Aryl-bis-(scorpiand)-aza receptors differentiate between nucleotide monophosphates by a combination of aromatic, hydrogen bond and electrostatic interactionsOrg. Biomol. Chem.


Jorge González-García, Sanja Tomić, Alberto Lopera, Lluís Guijarro, Ivo Piantanida, Enrique García-España
Organic Chemistry / Physical and Theoretical Chemistry / Biochemistry


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Aryl-bis-(scorpiand)-aza receptors differentiate between nucleotide monophosphates by combination of aromatic, hydrogen bond and electrostatic interactions

Jorge González-García,a Sanja Tomić,b Alberto Lopera,a Lluís Guijarro,a Ivo Piantanida*c and Enrique

García-España*a 5

Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X

First published on the web Xth XXXXXXXXX 200X

DOI: 10.1039/b000000x

Abstract: Bis-polyaza pyridinophane scorpiands bind nucleotides in aqueous medium by 10-100 micromolar affinity, dominantly by electrostatic interactions between nucleotide phosphates and 10 protonated aliphatic amines and assisted by aromatic stacking interactions. The pyridine-scorpiand receptor showed rare selectivity toward CMP in respect to other nucleotides, whereby two orders of magnitude affinity difference between CMP and UMP was the most appealing. The phenanthroline-scorpiand receptor revealed at pH 5 strong selectivity toward AMP in respect to other NMPs, based on the protonation of adenine heterocyclic N1. Results stress the efficient 15 recognition of small biomolecules within scorpiand-like receptors relies mostly on the electrostatic and H-bonding interactions despite the competitive interactions in the bulk solvent, thus supporting further optimisation of this versatile artificial moiety.


Nucleotides are amongst the most targeted anionic substrates 20 due to the key roles that they play in biology such as nucleic acid synthesis, transport across membranes, energy and electron-transfer events. Other relevant functions of nucleotides are related to cell-signalling processes.1 In this respect, the extracellular release of nucleotides serves as a 25 signal during inflammation through the activation of nucleotide receptors P1 and P2.2 Transmembrane protein channels have been implicated in the release of adenosine nucleotides from the intra- to the extracellular space in apoptotic cells.3 In addition, several studies have proved the 30 release of uridine nucleotides during cystic fibrosis.4

Therefore, the development of new abiotic receptors able to selectively bind nucleotides in aqueous solution is a relevant goal in chemical and biomedical research.5

The interaction among naturally occurring nucleobases and 35 abiotic receptors occurs mainly through columbic interactions, hydrogen bonding and π-π stacking. Very nice examples about the involvement of different forces in nucleotide binding were provided by the crystal structures of adducts formed between protonated terpyridinophane or phenanthroline macrocycles 40 with 5’-thymidine triphosphate (5’-TTP).6

Since the dominant driving force in nucleotide binding is charge-charge interaction a great deal of the studies so far reported describe the selection of the more charged nucleotides with respect to the less charged ones.7-10 Reversed 45 selectivity of ADP over ATP in water was recently reported to occur through the synergistic action of the different binding groups included in a tris(2-aminoethyl)amine receptor containing a pyrimidine group.11

A case of selectivity for AMP over ADP and ATP as a result 50 of strong electrostatic contacts supported by π-π interactions, was recently reported in a guanidinium-polypeptide-based polytopic receptor.12

However, achieving base-pair discrimination is a challenging target in biomedical and supramolecular chemistry. Very often 55 base-pair discrimination relies on different hydrogen bonding patterns between the partners which limit its effectivity in water due to competitive hydrogen bonding with the solvent.13

To overcome this difficulty, several years ago sapphyrin and calixpyrrole derivatives appended with nucleobases were 60 designed so that the interaction with the complementary nucleotide was enhanced by hydrogen bonding.14 Favourable discrimination for AMP over the other nucleotide monophosphates (NMPs) by hydrogen bonding was reported using a polytopic receptor with a bis(oxazolin-2-yl)pyridine 65 scaffold.15

Several bis-intercaland-type macrocycles constituted another example of nucleobase discrimination.16 For this work particularly interesting is the selectivity toward certain nucleobases ascribed to the interaction of the bases with the 70 polyamine-linkers connecting the intercalating subunits.17

Scheme 1. Studied PYPOD (left) and PHENPOD (right).

On the other hand, Kimura and co-workers reported for the first time, the ability of the Zn2+ complex of cyclen to interact 75