Theoretical background

In the Reinaud group at the University of Paris, three generations of calix[6]arene-based (funnel), as well as two generations of resorcinarene-based (bowl) supramolecular systems featuring three or four grafted methylimidazole-containing coordination arms (and two corresponding families of their transition metal complexes) with ever increasing level of biomimeticity, were developed, with the aim of mimicking a notorious mononuclear metalloenzymes active site (Figure T1).1 Major breakthrough in development of fully biomimetic systems has been achieved recently with the optimized synthetic procedure for water soluble structures which are now readily available.2

Figure T1. Supromolecular models of proteic metallo-sites based on calix[6]arenes and resorcin[4]arenes developed by Reinaud group

However, as the paradigm of molecular recognition evolves from now almost obsolete emphasis on the specific sites within the macromolecular structures, towards a more elaborate understanding of biomolecular processes involving allosteric effects, and as nucleic acids are becoming more and more attractive biomolecular target in various studies, a brand new research avenue, involving a whole different role of our versatile macrocycles, was created: as biomimetic recognition agents for nucleic acids.3 Macrocycles to be employed in this project are characterized by the funnel (calix[6]arene-based) or bowl (resorcinarene-based) shape. Based on the analysis of 54 of our calix[6]arene structures extracted from the current version of CSD,4 dimensions of their large and small rim diameters match remarkably the outer diameter of an alpha helix (10 – 12 Å) – part of the protein structures that is well known to fit snugly into the major groove of the DNA double strand during the protein/DNA recognition process. Nevertheless, major groove recognition is not at all the only possibility for the recognition of nucleic acid sequences by both proteins and artificial binders. Proteins enhance the stability of a complex with both single and double stranded DNA, as well as with RNA, by creating plethora of hydrogen bonds on the edges of the base pairs, and same is to be expected from our biomimetic binders which are suitably equipped with variety of H-bond donors and acceptors in order to mimic the systems developed by Nature in the recognition process. Most importantly, these systems are characterized by a number of biomimetic properties which make them very unique and promising for nucleic acid recognition:

  • They are highly flexible, adopting various conformations to optimize their interaction with the environment, and undergoing readily induced-shift processes,5
  • The amino arms, in their protonated form, spontaneously self-assemble with anions,6
  • In their neutral state, they can form metal complexes that are well-shaped and present a hemilabile arm for further interaction with other donor/acceptors,
  • They can form host-guest complexes with polyamine/ammonium, thereby providing supramolecular structures that are also well-shaped and polycationic,7
  • They are highly modular structures, and their synthesis is well mastered by the group.

Some of our systems are originally equipped with the hydrophilic cationic “feet”. For those which are not, the synthetic procedures that we have developed allow for a routine introduction of cationic species or fluorophore amino acids (or both) at the rim opposite to the one bearing coordination arms.8 The presence of the positive charge further increases potential of our systems to recognize and bind to DNA/RNA, where the electron-rich environment of the phosphate skeleton provides a strong target for such electrostatic interactions. Based on their structural and physico-chemical features, it is, therefore, predictable that out of four known ways of DNA interaction (intercalation, phosphate backbone binding, major grove insertion and minor groove insertion), our macrocycles are likely to undergo at least two: phosphate backbone binding and major groove insertion. Moreover, ability of our systems to routinely coordinate transition metals via their nitrogen-containing coordinating arms is very well documented.9 Metal coordination rigidifies the entire structure (with apparent effect on the recognition process) and brings three new elements into the binding/recognition/cleavage equation: i) possible coordination by heteroatom donors from the nucleobases of the Lewis acidic metal ion,10 ii) direct interaction with the phosphate backbone,11 and iii) possible introduction of a redox active metal ion that can generate oxygenated radicals leading to DNA/RNA cleavage.12

