach to conduct Suzuki cross-couplings with the protocol successfully employed in the synthesis of the current gold standard Hedgehog pathway inhibitor LDE225.]]> Wed 11 Apr 2018 17:16:27 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22205 0.5 mol CO₂/mol amine). HHPY exhibits similar reactivity toward CO₂ to PZ, but with improved aqueous solubility. The α-methyl-substituted MHHPY favours HCO₃− formation, but MHHPY exhibits comparable CO₂ absorption capacity to conventional amines MEA and DEA. MHHPY show improved reactivity compared to the conventional α-methyl-substituted primary amine 2-amino-2-methyl-1-propanol. DMHHPY is representative of blended amine systems, and its reactivity highlights the advantages of such systems. HHPZ is relatively unreactive towards CO₂. The CO₂ absorption capacity C_A (mol CO2/mol amine) and initial rates of absorption R_IA (mol CO₂/mol amine min⁻¹) for each reactive diamine are determined: PZ: C_A =0.92, R_IA=0.045; 2,6-DMPZ: C_A =0.86, R_IA=0.025; 2,5-DMPZ: C_A =0.88, R_IA=0.018; HHPY: C_A =0.85, R_IA=0.032; MHHPY: C_A =0.86, R_IA=0.018; DMHHPY: C_A =1.1, R_IA=0.032; and HHPZ: no reaction. Calculations at the B3LYP/6-31+G** and MP2/6-31+G** calculations show that the substitution patterns of the heterocyclic diamines affect carbamate stability, which influences hydrolysis rates.]]> Wed 11 Apr 2018 15:00:20 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:10991 Wed 11 Apr 2018 14:47:28 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20977 TM), approved by the U.S. Food and Drug Administration for the treatment of adult basal cell carcinoma. In this perspective we outline the current state of Hh pathway inhibitors with a particular focus on potential limitations of upstream Hh pathway inhibition in relation to resistance mutations and crosstalk pathways. Together, these limitations indicate that inhibition of downstream components, specifically the Gli family of transcription factors, may represent a next generation approach to suppress tumours associated with aberrant Hh pathway signalling. © 2014 The Royal Society of Chemistry.]]> Wed 11 Apr 2018 14:10:20 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:18276 Wed 11 Apr 2018 12:33:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20085 Wed 11 Apr 2018 12:17:41 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27739 Wed 11 Apr 2018 11:56:44 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20637 Wed 11 Apr 2018 11:51:22 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30063 50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8–0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.]]> Wed 11 Apr 2018 11:15:48 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40008 Enterococcus faecalis/faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, and Enterobacte spp.), have become a public health threat worldwide. Development of new antimicrobial classes and the use of drugs in combination are potential strategies to treat MDR ESKAPE pathogen infections and promote optimal antimicrobial stewardship. Here, the in vitro antimicrobial activity of robenidine analog NCL195 alone or in combination with different concentrations of three outer membrane permeabilizers [ethylenediaminetetraacetic acid (EDTA), polymyxin B nonapeptide (PMBN), and polymyxin B (PMB)] was further evaluated against clinical isolates and reference strains of key Gram-negative bacteria. NCL195 alone was bactericidal against Neisseria meningitidis and Neisseria gonorrhoeae (MIC/MBC = 32 μg/mL) and demonstrated synergistic activity against P. aeruginosa, E. coli, K. pneumoniae, and Enterobacter spp. strains in the presence of subinhibitory concentrations of EDTA, PMBN, or PMB. The additive and/or synergistic effects of NCL195 in combination with EDTA, PMBN, or PMB are promising developments for a new chemical class scaffold to treat Gram-negative infections. Tokuyasu cryo ultramicrotomy was used to visualize the effect of NCL195 on bioluminescent S. aureus membrane morphology. Additionally, NCL195’s favorable pharmacokinetic and pharmacodynamic profile was further explored in in vivo safety studies in mice and preliminary efficacy studies against Gram-positive bacteria. Mice administered two doses of NCL195 (50 mg/kg) by the intraperitoneal (IP) route 4 h apart showed no adverse clinical effects and no observable histological effects in major organs. In bioluminescent Streptococcus pneumoniae and S. aureus murine sepsis challenge models, mice that received two 50 mg/kg doses of NCL195 4 or 6 h apart exhibited significantly reduced bacterial loads and longer survival times than untreated mice. However, further medicinal chemistry and pharmaceutical development to improve potency, solubility, and selectivity is required before efficacy testing in Gram-negative infection models.]]