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2-(3'-Hydroxypropylidene)-1alpha-hydroxy-19-norvitamin D compounds with truncated side chains
Agnieszka Glebocka1, Rafal R Sicinski, Lori A Plum
1Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland.
The Journal of Steroid Biochemistry and Molecular Biology
|January 16, 2007
Summary
New 19-norvitamin D analogs with a 3'-hydroxypropylidene substituent show potent in vitro activity and similar vitamin D receptor affinity to the natural hormone.
Area of Science:
- Medicinal Chemistry
- Endocrinology
- Organic Synthesis
Background:
- The 2-substituent in 1alpha,25-dihydroxy-19-norvitamin D(3) analogs is crucial for potent biological activity.
- Selective vitamin D analogs are sought for therapeutic applications.
Purpose of the Study:
- To synthesize and evaluate novel 1alpha-hydroxy-19-norvitamin D analogs with a 3"-hydroxypropylidene group at C-2 and a truncated side chain.
- To assess the in vitro activity and vitamin D receptor (VDR) binding affinity of these new compounds.
Main Methods:
- Convergent synthesis strategies were employed to prepare the target vitamin D analogs.
- Key steps included the synthesis of Grundmann ketones and Wittig-Horner coupling with a phosphine oxide intermediate.
- Purification and characterization of the final 19-norvitamin compounds (7-11).
Main Results:
- All synthesized 1alpha-hydroxy-19-norvitamin D analogs, except for the 20R-compound, demonstrated significant in vitro activity.
- These analogs exhibited comparable or slightly reduced binding affinity to the vitamin D receptor (VDR) compared to the natural hormone 1alpha,25-(OH)(2)D(3).
- The compounds effectively induced differentiation of HL-60 cells into monocytes, similar to the natural hormone.
Conclusions:
- The 3 ahydroxypropylidene substituent at C-2 is a key structural feature for potent vitamin D analog activity.
- These novel 19-norvitamin D analogs represent promising candidates with potential therapeutic applications due to their VDR interaction and cellular effects.
- The synthetic route provides an efficient method for accessing these biologically active vitamin D derivatives.
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