Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis.

Arginine, due to the guanidine moiety, increases peptides' hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs.

An ab initio study on the stability of isolated phosphaalkene synthons.

Using ab initio methods and flexible basis sets, we examined the electronic, geometric, and thermodynamic stabilities of selected phosphaalkene synthons matching the (PCR2)- formula (R = H, CH3, C6H5, C6F5, and Mes). All isolated synthons considered were found to be electronically stable and susceptible to neither fragmentation nor isomerization processes. The structures corresponding to the most stable isomers of the studied phosphaalkene synthons contain a PC double-bond (whose presence was confirmed by natural bond orbital occupancies of σ(P-C) and π(P-C) approaching 2 electrons) and two R substituents connected to the carbon atom in either (PCR2)- (for R = H, CH3, C6H5, and Mes) or (PCF-R-R)- (for R = C6F5) manner. Vertical electron detachment energies (spanning the 0.924-3.118 eV range) characterizing the phosphaalkene synthons were predicted and discussed.

Superhalogen Anions Supported by the Systems Comprising Alternately Aligned Boron and Nitrogen Central Atoms.

Using DFT/(B3LYP/wB97XD/B2PLYPD) and OVGF electronic structure methods with flexible atomic orbital basis sets, we examined the series of polynuclear superhalogen anions matching the (BF3(BN) n F4n+1)- formula (for n = 1-10,13,18-20) containing alternately aligned boron and nitrogen central atoms decorated with fluorine ligands. It was found that the equilibrium structures of these anions correspond to fully extended chains (with each B and N central atom surrounded by four substituents arranged in a tetrahedral manner) and thus mimic the globally stable fully extended (all-trans) conformations of higher n-alkanes. The vertical electron detachment energies of the (BF3(BN) n F4n+1)- anions were found to exceed 8 eV in all cases and gradually increase with the increasing number of n. The approximate limiting value of vertical electron binding energy that could be achieved for such polynuclear superhalogen anions was estimated as equal to ca. 10.7 eV.

Electron attachment to representative cations composing ionic liquids.

Using ab initio electronic structure methods with flexible atomic orbital basis sets, we investigated the electronic structure and stability of reduction products of selected representative cations (C+) constituting ionic liquids. We found that an electron attachment to such cations leads to the neutral radicals, whereas a subsequent attachment of another (i.e., excess) electron leads to adiabatically stable anions only in two cases {[P(CH3)4]- and [MeMePyr]-}. The possibility of the formation of various dimers (such as CC+, CC, and CC-) was also considered, and the resulting systems were characterized by predicting their lowest energy structures, ionization potentials, electron affinities, and susceptibilities to the fragmentation process. Among the cations studied, only the [MeMePyr]+ was found to form a typical Rydberg radical (MeMePyr) and double-Rydberg anion ([MeMePyr]-), whereas the remaining cations were predicted to form neutral radicals of a primarily valence (MeMeIm and MePy) or mixed Rydberg-valence [P(CH3)4] character. Our calculations confirmed the stability of all CC+ and CC dimers against fragmentation yielding the corresponding monomers (the binding energies of 12.2-20.5 kcal/mol and 11.3-72.3 kcal/mol were estimated for CC+ and CC dimers, respectively). [(MeMePyr)2]- was identified as the only adiabatically stable CC- dimeric anion having its vertical electron detachment energy of 0.417 eV. We also found that in the [(MeMePyr)2]- anionic state, three outermost electrons are described by Rydberg orbitals, which results in the (σ)2(σ*)1 configuration.

An Excess Electron Bound to Magnesium Halides and Basic Grignard Compounds (RMgX and RMgR, R = Me, Et, Ph; X = F, Cl, Br).

