Abstract
Substitution of hydrogen (1H) with deuterium (2H or D) in drug molecules has sparked wide interest over the past two decades, for two main reasons. Firstly, the minimal physicochemical property changes caused by D incorporation allows deuterated drugs to largely retain their biological activities. Secondly, the stronger C-D bonds may allow drug metabolisms to be attenuated, resulting in improved bioavailabilities and possibly reduced side effects.Current syntheses of deuterated compounds mostly require metal catalysts and/or specialised technologies, which has limited their accessibilities. Herein we report a novel metal-free acid-catalysed deuteration method that is inexpensive, robust, and highly reproducible. A wide range of electron-rich aromatics including synthetically useful building blocks and bioactive agents were tested. High levels of D incorporation were achieved at activated positions, with quantitative yields in most cases. We also found reasonable correlations between the Hückel charges predicted by MM2 energy-minimised models in Chem3D and the percentage of D incorporation.
Combretastatin A4 (CA4) is a potent microtubule-destabilising agent that is limited as a pharmaceutical agent due to its poor pharmacokinetic properties. Six deuterated CA4 analogues 54-dn (with D incorporation on aromatic rings) were synthesised, and their in vitro activities were evaluated by the National Cancer Institute (NCI). The three deuterated cis-CA4 analogues displayed median GI50 values ranging from 0.026 µM to 0.028 µM. The three deuterated trans-CA4 analogues displayed less potent activities with median GI50 values ranging from 0.60 µM to 0.71 µM. The results were consistent with literature, in which Z-CA4 exhibits better potency in tubulin polymerisation inhibition than E-CA4.
The deuteration of controlled substances was also investigated due to their common uses as internal standards in quantifying controlled substances in biological samples. Deuterated psychoactive cannabidiol (CBD) derivatives including ∆9-tetrahydrocannabinol (THC) 123-d7, ∆8-THC 124-d14 and cannabinol (CBN) 140-d13 were synthesised. A group of novel deuterated iso-THC derivatives were also isolated under modified deuteration conditions. Deuterated semi-synthetic opioid oxycodone 142-d6 was obtained with high D incorporation on both aromatic and α positions. High D incorporation was achieved at the benzylic position of etonitazene 143-d2 under mild conditions, which would facilitate a quick access to all the other deuterated benzimidazole-class of opioids (also known as nitazenes).
| Date of Award | 7 May 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Lorenzo Caggiano (Supervisor) & Stephen Husbands (Supervisor) |