Title:Double Point Modified Analogs of Vitamin D as Potent Activators of Vitamin D Receptor
VOLUME: 21 ISSUE: 13
Author(s):Sharmin Nadkarni, Michal Chodynski, Aoife Corcoran, Ewa Marcinkowska, Geoffrey Brown and Andrzej Kutner
Affiliation:Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
Keywords:Antiproliferative activity, binding affinity, calcemic effect, cell differentiation, convergent synthesis, transcriptional activity,
vitamin D analog, X-ray crystallography.
Abstract: Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation
are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics
over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding
domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two
remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional
activity and lowered calcemic side effect. Recent in vivo experiments clearly demonstrated the potential use of
these analogs in new therapeutic areas such as autoimmune and hyper-proliferative diseases, including cancer and
the systemic treatment of psoriasis. Although some of these analogs are already approaching clinical trials, the molecular
mechanism of action and their improved efficiency still remain to be fully understood. In this review the key steps of the convergent
synthetic strategies that combine the modified A-ring and the CD-ring fragment carrying the altered side-chain are presented. The
advantages of using the natural alicyclic and acyclic precursors are demonstrated as well as all the modern synthetic methodologies used
for combining structural fragments. The results of molecular mechanics modeling are critically examined as well as the advantages and
limitations of the use of the models of vitamin D proteins for the docking experiments and the design of new analogs. The potential use
of advanced structural approaches, including high resolution X-ray crystallography, is discussed as to the prospect of providing a better
understanding of the observed activity of modified analogs. Biological profiles in vitro and in vivo for groups of analogs are presented in
a new tabular form to illustrate structure activity relationships.