> Wed 06 Jul 2022 11:20:52 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48768 Wed 05 Apr 2023 13:55:29 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:25063 Wed 04 Sep 2019 10:12:46 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34053 Wed 04 Sep 2019 09:39:49 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38104 Wed 04 Aug 2021 17:41:28 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:49034 Wed 03 May 2023 13:48:14 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45607 Wed 02 Nov 2022 14:14:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20160 36-fold reduced activity against rings, suggesting that they can discriminate between helical or ring oligomerization states. 4a and 6a inhibited dynamin-dependent endocytosis of transferrin in multiple cell types (IC50 of 5.7 and 5.8 μM, respectively), at least sixfold more potently than dynasore, but had no effect on dynamin-independent endocytosis of cholera toxin. 4a also reduced synaptic vesicle endocytosis and activity-dependent bulk endocytosis in cultured neurons and synaptosomes. Overall, 4a and 6a are improved and versatile helical dynamin and endocytosis inhibitors in terms of potency, non-specific binding and cytotoxicity. The data further suggest that the ring oligomerization state of dynamin is not required for clathrin-mediated endocytosis.]]> Tue 24 Aug 2021 14:23:34 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47992 Leptospermum petersonii is an aromatic native Australian plant that has been traditionally used as a medicine and a tea; however, its application in food products is increasing. The aim of this study was to investigate the most suitable and energy-efficient drying conditions to retain phenolic compounds, antioxidant properties, and, color in dried Leptospermum petersonii leaves. In this study, six drying techniques were investigated including hot air, vacuum, microwave, freeze, sun, and shade. Results showed that freeze-drying retained maximum color, phenolic compounds, and, antioxidant capacity, however, it consumed the most time and energy. Conversely, microwave drying (960 W, 0.1 hr) used the least amount of time and energy yet retained the second-highest levels of phenolics and antioxidant capacity. In conclusion, microwave drying is suggested for large-scale drying. This method is economical and it is approximately 480 times and 1,700 times more time and energy efficient compared to freeze-drying.]]> Tue 14 Feb 2023 15:04:58 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43145 Tue 13 Sep 2022 15:21:31 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43130 Tue 13 Sep 2022 15:07:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50596 Tue 08 Aug 2023 11:56:57 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51456 50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.]]> Tue 05 Sep 2023 18:22:02 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34739 50 was as low as 0.2 μM with corresponding MLCs as low as 2.8 μM. This is in contrast to metronidazole which required 24 h to exhibit inhibitory activity. A modified adherence assay, developed for this study, demonstrated that three of the compounds inhibited in vitro adherence of the parasite. The lead compound exhibited rapid giardicidal activity (<5hr). In addition, microscopy studies demonstrated damage to the plasma membrane of trophozoites. In conclusion, a class of aminoguanidines, represented by robenidine, has shown antigiardial activity warranting further investigation.]]