School of Chemistry - Research Publications

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    Total Synthesis of Icumazole A Using a Modified Cadiot-Chodkiewicz Coupling
    Buntine, J ; Dasgupta, S ; Dorney, K ; Rubinstein, O ; Salimimarand, M ; White, JM ; Rizzacasa, MA (AMER CHEMICAL SOC, 2024-01-29)
    The first total synthesis of myxobacteria metabolite icumazole A (1) is reported. Key steps in the route include an organocatalyzed asymmetric self-aldol reaction followed by an acetate aldol reaction to form the stereotriad present in the oxazole moiety, an intramolecular Diels-Alder reaction to form the isochromanone, and an acetylide addition and selective methylation. The final steps involved a high-yielding modified Cadiot-Chodkiewicz coupling and stereoselective reduction to secure the Z,Z-diene and afford 1.
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    Cooperative assemblies featuring hydrogen bonding and C-H...π interactions in 2-(methanesulfonamido)benzohydrazide derivatives: Experimental, computational and biochemical assessment
    Munir, R ; Zaib, S ; Khan, I ; Yousaf, A ; McAdam, CJ ; White, JM ; Hokelek, T ; Awwad, NS ; Ibrahium, HA ; Frontera, A (ELSEVIER, 2024-01-05)
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    Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Lamellodysidea Sponge
    Ramage, KS ; Lock, A ; White, JM ; Ekins, MG ; Kiefel, MJ ; Avery, VM ; Davis, RA (MDPI AG, 2024)
    The known oxygenated polyhalogenated diphenyl ether, 2-(2′,4′-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.
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    A cis-β-iron(iii) SALPN catalyst for hydrogen atom transfer reductions and olefin cross couplings
    Ricca, M ; Yao, S ; Le, T ; White, JM ; Donnelly, PS ; Rizzacasa, MA (ROYAL SOC CHEMISTRY, 2023-08-23)
    An inexpensive Fe(III) SALPN catalyst for MHAT reactions such as reductions of α,β-unsaturated carbonyl compounds and olefin cross couplings is reported. The majority of these reactions proceeded in good yields and high stereoselectivities with low catalyst loadings at room temperature.
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    Hammett Structural Relationships Revealed in Chalcogen-Bonded Co-Crystals of Electron-Rich Pyridines with 4′-Substituted Ebselen Derivatives
    Fellowes, T ; Lee, E ; Tran, J ; Xu, R ; Barber, A ; Brydon, SC ; Clegg, JK ; White, JM (AMER CHEMICAL SOC, 2023-08-30)
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    Synthesis of More Highly Oxidized Alkyl Citrates via Direct Regio- and Stereoselective Oxidation
    Rossouw, NP ; Chen, Z ; White, JM ; Rizzacasa, MA (AMER CHEMICAL SOC, 2023-11-02)
    An approach to more highly oxidized alkyl citrates by direct regio- and stereoselective oxidations is reported. The total synthesis and structural assignment of alkyl citrate L-731-128 are described, and the synthesis of its C4 oxidized congener L-731,127 utilized a regio- and stereoselective enolate oxidation with oxygen gas. A highly stereoselective Rubottom oxidation of a cyclic silylketene acetal then enabled oxidation at C2 to afford the cinatrins C1 and C3.
