Synthesis and biological evaluation of a series of A,B-ring modified 16,17-secoandrostane derivatives.
The starting compound for the synthesis of 16,17-secoandrostane derivatives with the 4-en-3-on, 1,4-dien-3-on, 4,6-dien-3-on, and 1,4,6-trien-3-on systems was 3beta-hydroxy-17-methyl-16,17-secoandrost-5-en-16-nitrile-17-one (1), the Oppenauer oxidation of which yielded the corresponding 4-en-3-one derivative 2. Dehydrogenation of compound 2 with the aid of 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil) gave the three products: 17-methyl-16,17-secoandrosta-1,4-dien-3,17-dione-16-nitrile (3), 17-methyl-16,17-secoandrosta-4,6-dien-3,17-dione-16-nitrile (4), and 17-methyl-16,17-secoandrosta-1,4,6-trien-3,17-dione-16-nitrile (5). On the other hand, epoxidation of compound 2 resulted in a mixture of alpha and beta isomers of 4,5-epoxy-17-methyl-16,17-secoandrosta-3,17-dione-16-nitrile (6 and 7). Opening of the oxirane rings of the mixture of 6 and 7 by the action of formic acid yielded the 4-hydroxy-4-en derivative 8. Antiaromatase activity and in vitro cytotoxicity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) of selected compounds were evaluated. Compound 2 exhibited a relatively strong inhibition of aromatase and extremely potent cytotoxicity against PC3 cells. Compound 8 showed satisfactory cytotoxicity against MCF-7 cells.
Sakac
Marija
M
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3, 21 000 Novi Sad, Serbia. marijas@ih.ns.ac.yu
Gaković
Andrea
A
Stojanović
Srdjan
S
Djurendić
Evgenija
E
Kojić
Vesna
V
Bogdanović
Gordana
G
Gasi
Katarina Penov
KP
D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry; D001141:Aromatase / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
D000731:Androstanes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D001141:Aromatase