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Abstract Macrocyclic Co(II) complexes with appended amide‐glycinate groups were prepared to develop paramagnetic Co(II) chemical exchange saturation transfer (CEST) agents of reduced overall charge. Complexes with reduced charge and lowered osmolarity are important for their loading into liposomes and to provide complexes that are highly water soluble and well tolerated in animals. Co(L1) has two non‐coordinating benzyl groups and two amide‐glycinate pendants, whereas Co(L2) has two unsubstituted amide pendants and two amide‐glycinate pendants on cyclam (1,4,8,11‐tetraazacyclododecane). The1H NMR spectrum of Co(L1) is consistent with a singlecis‐pendant isomer with both amide protons in thetrans‐configuration, as supported by an X‐ray crystal structure. Co(L2) has a mixture of different isomers in solution, including thetrans‐1,4 and 1,8 pendant isomers. The Z‐spectrum of Co(L1) shows one highly‐shifted CEST peak, whereas Co(L2) exhibits six CEST peaks. Encapsulation of 40 mM Co(L1) in a liposome with osmotically‐induced shrinking at 300 mOsm/L produces a liposomal CEST agent with saturation frequency offset of 3 ppm. Addition of the amphiphilic 1,4,7‐triazacyclononane‐based complex Co(L5) to the liposomal bilayer at 18 mM with Co(L1) encapsulated in the liposome at 50 mM changes the sign and increases the magnitude of the saturation frequency offset to −7.5 ppm at 300 mOsm/L.
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Co( ii ) complexes of tetraazamacrocycles appended with amide or hydroxypropyl groups as paraCEST agents
Co( ii ) complexes of 1,4,7,10-tetraazacyclododecane (CYCLEN) or 1,4,8,11-tetraazacyclotetradecane (CYCLAM) with 2-hydroxypropyl or carbamoylmethyl (amide) pendants are studied with the goal of developing paramagnetic chemical exchange saturation transfer (paraCEST) agents. Single-crystal X-ray diffraction studies show that two of the coordination cations with hexadentate ligands, [Co(DHP)] 2+ and [Co(BABC)] 2+ , form six-coordinate complexes; whereas two CYCLEN-based complexes with potentially octadentate ligands, [Co(THP)] 2+ and [Co(HPAC)] 2+ , are seven-coordinate with only three of the four pendant groups bound to the metal center. 1 H NMR spectra of these complexes suggest that the six-coordinate complexes are present as a single isomer in aqueous solution. For the complexes which are seven-coordinate in the solid state, one is highly fluxional in aqueous solution on the NMR time scale ([Co(HPAC)] 2+ ), whereas the NMR spectrum of [Co(THP)] 2+ is consistent with an eight-coordinate complex with all pendants bound. Co( ii ) complexes of CYCLEN derivatives show CEST effects of low intensity that are assigned to NH or OH groups of the pendants. One complex, [Co(DHP)] 2+ , shows a highly-shifted CEST peak at 113 ppm versus bulk water, attributed to OH protons. However, the CEST effect is largest for two Co( ii ) CYCLAM-based complexes with coordinated amide groups that undergo NH proton exchange. All five complexes are inert towards dissociation in buffered solutions containing carbonate and phosphate and towards trans-metalation by excess Zn( ii ). These data give insight into the production of an intense CEST effect for tetraazamacrocyclic complexes with pendant groups containing NH or OH exchangeable protons. The intense and highly shifted CEST peak(s) of the CYCLAM-based complexes suggest that they are promising for further development as paraCEST agents.
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- PAR ID:
- 10439076
- Date Published:
- Journal Name:
- Dalton Transactions
- Volume:
- 52
- Issue:
- 28
- ISSN:
- 1477-9226
- Page Range / eLocation ID:
- 9831 to 9839
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d3dt01572f
