Stereochemical effects during [M-H]⁻ dissociations of epimeric 11-OH-17β-estradiols and distant electronic effects of substituents at C₍₁₁₎ position on gas phase acidity

Abstract

The affinity of estradiol derivatives for the estrogen receptor (ER) depends strongly on nature and stereochemistry of substituents in C (11) position of the 17␤-estradiol (I). In this work, the stereochemistry effects of the 11␣-OH-17␤-estradiol (III ␣ ) and 11␤-OH-17␤-estradiol (III ␤ ) were investigated using CID experiments and gas-phase acidity (⌬H°a cid ) determination. The CID experiments showed that the steroids decompose via different pathways involving competitive dissociations with rate constants depending upon the ␣/␤ C (11) stereochemistry. It was shown that the fragmentations of both deprotonated [III ␣ -H] Ϫ and [III ␤ -H] Ϫ epimers were initiated by the deprotonation of the most acidic site, i.e. the phenolic hydroxyl at C (3) . This view was confirmed by H/D exchange and double resonance experiments. Furthermore, the ⌬H°a cid of both epimers (III ␣ and III ␤ ), 17␤-estradiol (I), and 17-desoxyestradiol (II) was determined using the extended Cooks' kinetic method. The resulting values allowed us to classify steroids as a function of their gas-phase acidity as follows:Interestingly, the ␣/␤ C (11) stereochemistry appeared to influence strongly the gas-phase acidity. This phenomenon could be explained through stereospecific proton interaction with -orbital cloud of A ring, which was confirmed by theoretical calculation. . The E 2 /ER␣ complex is stabilized by hydrogen contacts occurring between, on the one hand, the hydroxyl group of phenolic A ring (E 2 ) and Glu-353 as well as Arg-394 of the hormone binding pocket (HBP), and on the other hand, between the 17␤-hydroxyl of D-ring and His-524 (Scheme 1a) [5][6][7]. Moreover, position around the functionalized site at the C (11) position (C ring) seems to contribute to the anchorage of the hormone within this pocket of the receptor [7][8][9][10][11][12][13], suggesting that steric effects at this position are important for binding affinity. Accordingly, we may consider that the proton donor character efficiency could be reinforced through electrostatic effects mediated by the nature and the stereochemistry of substituent in position 11 [14].Mass spectrometry is widely used to characterize diastereoisomeric compound through stereochemical effects [15,16]. Many reviews have described stereochemistry differentiation of the hydroxyl group in gas phase on rigid rings [17][18][19][20][21][22]. The stereochemical effects could provide evidence that the chemical pathways for ion-molecule reaction as well as the dissociation mechanisms promoted by negative charge from stereoisomeric ion species prepared in chemical ionization and electrospray [23]. For instance, the differentiation of alkoxides of trans and cis-cyclohexanediols has been widely described in negative chemical ionization [24 -26]. This technique turned out to be also appropriate to distinguish more complex polycyclic molecules, such as mono-or polyhydroxyl norborneols, saccharides, and steroids [27][28][29][30]. The origin of stereochemical effects in these systems has been described in terms of...

May interstellar leucine react with NO radicals present in interstellar/interplanetary medium? An ion-trap mass spectrometry study

“…A method has been proposed [33,34] and used [35][36][37] to estimate the enthalpies of fragmentations from these curves. To this end, it was suggested to consider the phenomenological appearance energy AEs (AEexp), i.e.…”

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif—Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells

“…9), in agreement with the ability of these compounds to either up Hydrogen bridges involved in E 2 binding (3-OH and 17β-OH), which contribute to the displacement of H12 [5], are found here to be essential for optimal LxxLL recruitment. We show in this study that small hydrophobic substituents in C-11β, as well as the introduction of shows an unexpected behavior that could be relevant to electronic effects [28]. In fact, the nature of the interactions between ligand substituents and the LBD most likely influence the affinity of ERα for coactivators since (-CH 3 ) versus (-CH 2 Cl and -C CH) gave distinct LxxLL binding profiles.…”

“…indicating that particular electronic effects occur in 11β-OH E 2 [28]. Polarity appeared nevertheless of prime importance for LxxLL-containing coregulators recruitment because produced a shift in ERα-LxxLL binding (as compared to the curve generated by E 2 ), similar to that produced by the grafting of -CH 2 Cl of -C CH groups, revealed that it is the whole region around C-11 which exerts an influence on LxxLL recruitment (Fig.…”

Collision induced dissociations of non‐derivatized and trimethylsilyl‐derivatized estradiols: similarities in fragmentation patterns

“…[1] Some aspects of the MS fragmentation of estradiol have been previously addressed. [3,14,15] However, ion structures of important fragments observed in the mass spectrum have not been identified. For example, m/z 244 peak in the EI spectrum of estradiol has been suggested to arise inconclusively from loss of either CO or C 2 H 2 .…”