https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:45249 Wed 26 Oct 2022 19:43:42 AEDT ]]> 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: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:51031 Wed 16 Aug 2023 10:16:28 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:51022 Wed 16 Aug 2023 10:03:02 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:39597 Wed 15 Jun 2022 12:54:03 AEST ]]> 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:47111 Wed 14 Dec 2022 10:19:31 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:36223 Wed 11 Mar 2020 11:08:42 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: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: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:28469 Wed 11 Apr 2018 10:47:35 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28064 Wed 11 Apr 2018 09:24:57 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:34617 Wed 09 Feb 2022 15:55:15 AEDT ]]> 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:48769 Wed 05 Apr 2023 14:02:39 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:34052 Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB–NusE PPI as proposed.]]> Wed 04 Sep 2019 09:54:32 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:30033 1 (2,2′-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC’s of 8.1 and 4.7 μM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH₃ (22), and 4-C(CH₃)₃ (27) (23.7–71 μM) and with 3-Cl (3), 4-CH₃ (21), and 4-CH(CH₃)₂ (26) (8.1–13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH₂OH moiety (75; 2,2′-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2′-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2′-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC’s of 4.2–21.6 μM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T_1/2 > 247 min, CL_int < 7 μL/min/mg protein, and E_H < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75.]]> Wed 02 Mar 2022 14:27:39 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:54455 Tue 27 Feb 2024 13:53:27 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:48307 96%) were afforded on simple diethyl ether extraction from [BMIM][PF6] and [BMIM][OH]. The described procedure was highly substrate tolerant with methyl, methoxy, fluoro, trifluoromethyl, ester, cyano, hydroxy, naphthyl, and quinolone moieties well tolerated. Poor yields or no reactions were observed with –NH2 and –NO2 moieties. The use of microwave irradiation reduced reaction times from 3 h (thermal) to 5–15 min with no substantive effect on reaction outcome.]]> Tue 14 Mar 2023 14:34:50 AEDT ]]> 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:50247 Tue 11 Jul 2023 14:16:11 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:51301 Thu 31 Aug 2023 14:21:09 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:54007 Thu 25 Jan 2024 13:53:31 AEDT ]]> 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:34760 BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM⁻100 µM) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.]]> Thu 17 Mar 2022 14:34:42 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:26886 Thu 16 Mar 2017 16:43:39 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:44082 in vitro and orthotopic tumour growth in vivo. Dynamin inhibition reduced glioblastoma cell line viability and suppressed neurosphere formation and migration of GSCs. Tumour growth was reduced by CyDyn 4-36 treatment. Dynamin 2 inhibition therefore represents a novel approach for stem cell-directed Glioblastoma therapy.]]> Thu 06 Oct 2022 15:06:34 AEDT ]]> 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:32119 (CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D₂, histamine H₁ and H₂, melanocortin, melatonin, muscarinic M₁ and M₃, neurokinin, opioid KOP and serotonin receptors.]]> Thu 03 May 2018 12:18:53 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:20908 Thu 01 Aug 2019 17:22:27 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:21427 Sat 24 Mar 2018 08:05:48 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:19635 Sat 24 Mar 2018 08:01:14 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:20489 25 fold) and 13 (5.7 to >80 fold). Other analogues show high level of efficacy against specific cell lines with 10 showing excellent activity against MCF-7 (GI₅₀ = 1.7 µM) and A431 (GI₅₀ = 2.8 µM) cell lines. The most promising of the compounds identified herein were the 4-CF₃ substituted 10 and the 3,4-dichloro substituted 13 with excellent activities against MCF-7 and A431 cell lines. The 3,4-dichloro-13 was a 0.56 µM potent inhibitor of MCF-7 cell growth.]]