| Summary: | An efficient synthesis of several A- and B-modified D-homo lactone androstane
derivatives from 3β-hydroxy-17-oxa-D-homoandrost-5-en-16-one (1) is reported.
17-Oxa-Dhomoandrost- 4-ene-3,16-dione (2), obtained by the Oppenauer
oxidation of compound 1, was converted via the unstable intermediate
3,16-dioxo-4,17-dioxa-D-homoandrostane- 5α-carboxaldehyde (3) to
17-oxa-D-homo-3,5-seco-4-norandrostan-5-one-3-carboxylic acid (4), which was
also obtained directly from compound 2. Compound 1 was acetylated to give
17-oxa-D-homoandrost-5-en-16-on-3β-yl acetate (5) which was then oxidized
with chromium(VI)-oxide in 50% acetic acid or with meta-chlorperbenzoic acid
and chromium(VI)-oxide to yield compounds 6-8 and
5α-hydroxy-17-oxa-D-homoandrostane- 6,16-dion-3β-yl acetate (9),
respectively. The oximination of compound 9 gave a mixture of
6(E)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate (10)
and 6(Z)-hydroximino-5α-hydroxy-17-oxa-D-homoandrostan-16-on-3β-yl acetate
(11), the hydrolysis of which gave
6(E)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan- 16-one (12) and
6(Z)-hydroximino-3β,5α-dihydroxy-17-oxa-D-homoandrostan-16-one (13).
6-Nitrile-17-oxa-5,6-seco-D-homoandrostane-5,16-dion-3β-yl acetate (14) was
obtained under the Beckmann fragmentation of compounds 10 and 11. Only pure
and stable compounds (1, 2, 4, 5, 9 and 14) were tested in vitro on six
malignant cell lines (MCF-7, MDA-MB-231, PC-3, HeLa, HT-29, K562) and one
non-tumor MRC-5 cell line. Significant antiproliferative activity against
MDA-MB-231 cells showed compounds 1, 5 and 9, while compound 2 exhibited a
strong antiproliferative activity. Only compound 14 showed weak
antiproliferative activity against MCF-7 cells. All tested compounds were not
toxic on MRC-5 cells, whereas Doxorubicin was highly toxic on these cells.
[Projekat Ministarstva nauke Republike Srbije, br. 172021]
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