> Tue 03 Sep 2019 17:57:16 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34016 Thu 30 May 2019 15:47:52 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34014 Thu 30 May 2019 15:41:20 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45380 Thu 27 Oct 2022 15:58:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:247 Thu 25 Jul 2013 09:09:27 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38461 50=30 nM and 400-fold selective c.f. MCF10A (normal breast tissue). Acetamide moiety modification (13 a-g) to introduce additional hydrophobicity was favoured with MCF-7 breast cancer cell activity enhanced at 1.3 nM. Other analogues were potent against the HT29 colon cancer cell line at 23 nM. Textbook SAR data was observed in the MCF-7 cell line, in an MTT assay, via the ortho (17 a), meta (17 b) and para (13 f). The amino alcohol -OH moiety was pivotal, but no stereochemical preference noted. But, these data did not fit our homology modelling expectations. Aberrant MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) screening results and metabolic interference confirmed by sulforhodamine B (SRB) screening. Interfering analogues resulted in 120 and 80-fold CYP1A1 and CYP1A2 amplification, with no upregulation of SULT1A1. This is consistent with activation of the AhR pathway. Piperidine per-deuteration reduced metabolic inactivation. 3-OH / 4-OH piperidine analogues showed differential MTT and SRB activity supporting MTT assay metabolic inactivation. Data supports piperidine 3-OH, but not the 4-OH, as a CYP substrate. This family of β-amino alcohol substituted 3,4-dichlorophenylacetonitriles show broad activity modulated via the AhR pathway. By SRB analysis the most potent analogue was 23 b, (Z)-3-(4-(3-(4-phenylpiperidin-1-yl)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile.]]> Thu 18 Nov 2021 10:32:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48035  47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2-3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.]]> Thu 16 Feb 2023 11:04:01 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33539 Thu 15 Nov 2018 15:26:24 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31291 Thu 13 Jan 2022 10:28:35 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:37232 Acinetobacter baumannii [minimum inhibitory concentrations (MIC) mode = 8 μg/ml] and Acinetobacter calcoaceticus (MIC mode = 2 μg/ml). Against Acinetobacter spp., an additivity/indifference of the combination of robenidine/EDTA (0.53 > FICIs > 1.06) and a synergistic effect of the combination of robenidine/PMBN (0.5 < FICI) were obtained. DRIs of robenidine were significantly increased in the presence of both EDTA and PMBN from 2- to 2048-fold. Robenidine exhibited antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, in the presence of sub-inhibitory concentrations of either EDTA or PMBN. Robenidine also demonstrated potent antibacterial activity against multidrug-resistant Gram-positive pathogens and all Gram-negative pathogens isolated from cases of canine otitis externa in the presence of EDTA. Robenidine did not demonstrate antibiofilm activity against Gram-positive and Gram-negative bacteria. EDTA facilitated biofilm biomass degradation for both Gram-positives and Gram-negatives. The addition of robenidine to EDTA was not associated with any change in the effect on biofilm biomass degradation. The combination of robenidine with EDTA or PMBN has potential for further exploration and pharmaceutical development, such as incorporation into topical and otic formulations for animal and human use.]]> Thu 10 Sep 2020 18:17:17 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:31422 E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens.]]> Thu 09 Dec 2021 11:03:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40290 Thu 07 Jul 2022 14:57:42 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:38165 2/microwave-mediated approach afforded access to pure material, collected by cooling and filtration after 20-min microwave irradiation at 120°C. A total of 41 analogues were prepared in isolated yields of 17–99 %. This process was highly tolerant of aliphatic, aromatic, heterocyclic, and acyclic aldehydes, but furan, pyrrole, and thiophene aldehyde reactivity correlated with propensity towards electrophilic addition and/or Diels–Alder addition. As a result, thiophene afforded high yields (80 %) whereas pyrrole carboxaldehyde failed to react. With simple cinnamaldehydes, and in the SbCl₃-mediated reaction, and with α,β-unsaturated aldehydes the equivalent quinazolin-4(3H)-ones, and not the 2,3-dihydroquinazolin-4(1H)-ones, was favoured.]]