Browsing by Author "Schatzlein, Andreas"

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    Aminobenzofuran-containing analogues of proximicins exhibit higher antiproliferative activity against human UG-87 glioblastoma cells compared to temozolomide
    (Royal Society of Chemistry, 2023-03-14) Shokrzadeh Madieh, Nasrin; Brucoli, Federico; Tanna, Sangeeta; Alqurayn, Norah Ahmed; Vaideanu, Alexandra; Schatzlein, Andreas
    A new series of proximicin analogues containing a benzofuran moiety as the replacement of the di-furan scaffold of the parent compound were synthesised and evaluated for their anti-proliferative activities against human glioblastoma cells U-87 MG. Proximicins A, B, and C are secondary metabolites produced by Verrucosispora Fiedleri MG-37, a Gram-positive actinomycete isolated from deep-sea sediment. Proximicins exhibit significant cytotoxic and apoptotic effects in a number of tumour cell lines, although further investigations on these natural products biological activity are hampered by the challenging synthesis of their constitutive di-furan unit. Therefore, the easily-synthesisable benzofuran ring was elected as a replacement of the di-furan platform, and a library of proximicin analogues was prepared in which different substituents were introduced at both the N-terminus and C-terminus of the benzofuran core unit. The novel compounds were tested against U-87 MG, as it was previously found that proximicins targeted this cancerous cell line, and the human healthy cell line WI-38. Temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma, was used as a control. Analysis of growth inhibitory concentration values revealed that a number of furan-benzofuran-containing proximicin analogues, including 23(16) (IC50 U-87 MG = 6.54 μg mL−1) exhibited higher antiproliferative activity against glioblastoma cells compared to both proximicins A–C and temozolomide (IC50 U-87 MG = 29.19 μg mL−1) in U-87 MG.
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    C2- linked alkynyl poly-ethylene glycol(PEG) adenosine conjugates as water-soluble adenosine receptor agonists
    (Wiley, 2022-08-22) Ferguson, Lindsay; Madieh, Nasrin Shokrzadeh; Brucoli, Federico; Vaideanu, Alexandra; Schatzlein, Andreas; Festa, Joseph; Singh, Harprit; Wells, Geoffrey; Bhakta, Sanjib
    A series of 12 novel polyethylene-glycol(PEG)-alkynyl C2-adenosine(ADN) conjugates were synthesized using a robust Sonogashira coupling protocol and characterized by NMR spectroscopy and mass spectrometry analysis. The ADN-PEG conjugates showed null to moderate toxicity in murine macrophages and 12c was active against Mycobacterium aurum growth (MIC = 62.5 mg/L). The conjugates were not active against Mycobacterium bovis BCG. Conjugates 10b and 11b exhibited high water solubility with solubility values of 1.22 and 1.18 mg/ml, respectively, in phosphate buffer solutions at pH 6.8. Further, 10b and 11b induced a significant increase in cAMP accumulation in RAW264.7 cells comparable with that induced by adenosine. Analogues 10c, 11c and 12c were docked to the A1, A2A, A2B and A3 adenosine receptors (ARs) using crystal-structures and homology models. ADN-PEG-conjugates bearing chains with up to five ethyleneoxy units could be well accommodated within the binding sites of A1, A2A and A3 ARs. Docking studies showed that compound 10b and 11b were the best A2A receptor binders of the series, whereas 12c was the best binder for A1 AR. In summary, introduction of hydrophilic PEG substituents at the C2 of adenine ring significantly improved water solubility and did not affect AR binding properties of the ADN-PEG conjugates.