Grignard reagents are commonly used in organic synthesis, yet their ability to form stable anionic states has not been recognized thus far. In this work, representative examples of RMgF, RMgCl, and RMgBr molecules involving methyl, ethyl, and phenyl functional groups serving as R substituents are investigated regarding their equilibrium structures, adiabatic electron affinities, and vertical electron detachment energies of their daughter anions. The electronic stabilities determined for the negatively charged Grignard compounds are then compared to those predicted for their corresponding magnesium halides. The anions formed by RMgX (R = Me, Et, Ph; X = F, Cl, Br) molecules are found to be adiabatically electronically stable valence-bound systems characterized by relatively large vertical electron detachment energies spanning the 0.79-1.62 eV range. In addition, significant structural relaxation upon attachment of an excess electron is predicted for all Grignard compounds considered. Furthermore, the re-examination of the anions formed by magnesium halides resulted in recognizing them as valence-bound rather than dipole-bound anions, in contrast to the earlier interpretations.

In silico analysis of heparin and chondroitin sulfate binding mechanisms of the antiprotozoal drug berenil and pentamidine.

Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities.

Water-assisted peptide bond formation between two double amino acid molecules in the gas phase.

The gas phase mechanism of the peptide bond formation between two double amino acid (DAA) molecules described by the (NH2)2C(COOH)2 formula is investigated in the presence of a water molecule. Formations of trans and cis DAA-DAA dipeptide products along both concerted and stepwise mechanisms have been studied at the CCSD(T)/aug-cc-pVDZ//MP2/aug-cc-pVDZ level. The results indicate that the activation energy barriers estimated for the water-assisted mechanisms are significantly reduced in comparison to the corresponding uncatalyzed reactions. The trans DAA-DAA isomer is expected to dominate in the final product due to its larger stability compared to the cis DAA-DAA product.

Stability of Superhalogen Anions in the Aqueous Phase.

The issue of stability of superhalogen anions in an aqueous solution is investigated on the basis of theoretical calculations carried out at the CCSD(T)/6-311++G(d,p)//MP2/6-311++G(d,p) level for two representative negatively charged systems (NaF2- and AlF4-) whose fragmentation products differ in polarity. The presence of a water solvent is simulated independently by employing the polarized continuum solvation model and by involving eight H2O molecules explicitly to allow interactions at the molecular level. The best estimates of the Gibbs free energies characterizing the AlF4- and NaF2- fragmentation reactions in a water solvent are evaluated as equal to 33-34 and 12-14 kcal/mol, respectively (assuming the F- and AlF3/NaF products) or 14-15 and 26-28 kcal/mol, respectively (assuming the HF and AlF3OH-/NaFOH- products). The corresponding fragmentation routes are suggested to be nonoperative at T = 298.15 K. The conclusion concerning the thermodynamic stability of the AlF4- and NaF2- superhalogen anions in the aqueous phase is formulated and discussed.

Towards the Application of Structure-Property Relationship Modeling in Materials Science: Predicting the Seebeck Coefficient for Ionic Liquid/Redox Couple Systems.

This work focuses on determining the influence of both ionic-liquid (IL) type and redox couple concentration on Seebeck coefficient values of such a system. The quantitative structure-property relationship (QSPR) and read-across techniques are proposed as methods to identify structural features of ILs (mixed with LiI/I2 redox couple), which have the most influence on the Seebeck coefficient (Se ) values of the system. ILs consisting of small, symmetric cations and anions with high values of vertical electron binding energy are recognized as those with the highest values of Se . In addition, the QSPR model enables the values of Se to be predicted for each IL that belongs to the applicability domain of the model. The influence of the redox-couple concentration on values of Se is also quantitatively described. Thus, it is possible to calculate how the value of Se will change with changing redox-couple concentration. The presence of the LiI/I2 redox couple in lower concentrations increases the values of Se , as expected.

Why are SiX5(-) and GeX5(-) (X = F, Cl) stable but not CF5(-) and CCl5(-)?