> Thu 05 Aug 2021 11:45:40 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41781 (E)‐N′‐((E)‐1‐(4‐chlorophenyl)ethylidene)‐2‐(1‐(4‐chlorophenyl)ethylidene)hydrazine‐1‐carboximidhydrazide displays methicillin‐resistant Staphyoccoccus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE) MICs of 2 μg mL⁻¹. Herein we describe the structure‐activity relationship development of a novel series of guanidine to 2‐aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2‐NH₂ pyrimidine moiety renders these analogues inactive. Introduction of a central 2‐NH₂ triazine moiety saw a 10‐fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4‐BrPh and 4‐CH₃Ph with MIC values of 2 and 4 μg mL⁻¹, against MRSA and VRE respectively, are promising candidates for future development.]]> Thu 01 Sep 2022 12:33:12 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17953 85% and the products are isolated by ethanol-mediated precipitation direct from the ionic liquid, requiring no further purification.]]> Thu 01 Aug 2019 17:23:14 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20908 Thu 01 Aug 2019 17:22:27 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7141 Sat 24 Mar 2018 10:44:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:8246 Sat 24 Mar 2018 08:40:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9676 Sat 24 Mar 2018 08:39:16 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:7046 Sat 24 Mar 2018 08:37:54 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:8338 Sat 24 Mar 2018 08:37:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1259 Sat 24 Mar 2018 08:32:47 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1291 Sat 24 Mar 2018 08:32:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1334 Sat 24 Mar 2018 08:32:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1613 Sat 24 Mar 2018 08:30:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1773 1000 μM. Analogues possessing good PP1 and/or PP2A inhibition also returned moderate to good anti-cancer activity. Analogues with substituents directly attached to the intact bicyclo[2.2.1]heptane skeleton were poor to moderate anti-cancer agents. This correlates well with their lack of PP1 or PP2A activity. Analogues capable of undergoing a facile ring opening of the anhydride or with a single carboxylate were good PP1 and PP2A inhibitors, largely correlating to the observed anti-cancer activity in all cases, except 11. Analogue 11, whist neither a PP1 nor a PP2A inhibitor shows anti-cancer activity comparable to 1 and 2. We believe that intracellular esterases generate the corresponding dicarboxylate, which is a potent PP1 and PP2A inhibitor, and that it is this species which is responsible for the observed anti-cancer activity.]]> Sat 24 Mar 2018 08:27:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:2443 Sat 24 Mar 2018 08:26:53 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:13243 Sat 24 Mar 2018 08:17:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:12609 2 and piperidine, as well as commercially available functionalised piperidine derivatives, for example, those with methyl-, hydroxyl- and hydroxyalkyl substituents, has been investigated. The chemical reactions between CO₂ and the functionalised piperidines were followed in situ by using attenuated total reflectance (ATR) FTIR spectroscopy. The effect of structural variations on CO₂ absorption was assessed in relation to the ionic reaction products identifiable by IR spectroscopy, that is, carbamate versus bicarbonate absorbance, CO₂ absorption capacity and the mass-transfer coefficient at zero loading. On absorption of CO₂, the formation of the carbamate derivatives of the 3- and 4-hydroxyl-, 3- and 4-hydroxymethyl-, and 4-hydroxyethyl-substituted piperidines were found to be kinetically less favourable than the carbamate derivatives of piperidine and the 3- and 4-methyl-substituted piperidines. As the CO₂ loading of piperidine and the 3- and 4-methyl- and hydroxyalkyl-substituted piperidines exceeded 0.5 moles of CO₂ per mole of amine, the hydrolysis of the carbamate derivative of these amines was observed in the IR spectra collected. From the subset of amines analysed, the 2-alkyl- and 