Isosteric Molecules Research Articles

A rationale for the contrasting activity (towards globular proteins) of tert-butyl alcohol and trimethylamine N-oxide

tert-Butyl alcohol, TBA, and trimethylamine N-oxide, TMAO, even though they are isosteric molecules, have contrasting activity towards globular proteins: the former destabilizes the native state, whereas the latter stabilizes it. TBA addition to water causes a density decrease and it tends to form self-aggregates; TMAO addition to water causes a density increase and it does not show any tendency to form self-aggregates. By inserting such experimental information in the framework of the statistical thermodynamic model devised to rationalize the conformational stability of globular proteins [G. Graziano, Phys. Chem. Chem. Phys., 2010, 12, 14245-14252], it emerges that: (a) TBA is a destabilizing agent because its addition to water causes a significant decrease in the magnitude of the contribution due to the solvent-excluded volume decrease associated with protein folding; (b) TMAO is a stabilizing agent because its addition to water causes a significant increase in the magnitude of the contribution due to the solvent-excluded volume decrease associated with protein folding.

Photoinduced electron transfer within a novel synthesized short-chain dyad

The investigations were made by using electrochemical, steady state and time resolved spectroscopic (time correlated single photon counting and laser flash photolysis) techniques on a novel synthesized dyad, 1-(4-chloro-phenyl)-3-(4-methoxy-naphthalen-1-yl)-propenone ( MNCA) where the donor 1-methoxy-naphthalene ( MNT) is connected with the acceptor p-chloroacetophenone ( PCA) by an unsaturated olefinic bond. This dyad possesses mainly extended ( E-type) conformation both in the ground and excited state. The unchanged conformational geometry of this dyad even after photoexcitation makes it different from the previously studied benzothiophene–p-chloroacetophenone dyads, though both the donors present are isosteric molecules. In the cases of the latter dyads though E-type isomeric structure dominates in the ground state, considerable amount of Z-type (folded) species are produced in the excited state. It is hinted that the proximity effect of methoxy functionality in donor moiety, may be the reason for the formation of mostly E-isomeric species in the case of the present dyad MNCA system. The observed unchanged values of charge recombination and ion-pair lifetime, estimated from the analysis of transient absorption spectra of the dyad in presence of βCD and without it, confirm the proposition about the maintenance of the extended conformation even upon photoexcitation. From the transient absorption measurements it appears that due to increase of delay times between the exciting and probe pulses, higher triplet T n of the donor being generated gets involved in PET reactions with the surrounding medium ACN. From the present findings, MNCA in aqueous medium seems to be better candidate to build light energy conversion devices than the previously studied benzothiophene dyads where artificial devices like βCD were used to make elongated geometry. This geometry would help to prevent charge recombination processes within the redox components due to minimal overlapping between them.

The Role of Water Coordination in Binary Mixtures. A Study of Two Model Amphiphilic Molecules in Aqueous Solutions by Molecular Dynamics and NMR

Two binary aqueous mixtures which contain the small amphiphilic molecules TMAO (trimethylamine-N-oxide) and TBA (tert-butyl alcohol) have been investigated by molecular dynamics simulations and NMR chemical shift and self-diffusion measurements. TMAO is an osmolyte, while TBA is a monohydrate alcohol. Both possess bulky hydrophobic groups and polar heads, namely, NO in TMAO and OH in TBA. The hydrophilic/hydrophobic content of these isosteric molecules strongly modulates the structure and dynamics of the hydration shell, which is thought to be responsible for the effects observed on proteins and phospholipids. Simulation results, especially on hydrogen-bond networking, spatial correlations, and self-diffusivity, are consistent with NMR data and agree well with previous numerical studies on similar solutions. The methods employed allow the elucidation of the microscopic features of the solutions. For TBA solutions, the hydration shell is found to have a low density and a large spatial spread, and thus, above the molar fraction of 0.03, reduction of hydrophobic hydration drives self-aggregation of the solute. This effect does not take place in TMAO solutions, where the hydration shell is more compact and stable, maintaining its structure over a wider range of solute concentrations.

