Tunable recognition of the steroid α-face by adjacent π-electron density

T. Friscic, R. W. Lancaster, Laszlo Fabian, P. G. Karamertzanis

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

We report a previously unknown recognition motif between the a-face of the steroid hydrocarbon backbone and p-electron-rich aromatic substrates. Our study is based on a systematic and comparative analysis of the solid-state complexation of four steroids with 24 aromatic molecules. By using the solid state as a medium for complexation, we circumvent solubility and solvent competition problems that are inherent to the liquid phase. Characterization is performed using powder and single crystal X-ray diffraction, infrared solid-state spectroscopy and is complemented by a comprehensive cocrystal structure prediction methodology that surpasses earlier computational approaches in terms of realism and complexity. Our combined experimental and theoretical approach reveals that the a?p stacking is of electrostatic origin and is highly dependent on the steroid backbone’s unsaturated and conjugated character. We demonstrate that the a?p stacking interaction can drive the assembly of molecules, in particular progesterone, into solid-state complexes without the need for additional strong interactions. It results in a marked difference in the solid-state complexation propensities of different steroids with aromatic molecules, suggesting a strong dependence of the steroid-binding af?nity and even physicochemical properties on the steroid’s A-ring structure. Hence, the hydrocarbon part of the steroid is a potentially important variable in structure-activity relationships for establishing the binding and signaling properties of steroids, and in the manufacture of pharmaceutical cocrystals.
Original languageEnglish
Pages (from-to)13216-13221
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America (PNAS)
Volume107
Issue number30
DOIs
Publication statusPublished - 2010

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