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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]

The d-homo androstane lactone 3β-hydroxy-17-oxa- d-homoandrost-5-en-16-one ( I) was transformed through intermediate compounds 17-oxa- d-homoandrost-4-ene-3,16-dione ( II) and/or 17-oxa- d-homoandrost-4-ene-3,6,16-trione ( III) to 3( E),6( E)-dihydroximino-17-oxa- d-homoandrost-4-en-16-one ( IV), which was characterized using analytical and spectral data. Compound IV was examined by X-ray crystallography, IR and NMR spectroscopy. Compound IV crystallized in a monoclinic system with a P2 space group. The dimensions of the unit cell are: a = 11.2815(5) Å; b = 13.1512(4) Å; c = 13.7145(8) Å; β = 110.890(5)°. The asymmetric unit cell consists of two symmetrically independent molecules ( A and B) of 3( E),6( E)-dihydroximino-17-oxa- d-homoandrost-4-en-16-one and one methanol molecule. In the molecular structure of compound IV, two molecules in the asymmetric unit are connected by O-H···N hydrogen bonds, while the crystal packing of compound IV is predominantly organized by a dense network of O-H···O hydrogen bonds, mostly involving the O atom from the methanol molecule as donor or acceptor. Derivatives I-IV were screened for antitumor activity against six human cancer cell lines and one non-tumor cell line. Graphical Abstract: The d-homo androstane lactone (3β-hydroxy-17-oxa- d-homoandrost-5-en-16-one) I was transformed through intermediate compounds 17-oxa- d-homoandrost-4-ene-3,16-dione ( II) and/or 17-oxa- d-homoandrost-4-ene-3,6,16-trione ( III) to 3( E),6( E)-dihydroximino-17-oxa- d-homoandrost-4-en-16-one ( IV) which was characterized according to the analytical and spectral data. Compound IV was examined by X-ray crystallography, IR and NMR spectroscopy. Derivatives I-IV were screened for antitumor activity against six human cancer cell lines and one non-tumor cell line.[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]