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Li, X, Payne, DT, Ampolu, B, Bland, N, Brown, JT, Dutton, MJ, Fitton, CA, Gulliver, A, Hale, L, Hamza, D, Jones, G, Lane, R, Leach, AG, Male, L, Merisor, EG, Morton, MJ, Quy, AS, Roberts, R, Scarll, R, Schulz-Utermoehl, T , Stankovic, T, Stevenson, B, Fossey, JS and Agathanggelou, A (2019) Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia. MedChemComm, 10 (8). pp. 1379-1390. ISSN 2040-2503
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Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.pdf - Published Version Available under License Creative Commons Attribution. Download (6MB) | Preview |
Abstract
Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated “drug-likeness” properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.
| Item Type: | Article |
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| Uncontrolled Keywords: | 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | Royal Society of Chemistry |
| Related URLs: | |
| Date Deposited: | 17 Mar 2020 13:02 |
| Last Modified: | 04 Sep 2021 07:40 |
| DOI or ID number: | 10.1039/c9md00297a |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/12527 |
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