Synthesis of some epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives and evaluation of their biological activity.
Steroidal epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives have been prepared using 3beta,17beta-dihydroxy-17alpha-picolyl-androst-5-ene (1), 3beta-acetoxy-17-picolinylidene-androst-5-ene (2), and 3beta-hydroxy-17-picolinylidene-androst-5-ene (3) as synthetic precursors. The compounds 2 and/or 3 were reacted with m-chloroperoxybenzoic acid (MCPBA). The compounds synthesized from 2 were 17-picolinylidene-N-oxide 4, 5alpha,6alpha-epoxy and 5beta,6beta-epoxy-17-picolinylidene-N-oxide 5 and 6, and 5alpha,6alpha:17alpha,20alpha- and 5beta,6beta:17alpha,20alpha-diepoxy-N-oxide 7 and 8. Starting from compound 3, a mixture of 5alpha,6alpha-epoxy and 5beta,6beta-epoxy-17-picolinylidene 9 and 10, 5alpha,6alpha-epoxy and 5beta,6beta-epoxy-17-picolinylidene-N-oxide 11 and 12, and 5alpha,6alpha:17alpha,20alpha- and 5beta,6beta:17alpha,20alpha-diepoxy-N-oxide 13 and 14 were obtained. From compounds 15 and 18, obtained from 1 and 3 by the Oppenauer oxidation, the 4alpha,5alpha-epoxy and 4beta,5beta-epoxy derivatives 16, 17 and 20, 21 were prepared by oxidation with 30% H(2)O(2). Oxidation of 18 with MCPBA yielded only the N-oxide 19. The structures of compounds 15 and 18 were proved by the X-ray analysis. Compounds 1-6, 9, 15, 17, 18, and 21 were tested on activity against the enzyme aromatase. Antitumor activity against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, and prostate cancer PC3) was evaluated. Three tested compounds (1, 4, and 19) showed strong activity against PC3, the IC(50) values being in the range 0.55-10microM, whereas compound 17 showed strong activity against MDA-MB-231 (IC(50) 10.4microM).
Djurendić
Evgenija
E
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21 000 Novi Sad, Serbia. djena@ih.ns.ac.yu
Daljev
Jovana
J
Sakac
Marija
M
Canadi
Janos
J
Santa
Suzana Jovanović
SJ
Andrić
Silvana
S
Klisurić
Olivera
O
Kojić
Vesna
V
Bogdanović
Gordana
G
Djurendić-Brenesel
Maja
M
Novaković
Sladjana
S
Gasi
Katarina Penov
KP
D000736:Androstenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002723:Chlorobenzoates / Q000737:chemistry; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D015394:Molecular Structure; D010053:Ovary / Q000201:enzymology; D051381:Rats
C518804:3-acetoxy-17-picolinylideneandrost-5-ene-16-one; C518805:3-acetoxy-17-picolinylmethylandrost-5-ene-16-one; C518803:3-hydroxy-17-picolinylideneandrost-5-ene-16-one; D000736:Androstenes; D047072:Aromatase Inhibitors; D002723:Chlorobenzoates; D001141:Aromatase; C000433:3-chloroperbenzoic acid