Creative synthesis of novel vitamin D analogs for health and disease.
We report new analogs of 1alpha,25-dihydroxyvitamin D(3) (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 C1alpha and C2alpha positions of 1 to study the biological activity of the mutant VDR. Among our synthetic analogs, 1alpha-methyl-2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) (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 D(3) 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 D(3) (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 1alpha-hydroxylase activity. Finally, we describe design and synthesis of a new TEI-9647 analog, 2alpha-(3-hydroxypropoxy)-24-propyl-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (17), which showed the strongest VDR antagonism. Its IC(50) value is 7.4pM to inhibit differentiation of HL-60 cells induced by 10nM of 1.
Kittaka
Atsushi
A
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 199-0195, Japan. akittaka@pharm.teikyo-u.ac.jp
Saito
Nozomi
N
Honzawa
Shinobu
S
Takenouchi
Kazuya
K
Ishizuka
Seiichi
S
Chen
Tai C
TC
Peleg
Sara
S
Kato
Shigeaki
S
Arai
Midori A
MA
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004194:Disease; D006262:Health; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010001:Osteitis Deformans / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D008024:Ligands; D014807:Vitamin D