Multicomponent Hydrogen-bonded Macrocyclic Assemblies from a DNA Base Toolkit

Resumo

The formation of discrete molecular assemblies that constitute the functional elements of biological and synthetic systems relies on cooperative effects between multiple non-covalent interactions. The effect that enhances the stability of a cyclic over a linear system is defined as chelate cooperativity and originates from the fact that intramolecular interactions are favoured over intermolecular interactions due to the entropic effects. Chelate cooperativity is responsible for many “all-or-nothing” processes observed in biological systems, such as protein folding or DNA assembly. The Thesis “Multicomponent Hydrogen-bonded Macrocyclic Assemblies from a DNA Base Toolkit “ aims to understand in deeper detail chelate cooperativity through synthetic models that share a common structure, comprising a rigid central block linearly disubstituted at both edges with nucleosides (Figure 1). Upon Watson-Crick pairing (G:C, A:U, iG:iC), the nucleobases adopt an exact angle of 90°, leading thus to the formation of discrete tetrameric H-bonded macrocycles in solution and onto solid substrates. We have focused on the study of this cyclotetramerization process by H-bonding by different NMR techniques (concentration- and temperature dependent measures, titrations, DOSY, NOESY, etc.), mass spectroscopy (ESI Q-TOF), X diffraction and, in a complementary way, absorption, emission and circular dichroism spectroscopic techniques. Furthermore, in this Thesis we have addressed different issues and concepts that are central in supramolecular chemistry: cooperativity, enthalpy-entropy interplay, self-sorting, multicomponent assembly. Publications. 1) Montoro-García, C.; Camacho-García, J.; López-Pérez, A. M.; Bilbao, N.; Romero-Pérez, S.; Mayoral, M. J.; González-Rodríguez, D., Angew. Chem. Int. Ed. 2015, 54, 6780–6784 (VIP Paper). A hydrogen-bonded cyclic tetramer is assembled with remarkably high effective molarities from a properly designed dinucleoside monomer. This self-assembled species exhibits an impressive thermodynamic and kinetic stability and is formed with high fidelities within a broad concentration range and very polar solvents. This work was finalist as the best article in the 2016 SUSCHEM Awards (PhD category) 2) Montoro-García, C.; Camacho-García, J.; López-Pérez, A. M.; Bilbao, N.; Mayoral, M. J.; González-Rodríguez, D., Angew. Chem. Int. Ed. 2016, 55, 223–227. The intrinsic chelate effect that multipoint H-bonding patterns exert on the overall energy of dinucleoside cyclic systems is studied. Our results indicate that the chelate effect is regulated by the symmetry of the H-bonding pattern, and that the effective molarity is reduced by about three orders of magnitude when going from the unsymmetric ADD–DAA or DDA–AAD patterns to the symmetric DAD–ADA pattern. 3) Montoro-García C.; Mayoral, M. J.; González-Rodríguez, D. Submitted to J. Am. Chem. Soc. Here, we analyse for the first time the influence of the length and structure of a central linker on the chelate cooperativity of a cyclic assembly. While maintaining the same G-C binding interaction, we have designed a series of monomers in which the terminal nucleosides are bound by diverse linear and rigid -conjugated spacers of different lengths, which produces self-assembled macrocycles of diverse diameters (from 3.6 to 7.4 nm). Our results demonstrate that the higher the number of torsionable/rotatable -bonds in the spacer the lower the stability of the cyclic system and that this effect has only an entropic origin. Furthermore, we provide here a method for determining how large a cyclic system can be quantitatively assembled. 4) Mayoral, M. J.; Montoro-García, C.; González-Rodríguez D. Self-assembled Systems via Nucleobase Pairing, Book chapter in Comprehensive Supramolecular Chemistry II, Elsevier Ltd.,UK. In Press, DOI:10.1016/B978-0-12-409547-2.12536-3. Nucleobase pairing has been exploited in many ways, but the main idea is to profit from the selective and complementary binding between DNA bases to bring together different molecular units for a particular function. In this chapter, we will cover discrete synthetic systems in solution, soft materials, condensed two-dimensional systems on surfaces, as well as polymeric systems in solution or in bulk phases. 5) Romero-Pérez, S.; Camacho-García, J.; Montoro-García, C.; López-Pérez, A. M.; Sanz, A.; Mayoral, M. J.; González-Rodríguez, D., Org. Lett. 2015, 17, 2664−2667. A given G-C dinucleoside is equipped with electron-poor aryl groups at the G-N2 amino group. Such monomers form unstrained cyclic tetramers in a wide variety of experimental conditions, including very polar solvent environments and low concentrations. G-arylation produces an increased stability of the cyclic assembly, as a result of a subtle interplay between enthalpic and entropic effects involving the solvent coordination sphere. 6) Camacho-García, J.; Montoro-García, C.; López-Pérez, A. M.; Bilbao, N.; Romero-Pérez, S.; González-Pérez, D., Org. Biomol. Chem. 2015, 13, 4506–4513. A series of lipophilic nucleosides comprising natural and non-natural bases that are -conjugated to a short oligophenylene-ethynylene fragment has been synthesized. The hydrogen-bonding dimerization and association processes between complementary bases were as well studied by 1H NMR and absorption spectroscopies by different mathematical methods in order to obtain the relevant association constants.