Synthesis and structure–activity relationships of TEI-9647 derivatives as Vitamin D 3 antagonists

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 89; pp. 31 - 34
• Main Authors: Takenouchi, Kazuya, Sogawa, Ryo, Manabe, Kenji, Saitoh, Hiroshi, Gao, Qingzhi, Miura, Daishiro, Ishizuka, Seiichi
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.05.2004
• Subjects: Antagonists; Molecular mechanism; Paget’s disease of bone; Vitamin D analogues; Antagonists; Molecular mechanism; Vitamin D analogues; Paget’s disease of bone
• DOI: 10.1016/j.jsbmb.2004.03.046
• ISSN: 0960-0760

The Vitamin D 3 lactone analogues, (23 S)- and (23 R)-25-dehydro-1α-hydroxyvitamin D 3-26,23-lactone (TEI-9647 and TEI-9648) are antagonists of the 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2D 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: α-exo-methylene-γ-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 “α-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 α-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.