2-hydroxyalkyl-substituted piperidines were found to favour bicarbonate formation in the reaction with CO₂. Based on IR spectral data, the ability of these amines to form the carbamate derivatives was also established. Computational calculations at the B3LYP/6-31+G** and MP2/6-31+G** levels of theory were also performed to investigate the electronic/steric effects of the substituents on the reactivity (CO₂ capture performance) of different amines, as well as their carbamate structures. The theoretical results obtained for the 2-alkyl- and 2-hydroxyalkyl-substituted piperidines suggest that a combination of both the electronic effect exerted by the substituent and a reduction in the exposed area of the nitrogen atom play a role in destabilising the carbamate derivative and increasing its susceptibility to hydrolysis. A theoretical investigation into the structure of the carbamate derivatives of these amines revealed shorter N-C bond lengths and a less-delocalised electron distribution in the carboxylate moiety.]]> Sat 24 Mar 2018 08:17:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:12523 Sat 24 Mar 2018 08:16:01 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11175 Sat 24 Mar 2018 08:14:32 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:11334 Sat 24 Mar 2018 08:13:29 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21428 50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC₅₀ values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC₅₀ values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure–activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal domain–amphiphysin inhibitor reported to date.]]> Sat 24 Mar 2018 08:05:47 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17426 Sat 24 Mar 2018 08:01:40 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17425 Sat 24 Mar 2018 08:01:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17423 TM, was sufficient to abolish BoNT/A-Hc internalization and BoNT/A-induced SNAP25 cleavage in hippocampal neurons. Dyngo-4a also interfered with BoNT/A-Hc internalization into motor nerve terminals. Furthermore, Dyngo-4a afforded protection against BoNT/A-induced paralysis at the rat hemidiaphragm. A significant delay of >30% in the onset of botulism was observed in mice injected with Dyngo-4a. Dynamin inhibition therefore provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin-dependent uptake mechanisms.]]> Sat 24 Mar 2018 08:01:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19635 Sat 24 Mar 2018 08:01:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19942 Sat 24 Mar 2018 07:58:35 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19846 Sat 24 Mar 2018 07:57:06 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19822 STY) with an imprinting factor (IF) = 1.3. An extreme vertices mixture design (EVMD) approach was applied, and in two design cycles, 15 total experimental points, the optimum composition for MIP_STY was determined as 0.40 : 0.05 : 0.55 (T : FM : CL) with IF = 2.8. Refinements gave optimum T : FM : CL ratios for the functional monomers: 4-vinylpyridine (4VP, 0.40 : 0.02 : 0.58); 2,4,6-trimethylstyrene (TMS, 0.40 : 0.02 : 0.58) and 2,3,4,5,6-pentafluorostyrene (PFS, 0.30 : 0.12 : 0.58) with IF = 2.8, 2.8 and 3.7 respectively. These ratios deviated significantly from the traditional MIP synthesis ratio. The low levels of FM for all MIPs, except for MIP_PFS, suggest that imprinting was more consistent with T–CL, than FM–T, interactions. Analysis of the specific interactions and removal (SR) of 7 with these MIPs revealed that the SR with MIP_STY increased from 36% at 0.02 STY to 48% at 0.13 STY; with MIP_TMS SR increased from 38% at 0.02 TMS to 42% at 0.10 TMS; and with MIP_PFSSR increased from 34% at 0.02 PFS to 56% at 0.14 PFS. MIP_4VP saw a decline in SR with increasing FM, with the highest SR was 35% at 0.02 4VP. This is consistent with changes in the non-specific interactions between 7 and the MIPs. Increasing the proportion of PFS produced the largest increase in imprinting of 7 demonstrated by the highest SR (56%) and highest IF (3.7). The application of an EVMD approach resulted in the IF of MIP_STY increased from 1.3 to 2.8. The highest IF achieved by this study was 3.7 for MIP_PFS in proportions of 0.30 : 0.12 : 0.48 (T : FM : CL).]]