  1. (a) J.-N. Rebilly, B. Colasson, O. Bistri, D. Over, O. Reinaud, Chem. Soc. Rev. 44 (2015) 467—489. (b) A. Višnjevac, J. Gout, N. Ingert, O. Bistri, O. Reinaud, Organic Letters, 12 (2010) 2044 – 2047. (c) A. Parrot, S. Collin, G. Bruylants and O. Reinaud, Chem. Sci., 9 (2018) 5479. (d) J. Gout, A. Višnjevac, S. Rat, A. Parrot, A. Hessani, O. Bistri, N. Le Poul, Y. Le Mest, O. Reinaud, Inorganic Chemistry, 53 (2014) 6224 – 6234.
  2. (a) O. Bistri, O. Reinaud, Org. Biomol. Chem. 13 (2015) 2849; (b) A. Inthasot , N. Le Poul , M. Luhmer , B. Colasson , I. Jabin, O. Reinaud , Inorg. Chem. 57 (2018) 3646; (c) S. Collin , A. Parrot, L. Marcelis , E. Brunetti , I. Jabin , G. Bruylants , K. Bartik, O. Reinaud , Chem. – Eur. J. 24 (2018) 17964.
  3. M. J. Hannon, Chem. Soc. Rev. 36 (2007) 280–295.
  4. C. R. Groom, I. J. Bruno, M. P. Lightfoot and S. C. Ward, Acta Cryst. (2016). B72,  171-179.
  5. Multipoint molecular recognition within a calix[6]arene funnel complex (Special Feature), D. Coquière, A. de la Lande, S. Martí, O. Parisel, T. Prangé, O. Reinaud, Proc. Natl. Acad. Sci. USA, 106(2009)10449-10454. DOI: org/10.1073/pnas.0811663106.
  6. (a)  U. Darbost, M. Giorgi, N. Hucher, I. Jabin, and O. Reinaud, Supramol. Chem. 17 (2005) 243-250; (b) S. Le Gac, J. Marrot, O. Reinaud, I. Jabin, Angew. Chem. Int. Ed. 45(2006)3123-312; (c) S. Le Gac, M. Luhmer, O. Reinaud, I. Jabin, Tetrahedron 63 (2007)10721-10730.
  7. D. Coquière, A. de la Lande, O. Parisel, T. Prangé, O. Reinaud, Chem. Eur. J. 15 (2009) 11912 – 11917.
  8. S. Zahim, D. Ajami, P. Laurent, H. Valkenier, O. Reinaud, M. Luhmer, I. Jabin, ChemPhysChem, 21 (2020) 83 – 89 and references therein.
  9. See, for example (a) S. Collin, N. Giraud, E. Dumont, O. Reinaud, Org. Chem. Frontiers, 6 (2019) 1627-1636; (b) G. De Leener, D. Over, C. Smet, D. Cornut, A. G. Porras-Gutierrez, I. Lopez, B. Douziech, F. Topić, K. Rissanen, Y. Le Mest, I. Jabin, O. Reinaud, Inorg. Chem. 56 (2017) 10971-10983 and the references therein; (c) J. Gout, A. Višnjevac, S. Rat, O. Bistri, N. Le Poul, Y. Le Mest, O. Reinaud, EJIC (2013) 5171 – 5180.
  10. D. Coquière, S. Le Gac, U. Darbost,  O. Sénèque,  I. Jabin, O. Reinaud, Org. Biomol. Chem. 7 (2009) 2485-2500.
  11. S. Collin, N. Giraud, E. Dumont, O. Reinaud, Org. Chem. Front. 6 (2019) 1627–1636.
  12. (a) G. Izzet, J. Zeitouny,  H. Akdas-Killig, Y. Frapart,  S. Ménage, B. Douziech, I. Jabin, Y. Le Mest, O. Reinaud, J. Am. Chem. Soc. 130 (2008)9514-9523; (b) N. Le Poul, Y. Le Mest, I. Jabin, O Reinaud, Acc. Chem. Res. 48(2015)2097–2106.