Synthesis and structure-activity relationships of TEI-9647 derivatives as Vitamin D3 antagonists

The Journal of Steroid Biochemistry and Molecular Biology
Kazuya TakenouchiSeiichi Ishizuka

Abstract

The Vitamin D(3) lactone analogues, (23S)- and (23R)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647 and TEI-9648) are antagonists of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. In order to clarify the structure-Vitamin D antagonistic activity relationship, we paid attention to the unique lactone moiety of TEI-9647 and TEI-9648: alpha-exo-methylene-gamma-lactone structure. We synthesized the exo-methylene-modified analogues (methylene saturated, endo-methylene, methylene-deleted, methyl-substituted, dimethyl-substituted, methylene-replaced with dimethyl and cyclopropane) and oxygen-modified analogues (oxygen atom replaced with nitrogen and carbon atom) by convergent method using palladium-catalyzed coupling reaction or direct modification of VD(3) skeleton. The antagonistic activity in HL-60 cell differentiation evaluating system of these analogues revealed that any exo-methylene-modified analogues and nitrogen analogue did not have the antagonistic activity, on the other hand carbon analogue did show. The results suggest that "alpha-exo-methylene carbonyl" structure of VD(3) side-chain is crucial for antagonistic acti...Continue Reading

References

Mar 11, 2000·The Journal of Clinical Investigation·N KuriharaG D Roodman
Jan 10, 2003·Journal of Cellular Biochemistry·Carsten Carlberg

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Citations

Aug 2, 2007·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Nozomi Saito
Jan 16, 2007·The Journal of Steroid Biochemistry and Molecular Biology·Atsushi KittakaMidori A Arai
Jul 28, 2006·Chembiochem : a European Journal of Chemical Biology·Nozomi Saito, Atsushi Kittaka
Jul 19, 2008·Bioorganic & Medicinal Chemistry Letters·Kaori ChoKazuo Nagasawa
Aug 21, 2018·The Journal of Steroid Biochemistry and Molecular Biology·María Julia FerronatoMaría Marta Facchinetti

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