Molecular Recognition of Steroid Hormones in the Solid State: Stark Differences in Cocrystallization of β-Estradiol and Estrone

Abstract

While the understanding of the supramolecular chemistry of steroidal hormones is largely based on receptor binding studies in vitro and in vivo, their solid-state molecular recognition properties remain unexplored. Here, we use mechanochemical cocrystallization and single crystal X-ray structure analysis to gain insight into the solid-state complexation of sex hormones with arenes, by systematic investigation of the ability of two important estrogens ß-estradiol (bes) and estrone (est) to form cocrystals with 1,2-dimethylnaphthalene, phenanthrene, anthracene, 9,10-anthraquinone, phenanthridine, benzo[h]quinoline, and perfluoronaphthalene. Cocrystallization of bes reveals the formation of a novel hydrogen-bonded lattice host, exhibiting rectangular channels occupied by arene guests. In striking contrast to bes, its 17-keto-analogue est did not yield cocrystals with any of the explored arenes except perfluoronaphthalene, revealing association via arene-perfluorarene π•••π stacking. The results reveal previously unknown solid-state complexation behavior of important estrogen hormones, demonstrating how minor changes in the steroid structure, in particular switching from a 17-hydroxyl to a 17-keto group, can result in extraordinary changes to their solid-state self-assembly. In that respect, solid-state chemistry of steroids appears to mirror their important signaling role in biological systems, as very small modifications to the steroid structure lead to large changes in cocrystallization propensity.

The solid state forms of the sex hormone 17-β-estradiol

“…39,40 The extension to co-crystallization with larger molecules has been partially in-vestigated, with cocrystals with isonicotinamide (ULUFIS) and piperazine dihydrate (ULUFOY) being reported from a search for increased solubility, 41 and with pyrene (CUTBEZ), phenanthrene (RUGYID), benzo[h]quinoline (RUFYIC) and 1,2-dimethylnapthalene (RUFOY) in investigations of the molecular recognition of steroids. 42,43 The crystal energy landscape ( Fig. 7) suggests that other polymorphs of BES are highly likely, although Form I may well be the most thermodynamically stable form given the accuracy of the calculations.…”

Mechanochemistry in Portugal—A Step towards Sustainable Chemical Synthesis

“…André, in collaboration with Friščić´s team, disclosed novel cocrystals of ß-estradiol and estrone with 1,2-dimethylnaphthalene, phenanthrene, anthracene, 9,10-anthraquinone, phenanthridine, benzo[h]quinoline, and perfluoronaphthalene [ 57 ]. Knowledge of the molecular recognition and complexation of steroids was already an established area of research, and solid-state chemistry, along with crystal engineering, had recently been proposed to explore their molecular recognition properties[ 58 ].…”

Chemistry 2.0: Developing a New, Solvent-Free System of Chemical Synthesis Based on Mechanochemistry

“…A subsequent study focusing on cocrystals of β-estradiol established that cocrystallization is not based on a particular type of steroid-arene interaction, but on the assembly of a square-grid hydrogen-bonded β-estradiol host templated exclusively by arene molecules of a specific size. 91 Mechanochemical cocrystallization screening was also utilized to elucidate which elements of a molecular structure are relevant for a small molecule to act as a template for the assembly of different hydrogen-bonded hosts based on caffeine and succinic acid (Figure 7 a). 73 A screen of a small library of 16 potential guest molecules based on differently substituted methane derivatives revealed that the formation of a host framework takes place only if the size of the potential guest lies between 3.5 Å and 3.8 Å (Figure 7 a).…”