pKa slide rule predictions against CSD structural results

Bond energies and intramolecular distances of normal chemical bonds are weakly affected by their environment, which has made it possible to produce extended compilations of these quantities. Hydrogen bonds (HBs) have a quite different behavior, their binding energies depending not only on the electronegativities of the HB donor (D) and acceptor (A) atoms, but displaying a large spread of values even for a same donor-acceptor couple. This surprising behavior (the H-bond puzzle) is presently interpreted by saying that the forces determining HB strength are a mixture of electrostatic and covalent contributions, that the covalent part is steeply increasing while the donor-acceptor difference of the proton affinities, DPA= PA(DG) – PA(A), or acidic constants, DpKa=pKAH(D-H) - pKBH+(A-H+), tends to zero, and that, when this limit is achieved, the strong and symmetrical D…H…A bond formed is better classified as a true three-center-four-electron covalent bond. This emphasizes the essential role played by PA/pKa equalization in strengthening the HB. We have undertaken a wide research program intended to verify the validity of such a PA/pKa equalization rule which consists of two steps. The first requires the compilation of pKa table for the most typical HB donor and acceptor molecules. The results so obtained have been organized in an unique graphical table called the pKa slide rule which is a practical tool for the prediction of HB strengths based on the fact that, according to the rule, only the donor-acceptor couples lying on a same horizontal line of the rule can give rise to strong HBs with DpKa=0. In the second part of the project the validity of the pKa equalization rule and the reliability of the pKa slide rule prediction has been carried out by a wide search on the Cambridge Structural Database (CSD) for specific classes of HBs. For each D-H…A bond the values of dD…A, dD-H, dH…A and D-H-A angle were registered and the relative HB strength were evaluated from the donor-acceptor distance corrected for the D-H-A angle. Such a verification is not an easy matter because there are tens of thousands of H-bonded crystal structures and thousands of combining molecules with often uncertain pKa values. We have pointed to two main projects that, though handling only a few thousand structures, still retain large diagnostic capabilities: (i) all strong (short) HBs have small or null DpKa value; (ii) in the selected N-H…O/O-H…N system, HB strengths (lengths) are modulated by DpKa in the full DpKa range

Pi-Bond Cooperativity and Anticooperativity Effects in Resonance-Assisted Hydrogen Bonds (RAHBs)

Bond cooperativity effects, which are typical of “resonant” chains or rings of p-conjugated hydrocarbons, can also occur in H-bonded systems in form of s-bond and p-bond cooperativity or anticooperativity. S-bond cooperativity is associated with the long chains of O-H...O bonds in water and alcohols, while s-bond anticooperativity occurs when the cooperative chain is interrupted by a local defect reversing the bond polarity. Both effects are known to play an important role in nature by controlling proton transmission in water and water flow without proton transmission in aquaporins. P-bond cooperativity is the driving force controlling resonance-assisted H-bonds (RAHBs). In typical intamolecular RAHBs enolones (...O=C-C=C-OH...) and enaminones (...O=C-C=C-NH...) form p-cooperative 6-membered rings closed by strong O-H...O or N-H...O bonds [1-4]. P-bond anticooperativity has never been considered so far and it is investigated here by studying couples of H-bonded b-enolone and/or b-enaminone 6-membered rings fused through a common C=O or C-C bond. The effect is studied by X-ray crystal structure determination of five compounds and by extensive CSD [5] search of related fragments. It is shown that fusion through the C=O bond is always anticooperative and such to weaken the symmetric O-H...O...H-O and N-H...O...H-N bonds formed but not the asymmetric O-H...O...H-N one, a fact that is interpreted in terms of equal or different proton affinities of the H-bond donor and acceptor atoms. Fusion through the C-C bond may produce either cooperative or anticooperative H-bonds, the former being more stable than the latter and giving rise to a unique resonance-assisted 10-membered ring running all around the two fused 6-membered ones that can be considered a type of prototropic tautomerism never described before. The possible applications of these fused rings as two-state centers in potentially ferro/ antiferroelectric systems are finally discussed

A structural study of new potent and selective antagonists to the A(2B) adenosine receptor

Xanthines, including the natural derivatives theophylline and caffeine, are non-selective antagonists of adenosine. They are able to bind with good affinity to all four adenosine-receptor subtypes A(1), A(2A), A(2B) and A(3). In order to develop new drugs with few side effects, over the last few years many efforts have been devoted to the discovery of new adenosine antagonists with enhanced selectivity properties. The present paper reports the crystal structures of five new xanthinic derivatives, which display different affinities and selectivity properties towards the A(2B) receptor. Besides the crystallographic study, a structural comparison has been made with the calculated geometry of other xanthinic derivatives which are reported to have similar biological characteristics to understand the structural features controlling their affinity capabilities and selectivity. This structural comparison has been interpreted in the light of a recently published study on the binding of N-benzo[1,3]-dioxol-5-yl-2[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)1-methyl-1-H-pyrazol-3-iloxy]-acetamide to a model of the A(2B) receptor, which shows the most interesting affinity and selectivity properties

New class of proteasome 20S inhibitors: a crystallographic and molecular modelling study

In this communication the crystallographic structures of two protesome 20s inhibitors are reported, together with a conformational study of the molecules in the solid state, in vacuum and in a polar environment which is in turn the basis for a docking study of such inhibitors to the crystallographic structure of the proteasome