The possible existence of the CF(5)(-), CCl(5)(-), SiF(5)(-), SiCl(5)(-), GeF(5)(-), and GeCl(5)(-) anions has been investigated using ab initio methods. The species containing Si and Ge as central atoms were found to adopt the D(3h)-symmetry trigonal bipyramidal equilibrium structures whose thermodynamic stabilities were confirmed by examining the most probable fragmentation channels. The ab initio re-examination of the electronic stabilities of the SiF(5)(-), SiCl(5)(-), GeF(5)(-), and GeCl(5)(-) anions [using the OVGF(full) method with the 6-311+G(3df) basis set] led to the very large vertical electron detachment (VDE) energies of 9.316 eV (SiF(5)(-)) and 9.742 eV (GeF(5)(-)), whereas smaller VDEs of 6.196 and 6.452 eV were predicted for the SiCl(5)(-) and GeCl(5)(-) species, respectively. By contrast, the high-symmetry and structurally compact anionic CF(5)(-) and CCl(5)(-) systems cannot exist due to the strongly repulsive potential predicted for the X(-) (F(-) or Cl(-)) approaching the CX(4) (CF(4) or CCl(4)). The formation of weakly bound CX(4)···X(-) (CF(4)···F(-) and CCl(4)···Cl(-)) anionic complexes (consisting of pseudotetrahedral neutral CX(4) with the weakly tethered X(-)) might be expected at low temperatures (approaching 0 K), whereas neither CX(5)(-) (CF(5)(-), CCl(5)(-)) systems nor CX(4)···X(-) (CF(4)···F(-) and CCl(4)···Cl(-)) complexes can exist in the elevated temperatures (above 0K) due to their susceptibility to the fragmentation (leading to the X(-) loss).

Theoretical search for alternative nine-electron ligands suitable for superhalogen anions.

The calculations performed at the OVGF/6-311++G(3df,3pd)//MP2/6-311++G(d,p) level for the representative NaX(2)(-) and AlX(4)(-) anions matching the MX(k+1)(-) superhalogen formula and utilizing 9-electron systems (i.e., consisting of various possible combinations of atoms containing nine electrons when brought together) revealed that the OH, Li(2)H(3), and NH(2) groups might be considered as alternative ligands X due to their thermodynamic stability and large values of electron binding energy (approaching or even exceeding 6 eV in some cases). All aluminum-containing AlX(4)(-) anions (excluding Al(HBLi)(4)(-)) were predicted to be thermodynamically stable, whereas the NaX(2)(-) anions for X = CH(3), HBLi, CLi, BeB, and H(2)BeLi were found to be susceptible to the fragmentations leading to Na(-) loss. Among the MX(k+1)(-) (M = Na, Al; X = Li(2)H(3), OH, H(2)BeLi, BeB, NH(2), HBLi, CH(3), Be(2)H, CLi) anions utilizing systems containing 9 electrons (and thus isoelectronic with the F atom) the largest vertical electron detachment energy of 6.38 eV was obtained for Al(OH)(4)(-).

The reason why HAlCl(4) acid does not exist.

The explanation of the hypothetical HAlCl(4) acid instability is provided on the basis of theoretical considerations supported by ab initio calculations. The equilibrium structures of LiAlCl(4), NaAlCl(4), and KAlCl(4) salts were examined and compared to that of their corresponding parent acid. The process of formation of the representative NaAlCl(4) salt was analyzed, and the interaction energy between NaCl and AlCl(3) was estimated to be ca. 55 kcal/mol while that between HCl and AlCl(3) (when the HAlCl(4) species is formed) was calculated to be smaller by an order of magnitude (ca. 8 kcal/mol). The hypothetical HAlCl(4) acid was identified as an HCl...AlCl(3) adduct (with the hydrogen chloride tethered weakly to the quasi-planar aluminum chloride molecule). The electron affinity of the neutral AlCl(4) superhalogen molecule was found to be the factor determining the ability to form a stable compound of MAlCl(4) type.