Electronic effects of 11β substituted 17β-estradiol derivatives and instrumental effects on the relative gas phase acidity.
Numerous studies have highlighted the role of the proton donor characteristics of the phenol group of 17β-estradiol (E(2)) in its association with the estrogen receptor alpha (ERα). Since the substitutions at position C((11)) have been reported to modulate this association, we hypothesized that such substitutions may modify the phenol acidity. Hence, phenol gas-phase acidity of nine C((11))-substituted E(2)-derivatives were evaluated using the extended Cooks' kinetic method, which is a method widely used to determine thermochemical properties by mass spectrometry. To enhance accuracy in data collection we recorded data from several instruments, including quadrupole ion trap, triple quadrupole, and hybrid QqTOF. Indeed, we report for the first time the use of the QqTOF instrument to provide a novel means to improve data accuracy by giving access to an intermediate effective temperature range. All experimental gas-phase acidity values were supported by theoretical calculations. Our results confirmed the ability of distant substituents at C((11)) to modulate the phenol acidity through electrostatic interactions, electron withdrawing inductive effects, and mesomeric effects. However, no relationship was found between the phenol gas-phase acidity of investigated steroids and their binding affinity for ERα assessed in solution. Thus, our results highlight that the intrinsic properties of the hormone do not influence sufficiently the stabilization of the hormone/ERα complex. It is more likely that such stabilization would be more related to factors depending on the environment within the binding pocket such as hydrophobic, steric as well as direct intermolecular electrostatic effects between ERα residues and the substituted steroidal estrogens.
Equipe de Spectrométrie de masse, Institut Parisien de Chimie Moléculaire, UMR 7201, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75252, Paris Cedex 05, France.
Sandrine
S
Bourgoin-Voillard
Françoise
F
Fournier
Carlos
C
Afonso
Emilie-Laure
EL
Zins
Yves
Y
Jacquot
Claude
C
Pèpe
Guy
G
Leclercq
Jean-Claude
JC
Tabet
D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005740:Gases / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D013058:Mass Spectrometry / Q000295:instrumentation* / Q000379:methods*; D008958:Models, Molecular; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D013696:Temperature
D047628:Estrogen Receptor alpha; D005740:Gases; D011994:Recombinant Proteins; D004958:Estradiol