C15-functionalized 16-ene-1α,25-dihydroxyvitamin D3 is a new vitamin D analog with unique biological properties.
The Δ(16) structure as a vitamin D analog enhanced vitamin D receptor (VDR) binding affinity and induced significant cell differentiation, whereas its relative calcemic activity was reduced compared to 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)). Methodologies available to introduce a double bond at C16-C17 of the D-ring on the seco-steroidal skeleton were limited; therefore, a new synthetic strategy was developed to obtain not only the Δ(16) structure, but also a new C15-functional group. Since C15-functionalization was unprecedented in vitamin D analog studies, the hybrid structure of Δ(16) and the C15-OH group at the D-ring may provide important information on the structure-activity relationship with vitamin D analogs. The synthesized 16-ene-2α-methyl-1α,15α,25-trihydroxyvitamin D(3) showed almost 3-times higher VDR binding affinity and an equipotent level of osteocalcin promoter transactivation activity in human osteosarcoma cells as compared to 1α,25(OH)(2)D(3).
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa 252-5195, Japan.
Go
G
Kumagai
Masashi
M
Takano
Kanako
K
Shindo
Daisuke
D
Sawada
Nozomi
N
Saito
Hiroshi
H
Saito
Shinji
S
Kakuda
Ken-ichiro
K
Takagi
Midori
M
Takimoto-Kamimura
Kazuya
K
Takenouchi
Tai C
TC
Chen
Atsushi
A
Kittaka
D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D006801:Humans; D006887:Hydroxycholecalciferols / Q000494:pharmacology*; D015675:Osteocalcin / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology*
C570239:16-ene-2-methyl-1,15,25-trihydroxyvitamin D3; D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D015675:Osteocalcin; D014807:Vitamin D