title: Microwave assisted synthesis and biomedical potency of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives.
abstract: A convenient microwave assisted solvent free synthesis as well as conventional synthesis of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives 7-19 from appropriate steroidal precursors 1-6 and methyl salicylate is reported. The microwave assisted synthesis in most cases was more successful regarding reaction time and product yields. It was more environmentally friendly too, compared to the conventional method. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as their inhibition potency exerted on hydroxysteroid dehydrogenase enzymes (Δ(5)-3βHSD, 17βHSD2 and 17βHSD3). All of the tested compounds were effective in OH radical neutralization, particularly compounds 9, 11 and 14, which exhibited about 100-fold stronger activity than commercial antioxidants BHT and BHA. In DPPH radical scavenging new compounds were effective, but less than reference compounds. 2-Methoxybenzoyl ester 10 exhibited strong cytotoxicity against MDA-MB-231 cells. Most compounds inhibited growth of PC-3 cells, where salicyloyloxy stigmastane derivative 15 showed the best inhibition potency. Compounds 9, 10 and 11 were the best inhibitors of 17βHSD2 enzyme. X-ray structure analysis and molecular mechanics calculations (MMC) were performed for the best cytotoxic agents, compounds 10 and 15. A comparison of crystal and MMC structures of compounds 10 and 15 revealed that their molecules conformations are stable even after releasing of the influence of crystalline field and that the influence of crystal packing on molecular conformation is not predominant.
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Katarina M
authors.initials: KM
authors.lastname: Penov Gaši
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Evgenija A
authors.initials: EA
authors.lastname: Djurendić
authors.affiliation: First Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Szécsi
authors.affiliation: First Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Gardi
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: János J
authors.initials: JJ
authors.lastname: Csanádi
authors.affiliation: Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000 Novi Sad, Serbia.
authors.forename: Olivera R
authors.initials: OR
authors.lastname: Klisurić
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Sanja V
authors.initials: SV
authors.lastname: Dojčinović-Vujašković
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Nikolić
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Marina P
authors.initials: MP
authors.lastname: Savić
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Jovana J
authors.initials: JJ
authors.lastname: Ajduković
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Aleksandar M
authors.initials: AM
authors.lastname: Oklješa
authors.affiliation: Oncology Institute of Vojvodina, Put Dr Goldmana 4, 21204 Sremska Kamenica, Serbia.
authors.forename: Vesna V
authors.initials: VV
authors.lastname: Kojić
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Marija N
authors.initials: MN
authors.lastname: Sakač
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: suzana.jovanovic-santa@dh.uns.ac.rs.
authors.forename: Suzana S
authors.initials: SS
authors.lastname: Jovanović-Šanta
mesh_terms: D000731:Androstanes / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D062425:Hydroxybenzoate Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D008872:Microwaves; D008968:Molecular Conformation; D012459:Salicylates / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000731:Androstanes; D016166:Free Radical Scavengers; D062425:Hydroxybenzoate Ethers; D012459:Salicylates; D006913:Hydroxysteroid Dehydrogenases
keywords: 17β-Hydroxysteroid dehydrogenase type 2 and type 3 (17βHSD2 and 3) inhibition; Antioxidant activity; Cytotoxicity; Steroidal salicylic acid derivatives; X-ray structural analysis; Δ(5)-3β-Hydroxysteroid dehydrogenase (Δ(5)-3βHSD) inhibition