TY - JOUR
T1 - Creative synthesis of novel vitamin D analogs for health and disease
AU - Kittaka, Atsushi
AU - Saito, Nozomi
AU - Honzawa, Shinobu
AU - Takenouchi, Kazuya
AU - Ishizuka, Seiichi
AU - Chen, Tai C.
AU - Peleg, Sara
AU - Kato, Shigeaki
AU - Arai, Midori A.
N1 - Funding Information:
We thank Ms. Junko Shimode and Ms. Akiko Tonoki (Teikyo University) for spectroscopic measurements. This study has been supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#15790015 and 17790019 to N.S., #17790095 to S.H., and #16790027 to M.A.A.), and by Grants-in-Aid from Japan Society for the Promotion of Science (#15590021 and 17590012 to A.K.). N.S. deeply thanks Takeda Science Foundation, and A.K. gratefully acknowledges Uehara Memorial Foundation.
PY - 2007/3
Y1 - 2007/3
N2 - We report new analogs of 1α,25-dihydroxyvitamin D3 (1) in three categories. First, design and synthesis of ligands for a mutant vitamin D receptor (VDR)(Arg274Leu), which possess proper functional groups at both C1α and C2α positions of 1 to study the biological activity of the mutant VDR. Among our synthetic analogs, 1α-methyl-2α-(3-hydroxypropyl)-25-hydroxyvitamin D3 (8) showed 7.3-fold greater transcriptional activity for the VDR(Arg274Leu) than that of 1. Next, we examined the antiproliferative activity of 2-substituted 19-norvitamin D3 analogs on an immortalized normal prostate cell line, PZ-HPV-7, and we found MART 10 (14) showed the activity even at very low concentration of 10-10 to 10-11 M. We also synthesized 25-hydroxy-19-norvitamin D3 (13) using Julia-type olefination to connect between the C5 and C6 positions, effectively, to test it as a prohormone type agent for antiprostate diseases. Synthesized compound 13 showed potent antiproliferative activity in PZ-HPV-7, which has high 1α-hydroxylase activity. Finally, we describe design and synthesis of a new TEI-9647 analog, 2α-(3-hydroxypropoxy)-24-propyl-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (17), which showed the strongest VDR antagonism. Its IC50 value is 7.4 pM to inhibit differentiation of HL-60 cells induced by 10 nM of 1.
AB - We report new analogs of 1α,25-dihydroxyvitamin D3 (1) in three categories. First, design and synthesis of ligands for a mutant vitamin D receptor (VDR)(Arg274Leu), which possess proper functional groups at both C1α and C2α positions of 1 to study the biological activity of the mutant VDR. Among our synthetic analogs, 1α-methyl-2α-(3-hydroxypropyl)-25-hydroxyvitamin D3 (8) showed 7.3-fold greater transcriptional activity for the VDR(Arg274Leu) than that of 1. Next, we examined the antiproliferative activity of 2-substituted 19-norvitamin D3 analogs on an immortalized normal prostate cell line, PZ-HPV-7, and we found MART 10 (14) showed the activity even at very low concentration of 10-10 to 10-11 M. We also synthesized 25-hydroxy-19-norvitamin D3 (13) using Julia-type olefination to connect between the C5 and C6 positions, effectively, to test it as a prohormone type agent for antiprostate diseases. Synthesized compound 13 showed potent antiproliferative activity in PZ-HPV-7, which has high 1α-hydroxylase activity. Finally, we describe design and synthesis of a new TEI-9647 analog, 2α-(3-hydroxypropoxy)-24-propyl-25-dehydro-1α-hydroxyvitamin D3-26,23-lactone (17), which showed the strongest VDR antagonism. Its IC50 value is 7.4 pM to inhibit differentiation of HL-60 cells induced by 10 nM of 1.
KW - Antagonist
KW - Chemical synthesis
KW - Structure-activity relationships
KW - Vitamin D analogs
KW - Vitamin D receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=33947115881&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2006.12.002
DO - 10.1016/j.jsbmb.2006.12.002
M3 - Article
C2 - 17223554
AN - SCOPUS:33947115881
SN - 0960-0760
VL - 103
SP - 269
EP - 276
JO - Journal of Steroid Biochemistry
JF - Journal of Steroid Biochemistry
IS - 3-5
ER -
