S. Marczak et al. / Bioorg. Med. Chem. Lett. 11 (2001) 63±66
65
Scheme 3. Preparation of the ring A building block and the coupling reaction. (a) Dess±Martin reagent, CH2Cl2, 90%; (b) n-BuLi, THF, then 16
and 17 and after 1 h AcCl, 78!25 ꢀC; (c) Na±Hg, MeOH/Na2HPO4, 20 ꢀC, 45% overall from 12; (d) TBAF/4 A MS, THF, 80%.
Acknowledgements
from 15 (ratio 60:40, respectively, by NMR). These
experiments show that under the conditions of ole®na-
tion simultaneously with acetylation of the very steri-
cally hindered hydroxy group at C7, partial exchange of
the protective triethylsilyl group for the acyl group at
the C25 has also occurred. The mixture 19 was next
Financial support from the Polish State Committee for
Scienti®c Research is acknowledged (Grant No. 3 T09A
134 18).
.
treated with TBAF H2O and 4 A molecular sieves in
THF and the products were separated by ¯ash chroma-
tography to give triol 3 (27% yield from 16±17) and its
C25-acetate (8.4% yield). HPLC analysis of thus pre-
pared vitamin D analogue 3 (Nucleosil, EtOAc±
CH2C12, 1:1) indicated its contamination with small
amounts of double bond isomers.14 Finally, a sample of
3 was puri®ed by HPLC and its structure was con®rmed
by spectroscopic measurements (MS, UV, 1H NMR,
CD).
References
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In the biological screening15 the vitamin D analogue 3
displayed signi®cant binding anity to the vitamin D
receptor (11% compared to 1a,25-dihydroxyvitamin
D3). In cellular systems derivative 3 exerted weak ago-
nistic activity. Thus, the dierentiation of HL 60 cells to
monocytes is induced at dosages above 100 nM and the
inhibition of the proliferation of human peripheral
blood mononuclear cells (PBMC) occurs in the same
dose range. Upon administration to mice, the com-
pound is much better tolerated than 1a,25-dihydroxy-
vitamin D3. Whereas 1a,25-dihydroxyvitamin D3
induces hypercalcemia at dosages as low as 0.1 mg/kg,
analogue 3 does not aect serum calcium levels at
10 mg/kg.
In
conclusion,
(1S,14S,17S,20S)-1a,25-dihydroxy-
vitamin D3 (3) diering from the parent natural product
in con®guration at four asymmetric carbon atoms was
synthesized and shown to have signi®cant binding a-
nity for the vitamin D receptor.
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