https://ogma.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29815 Wed 24 Nov 2021 15:50:53 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: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:48151 Wed 08 Mar 2023 14:43:43 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:1663 50 : 1 noted. All analogues were screened for their ability to interact with CRH₁ and CRH₂ receptors. In all instances only poor agonistic and/or antagonistic behaviour was noted at CRH₂. However, several compounds were potent and selective CRH₁ antagonists, most notably 13a Ki = 39nM. Additionally we have utilized these data and that recently reported by others to refine our original CRH₁ pharmacophore.]]> Sat 24 Mar 2018 08:30:27 AEDT ]]> 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:20055 70/σ^A for the development of lead molecules exhibiting a novel mechanism of antibacterial activity. Several classes of structurally related bis-indole inhibitors of bacterial transcription initiation complex formation were synthesized and their antimicrobial activities were evaluated. Condensation of indole-7- and indole-2-carbohydrazides with 7- and 2-trichloroacetylindoles or indole-7- and indole-2-glyoxyloyl chlorides resulted in the successful synthesis of 7,7′-, 2,2′-, 2,7′- and 3,2′-linked bis-indole derivatives with –CO–NH–NH–CO– and –CO–CO–NH–NH–CO– linkers. Indole-7-glyoxyloyl chlorides were reacted with hydrazine hydrate in different ratios to afford respective –CO–CO–NH–NH–CO–CO– bis-indole or hydrazide derivatives. The resulting compounds were found to be active against the β′-CHσ⁷⁰/σ^A_2.2 interaction in ELISA assays and inhibited the growth of both Gram-positive and Gram-negative bacteria. Structure–activity relationship (SAR) studies were performed in order to identify the structural features of the synthesized inhibitors required for biological activity.]]> Sat 24 Mar 2018 08:00:13 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:19892 Sat 24 Mar 2018 07:57:02 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:19781 Sat 24 Mar 2018 07:56:52 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: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:20129 Sat 24 Mar 2018 07:51:33 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: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:3328 Sat 24 Mar 2018 07:23:20 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 ]]>