> Sat 24 Mar 2018 07:56:57 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17938 Sat 24 Mar 2018 07:56:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:17945 Sat 24 Mar 2018 07:56:29 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20674 Sat 24 Mar 2018 07:55:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20974 Sat 24 Mar 2018 07:54:19 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21238 N,N-dimethyl-4'-vinylbiphenyl-3-amine (M3), (4'-vinylbiphenyl-4-yl)methanol (M4), 4'-vinylbiphenyl-4-carboxylic acid (M5) and 4-hydroxy-5-methyl-4'-vinylbiphenyl-3-carboxylic acid (M6), were examined for their ability to imprint theophylline (1). Using a molecular modelling-NMR titration approach, M2 and M6 were predicted to give rise to the most specific molecularly imprinted polymers (MIPs). Rebinding analysis suggests that no imprinting effect resulted from the polymerisation of monomers M1 , M5 and M6, but modest to good levels of imprinting were evident from monomers M2, M3 and M4 with IF values ranging from 1.1 (MIP_M3, 20 mg) to 45 (MIP_M2, 10 mg). The selective recognition of 1 varied as a function of polymer mass used. At low polymer loadings MIP_M2 gave the very high IF of 45, reducing to IF = 4.1-2.3 at 20-40 mg polymer loading. With monomer M2, microwave synthesised MIP (MW-MIP_M2) was examined. The MW-MIP_M2 displayed lower specific rebinding than its conventionally produced counterpart (MIP_M2) with IF values ranging from 1.6-2.3 (cf., MIP_M2 IF 2.3-45), but significantly higher levels of rebinding with 25-52% of 1 rebound from a 0.080 mM CH₃CN solution of 1 (cf., MIP_M2 5-25%). MW-MIP_M2 displayed a lower BET surface area than MIP_M2 (185 m² g^-1vs. 240 m² g^-1), and lower surface (zeta) potential (-13.1 ± 8.22 mV vs. -31.4 ± 4.84 mV). Freundlich isotherm analysis revealed that MW-MIP_M2 possessed higher affinity binding sites for 1 than MIP_M2 with K_d values of 1.38 and 2.31 respectively. In addition, MW-MIP_M2 also exhibits a higher number of binding sites (N_⏉) compared to MW-NIP_M2 (0.72 and 0.41 mg g^-1, respectively). In specificity studies using caffeine (2), MIP_M2 displayed a two-fold preference for rebinding of 1 and MW-MIP_M2 a five-fold preference for 1 over 2 . The quantity of 2 bound in both cases was consistent with non-specific binding events. In competitive rebinding experiments, increased discrimination in favour of 1 over 2 was observed.]]> Sat 24 Mar 2018 07:53:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20159 Sat 24 Mar 2018 07:51:36 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:5000 Sat 24 Mar 2018 07:44:09 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:341 Sat 24 Mar 2018 07:42:27 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27293 Bacillus subtilis and Gram-negative Escherichia coli growth.]]> Sat 24 Mar 2018 07:40:19 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28474 in silico docking studies. Docking studies predicted enhanced Pitstop® 2 family binding, not a loss of binding, within the Pistop® groove of the reported clathrin mutant invalidating recent assumptions of poor selectivity for this family of clathrin inhibitors.]]> Sat 24 Mar 2018 07:39:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27976 50 = 6.7 nM) led to a significant reduction in dynamin phosphorylation (10.3% vs. 27.3%; P < 0.001), acrosomal exocytosis (9.7% vs. 25.7%; P < 0.01), and in vitro fertilization (53% vs. 100%; P < 0.01). GSK3 was shown to be present in developing germ cells where it colocalized with dynamin in the peri-acrosomal domain. However, additional GSK3 was acquired by maturing mouse spermatozoa within the male reproductive tract, via a novel mechanism involving direct interaction of sperm heads with extracellular structures known as epididymal dense bodies. These data reveal a novel mode for the cellular acquisition of a protein kinase and identify a key role for GSK3 in the regulation of sperm maturation and acrosomal exocytosis.—Reid, A. T., Anderson, A. L., Roman, S. D., McLaughlin, E. A., McCluskey, A., Robinson, P. J., Aitken, R. J., Nixon, B. Glycogen synthase kinase 3 regulates acrosomal exocytosis in mouse spermatozoa via dynamin phosphorylation.]]