Study by electronic circular dichroism spectroscopy of the interaction between aminooxy analogues of biogenic polyamines and selected oligonucleotides

The interaction between a series of aminooxy analogues of the biogenic polyamines spermine and spermidine and selected 15-mer oligodeoxyribonucleotides with alternating purine–pyrimidine base sequences, adenine–thymine (AT) and guanine–cytosine (GC), has been studied using electronic circular dichroism (CD) spectroscopy. These analogues resulted from the substitution of the two terminal aminomethylene groups of the polyamines, –CH 2NH 2 +, by an aminooxy one, –ONH 2. Since spermidine has no centre of symmetry, it gives rise to two different isosteric molecules, which have been named AOEPUT and APAPA. On the contrary, spermine gives rise to a single aminooxy analogue, named as AOSPM. As the p K a of an aminooxy group (about 5) is not high enough to be protonated at a neutral pH, these analogues have a positive charge less than the corresponding polyamine under physiological settings, which makes them suitable models to investigate the roles of the charge and the structure in the polyamine–DNA interaction. At low pH values, both the biogenic polyamine and their aminooxy analogues have a similar positive charge. The CD spectra of solutions containing different concentrations of the three aminooxy analogues and a 15-mer oligonucleotide, containing either the GC or the AT sequence, at a fixed concentration 60 μM in phosphate, were recorded. Solutions at pH values 7.5 and 5.0 were studied in order to investigate the role of the molecular charge. The spectra demonstrated that the interaction of these oligonucleotides with the aminooxy analogues had a significant sequence-selectivity. Spectra of the oligonucleotides in the presence of AOSMP showed two isodicroic points, thus indicating the presence of different oligonucleotide conformations in solution. The CD spectra of AOEPUT and APAPA supported the non-equivalent role that the outer ammonium groups of spermidine, N1 and N8 positions, could have in the interaction of this biogenic polyamine with DNA.

Characterization by Raman spectroscopy of conformational changes on guanine–cytosine and adenine–thymine oligonucleotides induced by aminooxy analogues of spermidine

AbstractThe interactions between aminooxy analogues of the biogenic polyamine spermidine and selected 15‐mer oligodeoxyribonucleotides with alternating purine–pyrimidine base sequences, adenine–thymine (AT) and guanine–cytosine (GC), have been studied using Raman spectroscopy. These analogues resulted from the substitution of the two terminal aminomethylene groups of spermidine, +NH3CH2, by an aminooxy one, H2NO. Since this biogenic polyamine has no centre of symmetry, there are two different isosteric molecules, which have been named AOEPUT and APAPA. However, the pKa of an aminooxy group (about 5) is not high enough to be protonated at neutral pH. Therefore, under physiological conditions, these analogues have a positive charge less than spermidine, which makes them suitable models to investigate the roles of both charge and structure in the polyamine–DNA interactions. Raman spectra of solutions containing different concentrations of the analogues, from 10 to 75 mM, and either a GC and an AT oligonucleotide, at a fixed concentration 60 mM (in phosphate), were recorded. The spectra demonstrated the existence of strong differences in the oligonucleotide‐analogue interactions depending on the base sequences. In the presence of the aminooxy analogues, a 15‐mer GC oligonucleotide adopted a highly ordered tertiary structure (aggregate state or Ψ‐DNA) and, at the same time, it changed its secondary structure (from B to Z‐DNA). Evidence of macromolecular transitions was not achieved from the Raman spectra of a 15‐mer AT oligonucleotide. However, the assignments of the Raman bands indicated that both H2NO groups of the aminooxy analogues and exocyclic NH2 groups of the oligonucleotides could act as preferential binding sites. However, different spectral features were observed between AOEPUT and APAPA in the presence of the oligonucleotides. This fact supports the idea that the two amino terminal groups of spermidine could have different roles in the interaction of this biogenic polyamine with DNA. Our results also confirm that the aminooxy analogues of biogenic polyamines could act as stabilizers of non‐viral transfection vectors, thus improving the efficiency of gene therapy protocols. Copyright © 2004 John Wiley & Sons, Ltd.

