Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs
Regions of insufficient oxygen supply-hypoxia-occur in diverse contexts across biology in both healthy and diseased organisms. The difference in the chemical environment between a hypoxic biological system and one with normal oxygen levels provides an opportunity for targeting compound delivery to h...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2016
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| _version_ | 1797075579118288896 |
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| author | O'Connor, L Cazares-Körner, C Saha, J Evans, C Stratford, MR Hammond, E Conway, S |
| author_facet | O'Connor, L Cazares-Körner, C Saha, J Evans, C Stratford, MR Hammond, E Conway, S |
| author_sort | O'Connor, L |
| collection | OXFORD |
| description | Regions of insufficient oxygen supply-hypoxia-occur in diverse contexts across biology in both healthy and diseased organisms. The difference in the chemical environment between a hypoxic biological system and one with normal oxygen levels provides an opportunity for targeting compound delivery to hypoxic regions by using bioreductive prodrugs. Here we detail a protocol for the efficient synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which is a key intermediate that can be converted into a range of 1-methyl-2-nitro-1H-imidazole-based precursors of bioreductive prodrugs. We outline methods for attaching the bioreductive group to a range of functionalities, and we discuss the strategy for positioning of the group on the biologically active parent compound. We have used two parent checkpoint kinase 1 (Chk1) inhibitors to exemplify the protocol. The PROCEDURE also describes a suite of reduction assays, of increasing biological relevance, to validate the bioreductive prodrug. These assays are applied to an exemplar compound, CH-01, which is a bioreductive Chk1 inhibitor. This protocol has broad applications to the development of hypoxia-targeted compounds. |
| first_indexed | 2024-03-06T23:52:19Z |
| format | Journal article |
| id | oxford-uuid:7305f79b-59fc-4dbe-8fdc-5de41b62a152 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:52:19Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:7305f79b-59fc-4dbe-8fdc-5de41b62a1522022-03-26T19:53:51ZDesign, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7305f79b-59fc-4dbe-8fdc-5de41b62a152EnglishSymplectic Elements at OxfordNature Publishing Group2016O'Connor, LCazares-Körner, CSaha, JEvans, CStratford, MRHammond, EConway, SRegions of insufficient oxygen supply-hypoxia-occur in diverse contexts across biology in both healthy and diseased organisms. The difference in the chemical environment between a hypoxic biological system and one with normal oxygen levels provides an opportunity for targeting compound delivery to hypoxic regions by using bioreductive prodrugs. Here we detail a protocol for the efficient synthesis of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol, which is a key intermediate that can be converted into a range of 1-methyl-2-nitro-1H-imidazole-based precursors of bioreductive prodrugs. We outline methods for attaching the bioreductive group to a range of functionalities, and we discuss the strategy for positioning of the group on the biologically active parent compound. We have used two parent checkpoint kinase 1 (Chk1) inhibitors to exemplify the protocol. The PROCEDURE also describes a suite of reduction assays, of increasing biological relevance, to validate the bioreductive prodrug. These assays are applied to an exemplar compound, CH-01, which is a bioreductive Chk1 inhibitor. This protocol has broad applications to the development of hypoxia-targeted compounds. |
| spellingShingle | O'Connor, L Cazares-Körner, C Saha, J Evans, C Stratford, MR Hammond, E Conway, S Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title | Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title_full | Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title_fullStr | Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title_full_unstemmed | Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title_short | Design, synthesis and evaluation of molecularly targeted hypoxia-activated prodrugs |
| title_sort | design synthesis and evaluation of molecularly targeted hypoxia activated prodrugs |
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