> Sat 24 Mar 2018 07:38:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27742 Sat 24 Mar 2018 07:27:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:26323 NAr coupling with 1-fluoro-4-nitrobenzene. Microwave coupling of 4-morphilinoaniline 8 and 4-(piperazine-1-yl)aniline 9 with 2-(2,5-dichloropyrimidine-4-ylamino)-N-methylbenzamide 10, proved to be the most efficacious route to the target analogues 6 and 7. This hybrid methodology reduced the number of synthetic steps, gave enhanced overall yields and increased atom economy through step reduction and minimal requirement for chromatographic purification, relative to the original batch synthesis approach.]]> Sat 24 Mar 2018 07:24:11 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3268 Sat 24 Mar 2018 07:21:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3267 Sat 24 Mar 2018 07:21:22 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:3265 Sat 24 Mar 2018 07:21:21 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:4735 Sat 24 Mar 2018 07:21:10 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22284 Sat 24 Mar 2018 07:17:40 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22263 in vitro induction of acrosomal exocytosis by progesterone, but not by the calcium ionophore A23187, and elicited a concomitant reduction of in vitro fertilization. In vivo treatment with these inhibitors also resulted in spermatozoa displaying reduced acrosome reaction potential. Dynamin 1 and 2 phosphorylation increased on progesterone treatment, and this was also selectively blocked by dynasore. On the basis of our collective data, we propose that dynamin could regulate specific membrane fusion events necessary for acrosomal exocytosis in mouse spermatozoa.]]> Sat 24 Mar 2018 07:17:38 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22226 Sat 24 Mar 2018 07:17:37 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23187 50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC_50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.]]> Sat 24 Mar 2018 07:10:29 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41099 Pro.A > TFC for antioxidant properties.]]> Mon 25 Jul 2022 10:38:30 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44889 N′,2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL⁻¹. Five analogues were found to be equipotent or more potent than the lead 1. Introduction of an indole moiety resulted in the most active robenidine analogue against methicillin-resistant S. aureus (MRSA), with a MIC of 1.0 μg mL⁻¹. Imine C=NH isosteres (C=O/C=S) were inactive. Monomeric analogues were 16–64 μg mL⁻¹ active against MRSA and VRE. An analogue that lacks the terminal hydrazide NH moiety showed modest Gram-negative activity at 64 μg mL⁻¹. A 4-tert-butyl analogue was shown to be active against both Gram-positive and -negative strains at 16–64 μg mL⁻¹. In general, additional modifications with aromatic moieties was poorly tolerated, except with concomitant introduction of an imine C-alkyl group. The activity of these analogues against MRSA and VRE ranged from 8 μg mL−1 to inactive (MIC>128 μg mL⁻¹) with the naphthyl and indole analogues. Gram-negative activity was most promising with two compounds at 16 μg mL⁻¹ against E. coli. Against P. aeruginosa, the highest activity observed was with MIC values of 32 μg mL⁻¹ with another two analogues. Combined, these findings support the further development of the (E)-2-benzylidenehydrazine-1-carboximidamide scaffold as a promising scaffold for the development of antibiotics against Gram-positive and Gram-negative strains.]]> Mon 24 Oct 2022 14:46:25 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:43439 Mon 19 Sep 2022 13:06:45 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:53783 Mon 15 Jan 2024 10:24:12 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40209 Mon 08 Aug 2022 13:40:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:42808 Mon 05 Sep 2022 09:57:19 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:42606 Fri 26 Aug 2022 15:48:48 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36503 3 catalysed microwave ring opening with amines afforded a select range of β-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach.]]> Fri 22 May 2020 16:51:41 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:50925 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.]]> Fri 11 Aug 2023 15:54:32 AEST ]]>