Synthesis and biological evaluation of some new A,B-ring modified steroidal D-lactones.
Starting from the D-homo lactones of androst-4-en-3-one 3 and 4, prepared from 1 and 2, the new 17a homolactones 5-12, 14 and 15, were synthesized. The 4-hydroxy compounds 9 and 10 were obtained through the reaction of 4alpha,5alpha- (5 and 7) and 4beta,5beta- (6 and 8) epoxides with formic acid. The epoxides 5 and 6 were prepared from compound 3, and epoxides 7 and 8 from compound 4 by oxidation with H(2)O(2) under basic conditions. Compound 1 served as a starting substance for obtaining lactones 11-13. Oxidation of compound 1 with m-chloroperbenzoic acid yielded 11 and 12, but compound 13 gave 14. Compound 15 was obtained from 13 by oxidation with H(2)O(2) under basic conditions. The structures of epoxides 6 and 14 were confirmed by X-ray structural analysis. Cytotoxic 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. Compounds 6 and 14 showed strong activity against PC3, the IC(50) being 10.6 and 2.2 microM, respectively, whereas compounds 3 and 8 showed strong activity against MDA-MB-231 (IC(50) is 9.3 and 3.6 microM, respectively). Aromatase inhibition assay showed that the tested compounds 9, 10, and 14 possess lower activity compared to formestane.
Djurendić
Evgenija A
EA
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3, 21000 Novi Sad, Serbia.
Sakac
Marija N
MN
Zavis
Marina P
MP
Gaković
Andrea R
AR
Canadi
Janos J
JJ
Andrić
Silvana A
SA
Klisurić
Olivera R
OR
Kojić
Vesna V
VV
Bogdanović
Gordana M
GM
Gasi
Katarina M Penov
KM
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D007783:Lactones; D013256:Steroids