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

• Published in: Organic & biomolecular chemistry Vol. 9; no. 10; p. 3954
• Main Authors: Saitoh, Hiroshi, Chida, Takayuki, Takagi, Kenichiro, Horie, Kyohei, Sawai, Yoshiyuki, Nakamura, Yuko, Harada, Yoshifumi, Takenouchi, Kazuya, Kittaka, Atsushi
• Format: Journal Article
• Language: English
• Published: England 21-05-2011
• Subjects: Animals; Bone and Bones - drug effects; Bone and Bones - physiology; Bone Density - drug effects; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; Female; Humans; Ovariectomy; Rats; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Transcriptional Activation - drug effects; Vitamin D - analogs & derivatives; Vitamin D - chemical synthesis; Vitamin D - metabolism; Vitamin D - pharmacology
• ISSN: 1477-0539
• DOI: 10.1039/c1ob05142c

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.