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

• Published in: Journal of steroid biochemistry and molecular biology Vol. 89-90; no. 1-5; pp. 31 - 34
• Main Authors: TAKENOUCHI, Kazuya, SOGAWA, Ryo, MANABE, Kenji, SAITOH, Hiroshi, QINGZHI GAO, MIURA, Daishiro, ISHIZUKA, Seiichi
• Format: Conference Proceeding Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.05.2004
• Subjects: Biological and medical sciences; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - chemistry; Calcitriol - pharmacology; Cholecalciferol - antagonists & inhibitors; Diseases of the osteoarticular system; Fundamental and applied biological sciences. Psychology; Medical sciences; Osteoporosis. Osteomalacia. Paget disease; Structure-Activity Relationship; Vertebrates: endocrinology; Paget disease; Molecular mechanism; Diseases of the osteoarticular system; Biosynthesis; Bone disease; Antagonists; Vitamin D analogues; Synthesis; Vitamin D; Antagonist; Molecular biology; Colecalciferol; Paget's disease of bone
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2004.03.046

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.