Dichotomous Hydrogen Atom Transfer vs Proton-Coupled Electron Transfer During Activation of X–H Bonds (X = C, N, O) by Nonheme Iron–Oxo Complexes of Variable Basicity

We describe herein the hydrogen-atom transfer (HAT)/proton-coupled electron-transfer (PCET) reactivity for Fe(IV)-oxo and Fe(III)-oxo complexes (1-4) that activate C-H, N-H, and O-H bonds in 9,10-dihydroanthracene (S1), dimethylformamide (S2), 1,2-diphenylhydrazine (S3), p-methoxyphenol (S4), and 1,4-cyclohexadiene (S5). In 1-3, the iron is pentacoordinated by tris[N'-tert-butylureaylato)-N-ethylene]aminato ([H3buea](3-)) or its derivatives. These complexes are basic, in the order 3 ≫ 1 > 2. Oxidant 4, [Fe(IV)N4Py(O)](2+) (N4Py: N,N-bis(2-pyridylmethyl)bis(2-pyridyl)methylamine), is the least basic oxidant. The DFT results match experimental trends and exhibit a mechanistic spectrum ranging from concerted HAT and PCET reactions to concerted-asynchronous proton transfer (PT)/electron transfer (ET) mechanisms, all the way to PT. The singly occupied orbital along the O···H···X (X = C, N, O) moiety in the TS shows clearly that in the PCET cases, the electron is transferred separately from the proton. The Bell-Evans-Polanyi principle does not account for the observed reactivity pattern, as evidenced by the scatter in the plot of calculated barrier vs reactions driving forces. However, a plot of the deformation energy in the TS vs the respective barrier provides a clear signature of the HAT/PCET dichotomy. Thus, in all C-H bond activations, the barrier derives from the deformation energy required to create the TS, whereas in N-H/O-H bond activations, the deformation energy is much larger than the corresponding barrier, indicating the presence of a stabilizing interaction between the TS fragments. A valence bond model is used to link the observed results with the basicity/acidity of the reactants

pH dependence of a 3<SUB>10</SUB>-helix versus a turn in the M-loop region of PDE4: observations on PDB entries and an electronic structure study

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G&#8727; and B3LYP/6-31+G&#8727;:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules

Photophysical and duplex-DNA-binding properties of distamycin dimers based on 4,4'- and 2,2'-dialkoxyazobenzenes as the core

Distamycin-based tetrapeptide (1) was covalently tethered to both ends of the central dihydroxyazobenzene moiety at either the 2,2' or 4,4' positions. This afforded two isomeric, distamycin-azobenzene-distamycin systems, 2 (para) and 3 (ortho), both of them being photoisomerizable. Illumination of these conjugates in solution at approximately 360 nm induced photoisomerization and the time course of the process was followed by UV/Vis and 1H NMR spectroscopy. The kinetics of the thermal reversion at various temperatures of cis to trans isomers of the conjugates obtained after photoillumination were also examined. This afforded the respective thermal-activation parameters. Both the molecular architecture and the location of the substituent around the core azobenzene determined the rate and activation-energy barrier for the cis-to-trans back-isomerization of these conjugates in solution. Duplex-DNA binding of the conjugates and the changes in DNA-binding efficiency upon photoisomerization was also examined by CD spectroscopy, thermal denaturation studies, and a Hoechst displacement assay. The conjugate 2 showed higher DNA-binding affinity and a greater change in the DNA-binding efficiency upon photoisomerization compared with its 2,2'-disubstituted counterpart. The experimental findings were substantiated by using molecular-docking studies involving each conjugate with a model duplex d[(GC(AT)10CG)]2 DNA molecule

pH Dependence of a 3103_{10}-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a $3_{10}$-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains,and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a $3_{10}$-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules

Subtype Selectivity in Phosphodiesterase 4 (PDE4): A Bottleneck in Rational Drug Design

Subtype selectivity of phosphodiesterase 4 (PDE4) has been proposed to be the most salient feature for the development of drugs for asthma and inflammation. The present review provides an account of various strategies to overcome the side effects of the PDE4 inhibitors. Subtype selectivity and recent developments of molecular modeling approaches towards PDE4 were addressed using QSAR and docking, followed by a detailed structural analysis of more than three dozen available X-ray structures of PDE4B and PDE4D. Usually, the lack of a 3-dimensional structure of a target protein is a bottleneck for rational drug design approaches. However, in this case the availability of 39 X-ray structures along with co-crystals has not improved the therapeutic ratio of drugs through rational drug design approaches. The investigation of structures led to find significant variations in the M-loop region, which is the integral part of the active site of PDE4B and PDE4D. These differences can be accounted for by varying conformation of the Pro(430) residue and a Thr(436)/Asn(362) mutation in the M-loop that causes variations in adjacent residue properties and also the pattern of hydrogen-bonding interactions. The impact of the M-loop region on inhibitor binding has been further scrutinized by MOLCAD surfaces and hydrophobicity. These have shown that PDE4B is more hydrophobic in nature than PDE4D in the M-loop region. A review of the above aspects given the emphasis on a new PDE4 inhibitor which can access both metal and solvent pockets may possibly lead to ligands with enhanced potency. The lining of the Q2 pocket that involves the M-loop region may be considered for the design of potent subtype-selective inhibitors

Structure and bonding in stannadiphospholes and their dianions SnC<SUB>2</SUB>P<SUB>2</SUB>R<SUP>m</SUP><SUB>2</SUB> (R=H, tBu m=0, -2): A comparative study with C<SUB>5</SUB>H<SUB>5</SUB><SUP>+</SUP> and C<SUB>5</SUB>H<SUB>5</SUB><SUP>-</SUP> analogues