Isosteric molecules in non-isomorphous structures: A new route to new structures. The example of 9,10-dihaloanthracene

When isosteric molecules with non-isomorphous structures are combined into solid solutions they may arrange in yet another way: despite their obvious similarity at molecular level, 9,10-dichloro- and dibromoanthracene differ clearly in their crystal structures. From these two components a solid solution with the latter compound as the minor constituent can be obtained as a phase pure product—it represents an entirely new structure type.

Molecular dynamics simulation of aqueous solutions of trimethylamine-N-oxide and tert-butyl alcohol

In this work we have investigated hydration properties of aqueous solutions up to a solute molar fraction X2 = 0.125 of two isosteric molecules – the bioprotectant trimethylamine-N-oxide (TMAO) and the denaturant tert-butyl alcohol (TBA) – using molecular dynamics simulation at 298 K. Statistical analyses of the trajectories show in particular that as the solute concentration increases the number of the water molecules in the first hydration shell decreases uniformly for TMAO, while for TBA it decreases more rapidly in a concentration range where experiments indicate that TBA starts to self-aggregate. No appreciable solute segregation occurs for TMAO even in the most concentrated solution, where on the average each water molecule is shared by two solutes. This result parallels what has been recently found for glycine betaine, an organic osmolyte closely related to TMAO.

Structural Studies of Enantiomers, Racemates, and Quasiracemates. 2-(2,4,5-Trichloroanilino)propanoic Acid and 2-(2,4,5-Trichlorophenoxy)propanoic Acid

Cocrystallization of equimolar quantities of (S)-2-(2,4,5-trichloroanilino)propanoic acid and (R)-2-(2,4,5-trichlorophenoxy)propanoic acid yields molecular crystals with approximate centrosymmetric frameworks. Such molecular assemblies, termed quasiracemates, are constructed of pairs of isosteric molecules that differ in handedness and chemical composition. Despite the different hydrogen-bonding possibilities of the anilino −NH− and phenoxy −O− groups, the principal quasiracemate components align via topological influences to form molecular architectures nearly indistinguishable from the “true” racemic structures. The relation of molecular shape to crystal packing is examined in light of the complete family of structures (i.e., quasiracemate, racemates, and enantiomers) and the imposed −NH− and phenoxy −O− structural differences.

Electronic structures of analogous and isoelectronic main group and transition metal compounds - a gas phase (UV)-photoelectron spectroscopic and theoretical study

HeI/II-photoelectron (PE) spectra or respective ionisation potentials and results from self-consistent-charge Xα (SCC-Xα) MO calculations are presented for representative pairs of isosteric molecules from related transition metal and main groups with special emphasis on group 5 15 species (AsF 5/VF 5, Me 3AsCl 2/Me 3TaCl 2, Cl 3PNMe/Cl 3VNMe) and related compounds.

ChemInform Abstract: THE ELECTRONIC STRUCTURE OF 6A‐THIOTHIOPHTHEN AND RELATED MOLECULES‐ NON‐EMPIRICAL CALCULATIONS AND REASSIGNMENT OF THE PHOTOELECTRON SPECTRA

Abstract Non-empirical calculations of the electronic structure of the 2,5-dimethyl derivative of the title compound, and the isosteric molecules (1b–4b; 5a, b) formed by replacement of the 1- and/or 6-sulphur atoms by O or NMe are reported. A reassignment of the photoelectron spectra of the molecules in the light of these calculations, and using intensity changes between the unsubstituted and dimethyl derivatives, and substituent effects, shows substantial differences from those recently reported.

The electronic structure of 6a-thiothiophthen and related molecules: non-empirical calculations and reassignment of the photoelectron spectra

Non-empirical calculations of the electronic structure of the 2,5-dimethyl derivative of the title compound, and the isosteric molecules ( 1b–4b; 5a, b) formed by replacement of the 1- and/or 6-sulphur atoms by O or NMe are reported. A reassignment of the photoelectron spectra of the molecules in the light of these calculations, and using intensity changes between the unsubstituted and dimethyl derivatives, and substituent effects, shows substantial differences from those recently reported.