> Sat 24 Mar 2018 07:59:07 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:20625 Sat 24 Mar 2018 07:55:46 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:21262 Sat 24 Mar 2018 07:54:43 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:21239 4], [BMIM][PF₆], [HMIM][PF₆] and [OMIM][PF₆] and CHCl₃ were examined. The observed IF (imprinting factor) values for MIP_BF4, MIP_PF6 and MIP_CHCl3 were 1.0, 1.98 and 4.64, respectively. The longer chain HMIM and OMIM systems returned lower IF values of 1.1 and 2.3, respectively. MIP_PF6 also showed a ~25% binding capacity reduction vs. MIP_CHCl3 (5 μmol g^-1 vs. 7 μmol g^-1 respectively). MIP_CHCl3 and MIP_PF6 differed in terms of BET surface area (306 m² g^-1vs. 185 m² g^-1), pore size (1.10 and 2.19 nm vs. 0.97 and 7.06 nm), the relative number of pores (Type A: 10.4 vs. 7.5%; Type B: 8.5 vs. 3.0%), and surface zeta potential (-37.9 mV vs. -20.3 mV). The MIP specificity for 1 was examined by selective rebinding studies with caffeine (2) and ephedrine (3). MIP_PF6 rebound higher quantities of 2 than MIP_CHCl3 , but this was largely due to non-specific binding. Both MIP_CHCl3 and MIP_PF6 showed a higher affinity for 3 than for 2. Reduction in the Room Temperature Ionic Liquid (RTIL) porogen volume had little impact on the polymer morphology, but did result in a modest decrease in IF from 2.6 to 2.3 and in the binding capacity (30% to 19%). MIP_CHCl3 retained the highest template specificity on rebinding from CHCl₃ (IF = 4.6) dropping to IF = 0.6 in MeOH/[BMIM][PF₆]. The MIP_CHCl3 binding capacity remained constant using CHCl₃, CH₂Cl₂ and MeOH (46-52%), dropped to 6% on addition of [BMIM][PF₆] and increased to 83% in H₂O (but at the expense of specificity with IF_H2O = 1.4). MIP_PF6 rebinding from MeOH saw an increase in specific rebinding to IF = 4.9 and also an increase in binding capacity to 48% when rebinding 1 from MeOH and to 42% and 45% with H₂O and CH₂Cl₂, respectively, although in the latter case the increased capacity was at the cost of specificity with IF_CH2Cl2 = 1.2. Overall the MIP_PF6 capacity and specificity were enhanced on addition of MeOH.]]> Sat 24 Mar 2018 07:53:03 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:18787 50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI₅₀ values of <5 μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active.]]> Sat 24 Mar 2018 07:51:02 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:27080 Sat 24 Mar 2018 07:40:44 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:27301 50 2.6±0.7µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.]]> Sat 24 Mar 2018 07:38:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29890 Sat 24 Mar 2018 07:29:53 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:30867 H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: L-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six _L-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch₁ in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli₂ mRNA expression. Focused library development of the benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine scaffold afforded two sub-micro molar potent inhibitors of Gli expression with 5-methoxy-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 29 and 5-chloro-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 30 returning IC₅₀ values of 0.5 and 0.24 μM, respectively. Neither 29 nor 30 acted directly on Smo with our data supporting inhibition of the HSP downstream of Smo.]]> Sat 24 Mar 2018 07:26:40 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:28318 50), respectively. Of note, were a CF₃ functionalised anthracenone 4-pyranone (chromone) derivative 22, and an anthracenone-furan derivative 54 which displayed 0.20µM and 0.38µM growth inhibition, respectively, in the BE2-C neuroblastoma cell line.]]> Sat 24 Mar 2018 07:25:08 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: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:47778 Mon 30 Jan 2023 10:09:52 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:46213 Mon 14 Nov 2022 11:58:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:35728 TRIM >DV55. Meanwhile, in contrast with the observations in HMC-MIP, there was an enhancement on the fluorescent signal generated by BAP-MIP in the presence of template molecules. In addition, changing the molar ratio of EGDMA in MIP and NIP prepared from BAP functional monomer also could influence the fluorescence intensities. Results suggest that both MIP and NIP prepared using a molar ratio of 1:4:10 (DNT:BAP:EGDMA) generated the highest fluorescence intensity as compared to samples with ratio 1:4:20 and 1:4:30 (DNT:BAP:EGDMA).]]