Synthesis of some epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives and evaluation of their biological activity

• Published in: Steroids Vol. 73; no. 1; pp. 129 - 138
• Main Authors: Djurendić, Evgenija, Daljev, Jovana, Sakač, Marija, Čanadi, Janoš, Šanta, Suzana Jovanović, Andrić, Silvana, Klisurić, Olivera, Kojić, Vesna, Bogdanović, Gordana, Djurendić-Brenesel, Maja, Novaković, Sladjana, Gaši, Katarina Penov
• Format: Journal Article
• Language: English
• Published: NEW YORK Elsevier Inc 2008; Elsevier; Elsevier Science
• Subjects: Androst-5-ene derivatives; Androstenes - chemical synthesis; Androstenes - chemistry; Androstenes - pharmacology; Animals; Antitumor activity; Aromatase - metabolism; Aromatase inhibition; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Aromatase Inhibitors - pharmacology; Biochemistry & Molecular Biology; Biological and medical sciences; Cell Line; Cell Line, Tumor; Cell Survival - drug effects; Chlorobenzoates - chemistry; Crystallography, X-Ray; Endocrinology & Metabolism; Epoxidation; Female; Fundamental and applied biological sciences. Psychology; Humans; Inhibitory Concentration 50; Kinetics; Life Sciences & Biomedicine; Molecular Structure; Ovary - enzymology; Picolyl and picolinylidene derivatives; Rats; Science & Technology; Vertebrates: endocrinology; X-ray analysis; Epoxidation; Antitumor activity; X-ray analysis; Androst-5-ene derivatives; Picolyl and picolinylidene derivatives; Aromatase inhibition; BREAST-CANCER; 19-OXYGENATED ANALOGS; INACTIVATION; aromatase inhibition; derivatives epoxidation; 4-BETA,5-BETA-EPOXIDES; antitumor activity; picolyl and picolinylidene; ESTROGEN BIOSYNTHESIS; androst-5-ene derivatives; AROMATASE INHIBITORS; Antineoplastic agent; Androstenediol; X ray; Inhibition; Chemical synthesis; Biological activity
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2007.09.005

Steroidal epoxy and/or N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives have been prepared using 3β,17β-dihydroxy-17α-picolyl-androst-5-ene ( 1), 3β-acetoxy-17-picolinylidene-androst-5-ene ( 2), and 3β-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, 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene- N-oxide 5 and 6, and 5α,6α:17α,20α- and 5β,6β:17α,20α-diepoxy- N-oxide 7 and 8. Starting from compound 3, a mixture of 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene 9 and 10, 5α,6α-epoxy and 5β,6β-epoxy-17-picolinylidene- N-oxide 11 and 12, and 5α,6α:17α,20α- and 5β,6β:17α,20α-diepoxy- N-oxide 13 and 14 were obtained. From compounds 15 and 18, obtained from 1 and 3 by the Oppenauer oxidation, the 4α,5α-epoxy and 4β,5β-epoxy derivatives 16, 17 and 20, 21 were prepared by oxidation with 30% H 2O 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 0.55–10 μM, whereas compound 17 showed strong activity against MDA-MB-231 (IC 50 10.4 μM).