1. Academic Validation
  2. Synthesis and structure-activity relationships of TEI-9647 derivatives as Vitamin D3 antagonists

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

  • J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):31-4. doi: 10.1016/j.jsbmb.2004.03.046.
Kazuya Takenouchi 1 Ryo Sogawa Kenji Manabe Hiroshi Saitoh Qingzhi Gao Daishiro Miura Seiichi Ishizuka
Affiliations

Affiliation

  • 1 TEIJIN Institute for Bio-medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan. [email protected]
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 activity. The structure is integral building block of many Natural Products which have interesting biological and it is thought that Michael-type addition of alpha-exo-methylene carbonyl structure with protein nucleophiles such as cysteine would play an important role for the activities. According to this theory, Michael-type reaction of TEI-9647 and TEI-9648 with cysteine residue in protein related to VDR/VDRE-mediated genomic actions such as VDR would be essential step of the antagonistic action.

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