> Mon 11 Nov 2019 13:02:32 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:44187 Mon 10 Oct 2022 10:55:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:40592 Mon 08 Aug 2022 15:18:18 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:41065 50 values of 0.098, 0.97, 0.13 and 0.21 μM, respectively). Indeed, 6 is 55 times more potent in MDA-MB-468 cells than normal MCF10A breast cells (GI₅₀ of 0.098 vs 5.4 μM) and more than 130 times more potent than in cell lines derived from pancreas, brain and prostate (GI₅₀ of 0.098 vs 10–13 μM). Molecular docking poses of 5 and 6 together with analogue synthesis and phenotypic screening show the importance of the naphthalene moiety, and an ortho-disposed substituent on the N-phenyl moiety for biological activity.]]> Mon 08 Aug 2022 15:04:26 AEST ]]> 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:50565 Fri 28 Jul 2023 11:27:49 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:47451 Fri 20 Jan 2023 16:33:46 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46079 50 currently under investigation. These compounds inhibit biological targets spanning protein kinases, STAT3, BET, HDACs and Bcl-2 family proteins. Unsurprisingly, protein kinase inhibitors are overrepresented. Some trials show promise; a phase I combination trial of vorinostat 11 and capecitabine 17 gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 15 showed a MoS of 25 months. The current standard of care for metastatic pancreatic ductal adenocarcinoma, fluorouracil/folic acid (5-FU, Adrucil®), and gemcitabine (GEMZAR®) afforded a MoS of 23 and 23.6 months (EPAC-3 study), respectively. In patients who can tolerate the FOLFIRINOX regime, this is becoming the standard of treatment with a MoS of 11.1 months. Clinical study progress has been slow with limited improvement in patient survival relative to gemcitabine 1 monotherapy. A major cause of low PC survival is the late stage of diagnosis, occurring in patients who consider typical early stage warning signs of aches and pains normal. The selection of patients with specific disease phenotypes, the use of improved efficient drug combinations, the identification of biomarkers to specific cancer subtypes and more effective designs of investigation have improved outcomes. To move beyond the current dire condition and paucity of PC treatment options, determination of the best regimes and new treatment options is a challenge that must be met. The reasons for poor PC prognosis have remained largely unchanged for 20 years. This is arguably a consequence of significant changes in the drug discovery landscape, and the increasing pressure on academia to deliver short term ‘media’ friendly short-term news ‘bites’. PC research sits at a pivotal point. Perhaps the greatest challenge is enacting a culture change that recognises that major breakthroughs are a result of blue sky, truly innovative and curiosity driven research.]]> Fri 11 Nov 2022 10:04:19 AEDT ]]> 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 ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29199 Myoporaceae, which includes the genus Myoporum, are extremely prized by the Australian Aboriginal people for their medicinal properties. Leaves from a plant, which was subsequently identified as Myoporum montanum, were provided for chemical investigation by representatives of an Aboriginal community from the Northern Tablelands district of northern New South Wales, Australia. Acetone extraction of the leaves provided a complex mixture of compounds including sesquiterpene hydrocarbons and more polar furanosesquiterpenes, which were identified by gas-liquid chromatography and retention indices (sesquiterpene hydrocarbons) and spectrometric techniques (furanosesquiterpenes). The major compounds found in a water extract were studied for their antibacterial activity using a disc diffusion assay and for their cell growth inhibition activity. The acetone extract contained sesquiterpene hydrocarbons (~30% of the total extract) in which the major compounds were germacrene-D and bicyclogermacrene. In addition, the extract contained five known toxic furanosesquiterpenes: myoporum ketol, (-)-10,11-dehydroisomyodesmone, (+)-10,11-dehydromyodesmone, 10,11-dehydromyoporum ketol, (-)-10,11-dehydromyoporone, and (±)-myoporone. An aqueous extract of the leaves, emulating the medicinal tea used by the Australian Aboriginal community, was found not to contain significant quantities of the sesquiterpene hydrocarbons and the most toxic furanosesquiterpenes. (±)-Myoporone and (-)-10,11-dehydromyoporone remained in the extract as well as a new furanosesquiterpene, 11-hydroxymyoporone. These three compounds were found to have significant antibacterial activity against Staphylococcus epidermidis, Enterococcus faecalis, and Moraxella catarrhalis but low cytotoxicity against a range of cancer cell lines and normal breast cells at 25µM.]]> Fri 01 Apr 2022 09:25:59 AEDT ]]>