A set of cyclodextrins bearing iminodiacetic acid (IDA) moieties on the primary side and methylated on their secondary side has been proven as effective complexing agent for lanthanide-cations with interesting implications as contrast agents in MRI [2].
The synthesis of these CD-derivatives was further developed and optimized in order to produce a family of CD-materials bearing a primary side fully substituted with the chelating IDA moieties while their wider secondary side could be either unmodified (IDACYD-OHs, that possess a fully accessible cavity) or per-2,3-O-methylated (IDACYDs, that possess a distorted cavity). While the novel IDACYD-OHs required mandatory protection-deprotection steps, the synthesis of IDACYDs was achieved on a gram-scale with a shorter, eco-friendly process. All the compounds were fully characterized by NMR and MALDI-MS analysis.
All IDACYD- and IDACYD-OHs derivatives are very soluble in water thanks to the many ionisable IDA-groups. A combination of NMR and potentiometric data was used to determine average and discrete pKa values, identifying at neutral, physiological conditions the fully ionized, negatively charged species present with all IDA carboxyl groups ionized and all N-atoms protonated. NMR, ITC and computational data confirmed the possibility to coordinate 3 to 4 Zn2+ or Ga3+ cations according to the number of IDA substituents (different for α-, β- and γ-CD derivatives), the metal-to-ligand ratio and the pH. Binding constants were found in the range of ∼104 M−1/binding site, sufficiently strong to provide complex stability, yet avoiding chelating effects.
All the compounds were found to be non-toxic in vitro and tested as inhibitors for metallo-β-lactamases (MBLs), a class of enzymes produced by highly resistant bacteria in order to evade β-lactam antibiotics. MBLs exert their hydrolytic action thanks to the presence of Zn2+ cations in their active center and, currently, there are no approved drugs to target MBLs and combat the associated antimicrobial resistance (AMR). A very low (50 μM) concentration of IDA-derivatives was proven to completely re-sensitize Gram-negative, MBL-producing, carbapenem-resistant clinical bacterial strains (mainly Klebsiella pneumoniae) towards the β-lactam antibiotics imipenem and meropenem, even reaching >1024-fold reduction of the minimum inhibitory concentration (MIC). Moreover, radio-labeled [67Ga]Ga-β-IDACYD showed high radiochemical purity and stability to be considered as a promising tool for biodistribution and pharmacokinetic studies in vivo enabling the development of therapeutic protocols for animals infected with resistant bacteria. The content of this work is subject of a patent application from the same group [3].
- Metal-binding cyclodextrins: Synthesis and complexation with Zn2+ and Ga3+ cations towards antimicrobial applications – M. Agnes, E. M. Kasimati, M. Inclán, A. Thanassoulas, G. Miliotis, M. Malanga, G. Benkovics, G. Nounesis, E. García-España, P. Bouziotis, Y. G. Lazarou, V. Miriagou, I. M. Mavridis and K. Yannakopoulou, Carbohydr. Polym. 2023, 321, 121323. DOI: https://doi.org/10.1016/j.carbpol.2023.121323
- Novel polycarboxylated EDTA-type cyclodextrins as ligands for lanthanide binding: study of their luminescence, relaxivity properties of Gd(iii) complexes, and PM3 theoretical calculations – D. Maffeo, M. Lampropoulou, M. Fardis, Y. G. Lazarou, I. M. Mavridis, D. A. I. Mavridou, E. Urso, H. Pratsinis, D. Kletsas and K. Yannakopoulou, Org. Biomol. Chem., 2010, 8, 1910. DOI: https://doi.org/10.1039/B924980J
- Iminodiacetic acid substituted cyclodextrins as potentiators of beta-lactam antibiotics – K. Yannakopoulou, M. Agnes, V. Miriagou, S. Kotsakis, G. Miliotis, Vol. Bullettin 2020/40 (Patent Appl. No. EP3714904A1)