Crystal and Molecular Structure and DFT Calculations of the Steroidal Oxime 6E-Hydroximino-androst-4-ene-3,17-dione (C19H25NO3) a Molecule with Antiproliferative Activity

Rex A Palmer,David R Lisgarten,Ranju Bansal,Trevor Dines,Jeremy K Cockcroft,Rosemary Talbert,Amruta Suryan,Pratap Chandra Acharya,John N Lisgarten

doi:10.1007/s10870-018-0747-x

Abstract

The single crystal X-ray structure of the novel steroid derivative, 6E-hydroximino-androst-4-ene-3,17-dione (C19H25NO3) (code name RB-499), possessing antiproliferative activity against various cell lines is presented. The analysis produced the following results: chemical formula C19H25NO3; Mr = 315.40; crystals are orthorhombic space group P212121 with Z = 4 molecules per unit cell with a = 6.2609(2), b = 12.5711(4), c = 20.0517(4) Å,Vc = 1578.18(7) Å3, crystal density Dc = 1.327 g/cm³. Structure determination was performed by direct methods, Fourier and full-matrix least-squares refinement. Hydrogens were located in the electron density and refined in position with isotropic thermal parameters. The final R-index was 0.0324 for 3140 reflections with I > 2σ and 308 parameters. The Absolute Structure Parameter − 0.07(5) confirms the correct allocation of the absolute configuration. The presence of the double bond C=O at position 3 in Ring A has caused a distortion from the usual chair conformation and created an unusual distorted sofa conformation folded across an approximate m-plane through C(1)–C(4). Ring B is a distorted chair, its conformation being influenced by the presence of the C(6)=N(6)–O(6)H group in position 6. Ring C is a symmetrical chair. Ring D exhibits both a distorted mirror symmetry conformation [influenced by the C(17)=O(17) group] and a distorted twofold conformation. DFT calculations indicated some degree of flexibility in rings A, C and D with ring A showing the greatest variation in torsion angles. The crystal packing is governed by H-bonds involving O(3), O(6) and O(17). DFT calculations of bond distances and angles, optimized at the B3LYP/6–31++G(d,p) level, were in good agreement with the X-ray structure.Graphical Ring A conformations: (a) Experimental and (b) Calculated. The differences in torsion angle values indicate a degree of flexibility in the ring. The ring conformations are shown in Figures (ii) and (iv) respectively (drawn with BIOVIA [12]. Regions A1 and A2 are approximately planar in both, being planar within 0.048 Å and 0.105 Å respectively.

Highlights

X‐Ray Data Collection and ResultsSteroidal oximes have emerged as a new class of anticancer agents with either endocrine activity against aromatase and 5α-reductase enzymes or direct cytotoxicity on human cancer cells [1, 2]
C6=N6–O6-H6 showing the geometry in a the experimental structure and b the calculated structure general, similarities in the A-ring region and dissimilarities in the D-ring region were observed when the structures of agonists and antagonists of specific steroid hormones were compared
The present high resolution X-ray structure revealed an unusual Ring A conformation associated with the double bond C(4)=C(5)

Summary

Graphical Abstract

Ring A conformations: (a) Experimental and (b) Calculated. The differences in torsion angle values indicate a degree of flexibility in the ring. The ring conformations are shown in Figures (ii) and (iv) respectively Regions A1 and A2 are approximately planar in both, being planar within 0.048 Å and 0.105 Å respectively. Keywords Steroidal oximes · Cytotoxic steroids · Antiproliferates · Crystal structure · X-ray crystallography · DFT calculations

Introduction

Discussion of the Crystal Structure

Conclusions and Proposed Future