N-dealkylation of tertiary amines is an important biochemical transformation and is one of the major processes involved in the cytochrome P450 mediated detoxification of drugs in mammalian tissues. We have been investigating novel medical countermeasures for the treatment of opioid exposure in humans and the use of an aqueous phase porphyrin-based system for opioid degradation in vivo presents an intriguing possibility. Furthermore, the multivalent display of a molecular catalyst on a nanoparticle platform e.g. liposomes or gold nanoparticles may further enhance activity through concentration effects. Previously, the rhodium porphyrin complex Na3[(TSPP)Rh(H2O)2] was used for the catalytic N-dealkylation of simple tertiary amines under aerobic conditions and in the presence of acid (Ling et al., 2013). We chose the porphryin tri(p-sulfonatophenyl)mono(4-carboxyphenyl)rhodium(III) (C1S3TPP)Rh(III) (1) for our studies as the -COOH group allows for amide coupling to a amine-functionalized nanoparticle. Under ambient conditions, complex 1 mediated the degradation of fentanyl in water without the need for acid promoter or added O2. The secondary amine and aldehyde degradation products were identified by high-resolution mass spectrometry. We have also shown that 1 reduces fentanyl activation of the mu opioid receptor by ~1000-fold (comparable to the activity of norfentanyl), shows little cross reactivity with morphine, and exhibits negligible cytotoxicity in cell culture ([1 µM porphyrin complex]). Preliminary experiments suggest that 1 may be covalently attached to amine-functionalized Au nanoparticles using standard EDC coupling chemistry. Due to the known biocompatibility of therapeutics based on nanoparticles, we suggest that these hybrid nanoparticle-metal complexes can (a) act as an effective therapeutic for opioid exposure and (b) potentially serve as a prophylaxis for pre-opioid exposure in environments that possess high risk for exposure to opioids.

Aqueous-phase N-dealkylation of fentanyl using a water-soluble rhodium(III) porphyrin complex

ACS Spring Meeting 2021

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