Novel vitamin D analogs as potential therapeutics: metabolism, toxicity profiling, and antiproliferative activity.
OBJECTIVE
To discover novel [20(OH)D3] analogs as antiproliferative therapeutics.


METHODS
We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism.


RESULTS
20S- and 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 μg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes.


CONCLUSIONS
Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.
Department of Pharmaceutical Science, University of Tennessee Health Science Center, 847 Monroe Avenue, Memphis, TN 38163, U.S.A. wli@uthsc.edu.
Jianjun
J
Chen
Jin
J
Wang
Tae-Kang
TK
Kim
Elaine W
EW
Tieu
Edith K Y
EK
Tang
Zongtao
Z
Lin
Dianne
D
Kovacic
Duane D
DD
Miller
Arnold
A
Postlethwaite
Robert C
RC
Tuckey
Andrzej T
AT
Slominski
Wei
W
Li
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D006207:Half-Life; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects*; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D014807:Vitamin D
20(OH)D3 analogs; VDR translocation; hypercalcemic effect; liver microsomal stability