title: Synthesis of C-2 substituted vitamin D derivatives having ringed side chains and their biological evaluation, especially biological effect on bone by modification at the C-2 position.
abstract: In order to obtain vitamin D derivatives, which have strong activity for enhancing bone growth, we designed vitamin D derivatives with various substitutions at the C-2 position. Novel 2 α-substituted vitamin D derivatives were synthesized starting from d-glucose as a chiral template of the A-ring with a CD-ring bromoolefin unit using the Trost coupling method. We evaluated these compounds by two in vitro assays, affinity to VDR and transactivation assays, using human osteosarcoma (Hos) cells, and demonstrated the SAR of the C-2 position of VD(3). Furthermore, by using the OVX model, we found that compound 5c, which has a hydroxypropoxy side chain at C-2 and 2,2-dimethyl cyclopentanone in the CD-ring side chain, has a strong activity for enhancing bone growth, same as the reported compound, 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D(3)1d, and this derivative shows a possibility that calcemic activity is less than 1d in vivo.
authors.affiliation: Teijin Institute for Bio-Medical Research, Asahigaoka, Hino, Tokyo, Japan. hi.saitou@teijin.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saitoh
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chida
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Takagi
authors.forename: Kyohei
authors.initials: K
authors.lastname: Horie
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sawai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Harada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D010052:Ovariectomy; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D