The potential energy surfaces of both neutral and dianionic SnC2P2R2 (R=H, tBu) ring systems have been explored at the B3PW91/LANL2DZ (Sn) and 6-311+G* (other atoms) level. In the neutral isomers the global minimum is a nido structure in which a 1,2-diphosphocyclobutadiene ring (1,2-DPCB) is capped by the Sn. Interestingly, the structure established by X-ray diffraction analysis, for R=tBu, is a 1,3-DPCB ring capped by Sn and it is 2.4 kcal mol-1 higher in energy than the 1,2-DPCB ring isomer. This is possibly related to the kinetic stability of the 1,3-DPCB ring, which might originate from the synthetic precursor ZrCp2tBu2C2P2. In the case of the dianionic isomers we observe only a 6π-electron aromatic structure as the global minimum, similarly to the cases of our previously reported results with other types of heterodiphospholes.1,4,19 The existence of large numbers of cluster-type isomers in neutral and 6π-planar structures in the dianions SnC2P2R22- (R=H, tBu) is due to 3D aromaticity in neutral clusters and to 2D π aromaticity of the dianionic rings. Relative energies of positional isomers mainly depend on: 1) the valency and coordination number of the Sn centre, 2) individual bond strengths, and 3) the steric effect of tBu groups. A comparison of neutral stannadiphospholes with other structurally related C5H5+ analogues indicates that Sn might be a better isolobal analogue to P+ than to BH or CH+. The variation in global minima in these C5H5+ analogues is due to characteristic features such as 1) the different valencies of C, B, P and Sn, 2) the electron deficiency of B, 3) weaker pπ-pπ bonding by P and Sn atoms, and 4) the tendency of electropositive elements to donate electrons to nido clusters. Unlike the C5H5+ systems, all C5H5- analogues have 6π-planar aromatic structures as global minima. The differences in the relative ordering of the positional isomers and ligating properties are significant and depend on 1) the nature of the π orbitals involved, and 2) effective overlap of orbitals

Photophysical and Duplex-DNA-Binding Properties of Distamycin Dimers Based on 4,4'- and 2,2'-Dialkoxyazobenzenes as the Core

Distamycin-based tetrapeptide (1) was covalently tethered to both ends of the central dihydroxyazobenzene moiety at either the 2,2 or 4,4 positions. This afforded two isomeric, distamycin-azobenzene-distamycin systems, 2 (para) and 3 (ortho), both of them being photoisomerizable. Illumination of these conjugates in solution at approximately 360 nm induced photoisomerization and the time course of the process was followed by UV/Vis and 1H NMR spectroscopy. The kinetics of the thermal reversion at various temperatures of cis to trans isomers of the conjugates obtained after photoillumination were also examined. This afforded the respective thermal-activation parameters. Both the molecular architecture and the location of the substituent around the core azobenzene determined the rate and activation-energy barrier for the cis-to-trans back-isomerization of these conjugates in solution. Duplex-DNA binding of the conjugates and the changes in DNA-binding efficiency upon photoisomerization was also examined by CD spectroscopy, thermal denaturation studies, and a Hoechst displacement assay. The conjugate 2 showed higher DNA-binding affinity and a greater change in the DNA-binding efficiency upon photoisomerization compared with its 2,2-disubstituted counterpart. The experimental findings were substantiated by using molecular-docking studies involving each conjugate with a model duplex d[(GC(AT)10CG)]2 DNA molecule

Structure and Bonding in Stannadiphospholes and their Dianions SnC(2)P(2)R(2)(m) (R=H, tBu m=0,-2): A Comparative Study with C(5)H(5)(+) and C(5)H(5)(-) Analogues

The potential energy surfaces of both neutral and dianionic SnC(2)P(2)R(2) (R=H, tBu) ring systems have been explored at the B3PW91/LANL2DZ (Sn) and 6-311 + G* (other atoms) level. In the neutral isomers the global minimum is a nido structure in which a 1,2-diphosphocyclobutadiene ring (1,2-DPCB) is capped by the Sn. Interestingly, the structure established by Xray diffraction analysis, for R=tBu, is a 1,3-DPCB ring capped by Sn and it is 2.4 kcal mol(-1) higher in energy than the 1,2-DPCB ring isomer. This is possibly related to the kinetic stability of the 1,3-DPCB ring, which might originate from the synthetic precursor ZrCp(2)tBu(2)C(2)P(2). In the case of the dianionic isomers we observe only a 6 pi-electron aromatic structure as the global minimum, similarly to the cases of our previously reported results with other types of heterodiphospholes.([1,4,19]) The existence of large numbers of cluster-type isomers in neutral and 6 pi-planar structures in the dianions SnC(2)P(2)R(2)(2-) (R=H, tBu) is due to 3D aromaticity in neutral clusters and to 2D pi aromaticity of the dianionic rings. Relative energies of positional isomers mainly depend on: 1) the valency and coordination number of the Sn centre, 2) individual bond strengths, and 3) the steric effect of tBu groups. A comparison of neutral stannadiphospholes with other structurally related C(5)H(5)(+) analogues indicates that Sn might be a better isolobal analogue to P(+) than to BH or CH(+). The variation in global minima in these C(5)H(5)(+) analogues is due to characteristic features such as 1) the different valencies of C, B, P and Sn, 2) the electron deficiency of B, 3) weaker p pi-p pi bonding by P and Sn atoms, and 4) the tendency of electropositive elements to donate electrons to nido clusters. Unlike the C5H5+ systems, all C(5)H(5)(-) analogues have 6 pi-planar aromatic structures as global minima. The differences in the relative ordering of the positional isomers and ligating properties are significant and depend on 1) the nature of the pi orbitals involved, and 2) effective overlap of orbitals