Abstract text (incl. figure legends and references)

Introduction. Vitamins D are a group of fat-soluble secosteroids. Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are major forms of vitamins D which occur in fungi and animal organisms.[1] 1α,25-Dixydroxyvitamin D2 (ercalcitriol, 1,25(OH)2D2) and 1α,25-dihydroxyvitamin D3 (calcitriol, 1,25(OH)2D3) are the most active forms of vitamin D2 and D3, respectively. The biological activity of vitamins D (Fig. 1) is expressed mostly through the interactions with the nuclear vitamin D receptor (VDR). VDR, after binding natural agonists, calcitriol or ercalcitriol, forms the heterodimer with nuclear retinoid X receptor (RXR). This complex binds with DNA and regulate the vitamin D-dependent gene expression. Autoimmune diseases such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and others such as influenza or tuberculosis occur more often in countries with limited access to sunlight and thus the lowered vitamin D endogenous production.

Objectives and results. We will present details of series of structures of the studied derivatives of the vitamin D resulting from kinematic refinement of the electron diffraction data collected in our Lab., comparison of the ED structures with known X-ray structures of the corresponding vitamin D derivatives, results of HAR and TAAM refinements [2] based on aspherical atomic electrostatic potentials and utilizing results of kinematic refinement, and, hopefully, also results of dynamical refinement [3] for the best ED data sets.

Materials. Only a small number of the vitamin D analogues crystalize well enough for structural X-ray studies [4-6]. We have previously solved the X-ray structure of the synthetic precursor of 1,25(OH)2D2, i.e. 1a-hydroxyvitamin D2 (1a-OH-D2) and showed that the molecule adopts exclusively an A-ring chair b-conformation [7]. Most vitamin D compounds form nanocrystals which can be structurally characterized only by more advanced techniques, including electron diffraction (ED). In this communication, we will also present ED structures of 1,25(OH)2D3 analogs, the side-chain, and A-ring modified VDR agonists coded PRI-2204 and PRI-1901, respectively.

References

1 A. Norman, Vitamin D; Elsevier, 2012; ISBN 978-0-323-14143-7; S. Kato, J. Biochem. (Tokyo) 127 (2000) 717

2 B. Gruza, M. L. Chodkiewicz, J. Krzeszczakowska, P. M. Dominiak, Acta Cryst.. A76 (2020) 92.

3 L. Palatinus, V. Petricek, C. A. Correa, Acta Cryst., A71 (2015) 235

4 M. Wanat, M. Malinska, A. Kutner, K. Woźniak, Molecules, 27(6) (2022) 1757

5 M. Wanat, M. Malińska, A. Kutner, K. Woźniak, Molecules, 25(8) (2020) 802

6 M. Wanat, M. Malińska, A. Kutner, K. Wozniak, Cryst. Growth Des. 18(6) (2018) 3385

7 WKołodziejski, K. Woźniak, P., J. Herold, M. Dominiak, A. Kutner, J. Mol. Structure,734, (2005) 149

Acknowledgments: This research was funded by the University of Warsaw IDUB grants BOB-IDUB-622-20/2021, IUDUB PSP: 501-D112-20-0006100 and by Polish NCN grant 2020/39/I/ST4/02904.

Figure 1. Structures and the numbering system of vitamins D: (a) 1,25(OH)2D2 (ercalcitiol) and (b) 1,25(OH)2D3 (calcitriol) and structures of the vitamin D analogs studied: (c) PRI-2204, (d) PRI-1901 (Solverol), (e) 1a-hydroxyvitamin D2 and (f) PRI-2191 (Tacalcitol). H-atoms omitted for clarity.