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

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.