MOLECULAR RECOGNITION VIA BASE-PAIRING - AMINE-CONTAINING, CYTOSINE-BASED DITOPIC RECEPTORS THAT COMPLEX GUANOSINE-MONOPHOSPHATE

The synthesis and binding properties of two types of amine-containing, cytosine-based ditopic receptors, 4-amino-1-[4-[N,N-bis[2-(N,N-diethylamino)ethyl]amino]butyl]-2(1H)-pyrimidinone (1) and 4-amino-1-[4-(N,N-diethylamino)butyl]-2(1H)-pyrimidinone (2a), 4-amino-1-[5-(N,N-diethylamino)pentyl]2(1H)-pyrimidinone (2b), and 4-amino-1-]6-(N,N-diethylamino)hexyl[-2(1H)-pyrimidinone (2c), are described. These systems were prepared by the functionalization of the trityl-protected iodoalkyl-substituted cytosine derivatives of general structure 9, with the appropriate secondary amines [bis(diethylaminoethyl)amine and diethylamine, in the cases of 1 and 2a-c, respectively] and subsequent deprotection with trifluoroacetic acid. The nitrogen-free cytosine derivative, 4-amino-1-(5-ethylheptyl)-2(1H)-pyrimidinone (3), was synthesized directly from the sodium salt of cytosine by reaction with 5-ethyl-1-iodoheptane in DMF. The four cytosine derivatives 1 and 2a-c contain both base pairing and ammonium electrostatic binding subunits. As such, they were expected to act as efficient ditopic receptors for the complexation of guanosine 5'-monophosphate (GMP), a prototypical purine-derived substrate. Quantitative binding studies carried out in DMSO-d6 indicate that compounds 1,2a, 2b, and 2c in their neutral forms bind GMP free acid with first association constants, K11, of 26 000 +/- 3900, 820 +/- 120, 1000 +/- 150, and 1300 +/- 200 M-1 and second association constants, K12 (for 1) and K21 (for 2a-c), of 1500 +/- 230, 660 +/- 100, 720 +/- 110, and 1200 +/- 180 M-1, respectively (where K11, K21, and K12 represent the formation of 1:1, 2:1, and 1:2 receptor-to-GMP complexes, respectively), whereas the ammonium-free system 3 was found to bind this same substrate as a 1:1 complex with a K11 of only 5 +/- 2 M-1. The greater binding affinity of receptor 1, relative to that of 2a-c (and 3), is ascribed to the additional electrostatic interactions possible in the supramolecular GMP-receptor complex derived from this more precisely elaborated system.