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    Mono and binuclear cadmium complexes: X-ray crystal structures, Hirshfeld surface analysis and antimicrobial/antioxidant studies
    Akbari, Z ; Montazerozohori, M ; Joohari, S ; Hayati, P ; Micale, N ; Cristani, M ; Bruno, G ; White, JM (Elsevier BV, 2023-12-01)
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    Photophysics and spectroscopy of 1,2-Benzazulene
    Awuku, S ; Bradley, SJ ; Ghiggino, KP ; Steer, RP ; Stevens, AL ; White, JM ; Yeow, C (Elsevier, 2021-12)
    The electronic spectroscopy and photophysics of 1,2-benzazulene (BzAz) have been examined in solution and in thin solid films, with the objective of comparing its intramolecular and intermolecular excited state decay processes with those of azulene. Unlike azulene, the S2 – S0 absorption and fluorescence spectra exhibit a clear mirror image relationship dominated by a single strong Franck-Condon active progression. Picosecond transient absorption spectra and non-linear S2 fluorescence upconversion experiments reveal lifetimes that follow a well-established energy gap law correlation, indicative of a dominant S2 – S1 decay route. Mechanistic interpretations, including the possibility of S2 singlet fission in aggregates, are discussed.
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    Pyrimidine-morpholine hybrids as potent druggable therapeutics for Alzheimer's disease: Synthesis, biochemical and in silico analyses
    Zaib, S ; Younas, MT ; Khan, I ; Ali, HS ; McAdam, CJ ; White, JM ; Jaber, F ; Awwad, NS ; Ibrahium, HA (Elsevier, 2023-12-01)
    The identification of effective and druggable cholinesterase inhibitors to treat progressive neurodegenerative Alzheimer’s disorder remains a continuous drug discovery hunt. In this perspective, the present study investigates the design and discovery of pyrimidine-morpholine hybrids (5a-l) as potent cholinesterase inhibitors. Palladium-catalyzed Suzuki-Miyaura cross-coupling reaction was employed to introduce the structural diversity on the pyrimidine heterocyclic core. A range of commercially available boronic acids was successfully coupled showing a high functional group tolerance. In vitro cholinesterase inhibitory potential using Ellman’s method revealed significantly strong potency. Compound 5h bearing a meta-tolyl substituent at 2-position of pyrimidine ring emerged as a lead candidate against AChE with an inhibitory potency of 0.43 ± 0.42 µM, ∼38-fold stronger value than neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 5h also showed the lead inhibition against BuChE with an IC50 value of 2.5 ± 0.04 µM. The kinetics analysis of 5h revealed the non-competitive mode of inhibition against AChE whereas computational modelling results of potent leads depicted diverse contacts with the binding site amino acid residues. Molecular dynamics simulations revealed the stability of biomolecular system, while, ADME analysis demonstrated druglikeness behaviour of potent compounds. Overall, the investigated pyrimidine-morpholine scaffold presented a remarkable potential to be developed as efficacious anti-Alzheimer’s drugs.
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    An approach to assessing the contribution of the high LET effect in strategies for Auger endoradiotherapy
    Lobachevsky, P ; Skene, C ; Munforte, L ; Smith, A ; White, J ; Martin, RF (TAYLOR & FRANCIS LTD, 2023-01-02)
    Purpose: The interest in exploiting Auger emitters in cancer therapy stems from their high linear energy transfer (LET)-type radiation damage to DNA. However, the design of Auger-emitter labeled vehicles that target the Auger cascade specifically to the DNA of tumour cells is challenging. Here we suggest a possible approach to evaluate tumour-targeting Auger-labeled conjugates by assessing the impact of a radioprotector known to be effective in protecting from low LET radiation, but not high LET radiation. Given some similarity between the energy spectrum of Auger electrons and that of secondary electrons from soft X-rays, we report the results of radioprotection experiments with 25 kVp X-rays. Materials and methods: Clonogenic survival curves for cultured human keratinocytes were established for three different irradiation conditions: 137Cs γ-rays, 25 kVp X-rays and 320 kVp X-rays, and the effect of including a new radioprotector, denoted "2PH", was investigated.Results: The extent of radioprotection by 2PH was comparable for all radiation conditions, although RBE was higher (about 1.7) for soft X-rays. Conclusions: Radioprotectors like 2PH will help to evaluate Auger endoradiotherapy strategies, by determining the relative contributions of the high-LET effects (not protected), compared to other components, such as Auger electrons not effectively targeted to DNA.