First Experimental Quantitative Charge Density Studies of Advanced Intermediate of Vitamin D Analogues.

Monika Wanat,Andrzej Kutner,Krzysztof Woźniak,Maura Malinska

doi:10.3390/molecules27061757

Abstract

Vitamins D are a group of fat-soluble secosteroids which play a regulatory role in the functioning of most cells. Rational design of new vitamin D analogs, of increased therapeutic potency and lowered calcemic side effects, requires high-resolution initial structures and a deep understanding of interactions with the molecular targets. In this paper, using quantum crystallography, we present the first determination of the experimental quantitative charge density of an advanced intermediate of vitamin D analogues as well as a reconstruction of the theoretical electron density of final vitamin D analogues. Application of these methods allows for topological and electrostatic interaction energy analysis. We showed that the A-ring chair conformation has a significant influence on the topological properties of vitamin D compounds. Moreover, the interactions between the CD-ring and side-chain additionally stabilize the crystal structure. These results are supported by our theoretical calculations and previous biological studies.

Highlights

The activity of vitamins D is mostly expressed through the binding to the vitamin D receptor (VDR)
We have demonstrated that it is the polymorphism of the VDR gene and the level of the total VDR that is responsible for the sensitivity of human leukemia and lymphoma cells to vitamin D
In our previous X-ray studies of four new vitamin D analogues [10] we revealed that it was the hydrogen bond between 1- and 3-hydroxyls that led to the β-conformation of the A-ring

Summary

Introduction

Cholecalciferol (vitamin D3 ) are the two major forms activated by hydroxylations at the C-1 and C-25 carbon atoms (Figure 1). As a result of the wide presence of VDR in most systems, i.e., immune, muscle and circulatory, active vitamins D regulate the functions of most cells For this reason, vitamin D analogues have found broad therapeutic applications, for instance, against secondary hyperparathyroidism (paricalcitol), and psoriasis (calcipotriol, Figure 2, and tacalcitol) [2–6]. The data collection of high-resolution XRD data of this class of compounds was not achieved This is a result of poor quality and low scattering power of crystals of (with additional 2-methylene group), which are currently in clinical trials [6] against prosvitamin D analogues. The experimental quantitative charge density studies for tate tumor and psoriasis, respectively This shows the influence of the exocyclic methylene this group of compounds have not been performed, i.e., studies that require high-resolumethylene on theactivity biological activity of vitamin D analogues and its importance in vitaminon the biological of vitamin. This is the first work where high-resolution data of an advance intermediate of

Objectives

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Results

Conclusion