Pyrimidine, electrostatic potentials

In a recent paper by Salimbeni et al. [2], a novel series of such All antagonists has been presented on the basis of a comparative analysis of theoretical distributions of the electrostatic potential (inactive compounds and overlay studies, employing a computational model of an All active conformation, it was found that the compound named LR-B/081 [3, 4] (C3oH30N603S), i.e. 2-[(6-butyl-2-methyl-4-oxo-5- 4-[2-(lH-tetrazol-5-yl)phenyl] benzyl -3H-pyrimidin-3-yl)methyl]-3-thiophenecarboxylate (Scheme 1), was one of the most potent in the series, and was selected as a candidate for further studies. 

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

With aquated Pt(II) compounds, numerous studies have revealed the kinetic preference of the 6-oxopurine N7 site [15,35]. In addition to the favorable electrostatic potential mentioned above [23] also steric factors seem to favor coordination to the guanine N7 site, in particular [36]. Estimated relative steric parameters (in parenthesis) suggest that the guanine N7 (1.00) and hypoxanthine N7 (1.03) atoms are the least sterically hindered binding sites in alkylated nucleobases, followed by the adenine N7 (1.17) and deprotonated hypoxanthine N1 (1.17) sites and the deprotonated N3 atoms of the different pyrimidine bases (1.39 for U, 1.44 for T, and 1.56 for C), while the adenine N1 (1.58) and... 

Figure 1-1. Graphical representation of the three diazines, pyridazine (1,2-diazine), pyrimidine (1,3-diazine) and pyrazine (1,4-diazine), in terms of their structure and the electron density surface colored according to the value of the electrostatic potential...

M. Eisenstein, Int. J. Quantum Chem., 33, 127 (1988). SCF Deformation Densities and Electrostatic Potentials of Purines and Pyrimidines. 

In the fields of molecular associations, G. Port and A. Pullman have determined the location of the main hydration sites in the purinic and pyrimidinic bases of nucleic acids 77>. An expansion of the electrostatic potential somewhat different from those reported in Chap. VIII was employed 78>. The results show that association with a water molecule is preferred in every case on the ring plane, with well evidenced minima. 

The potential for RNA to act as a catalyst is dictated by its structure as a linear polymer of the four common ribonucleotides. Like DNA, RNA can form double stranded, antiparallel helices via traditional Watson-Crick base pairing. However, the backbone of nucleic acid is highly flexible and RNA can form complex tertiary structures that often involve non-Watson-Crick base pairing to create active site crevices for catalysis. The phosphodiester backbone is charged negatively and interacts electrostatically as well as by direct coordination with solution divalent cations. Ribose, purines, and pyrimidine bases contain both H-bond donors and acceptors that help stabilize higher-order stmcture and provide for substrate positioning, as well as participate in active site interactions. 

There have been many studies that contrast the accuracy of various atomic charge and distributed multipole models. These studies include the extensive tests provided when various distributed multipole methods were first proposed. For example, there are published contour plots of the potential around a water molecule, the amino acid histidine, and variations in the electrostatic energies of nucleic acid bases,which confirm the significance of the atomic anisotropy shown in the color three-dimensional displays of the electrostatic field around uracil and pyrimidine. It is clear that the difference... 

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