title: Facile and efficient access to Androsten-17-(1',3',4')-pyrazoles and Androst-17β-(1',3',4')-pyrazoles via Vilsmeier reagents, and their antiproliferative activity evaluation in vitro.
abstract: In this work, twenty-seven novel steroidal pyrazole derivatives were designed and effectively synthesized with two different commercially available staring material, Isopregnanolone 1 and 5,16-Pregnadienolone 7, via the key intermediates, 17β-(4'-formyl)pyrazolylandrost-3β-yl formate and 17-(4'-formyl)pyrazolylandrost- 5,16-dienes-3β-yl formate, which were obtained from the cyclization of steroidal phenylhydrazone with Vilsmeier reagent catalyzed by phosphorous oxychloride followed by hydrolysis, then Borch reduction to afford the target derivatives under mild conditions. Structures of these compounds were identified by1H NMR,13C NMR and high resolution mass spectrometry. Based on our previous work, the cytotoxicity of these derivatives were evaluated by the SRB method against 293T cell lines and three cancer cell lines: A549, Hela and MCF-7. The results indicated that compounds 5b-d, and 11a-e exhibited moderate to high cytotoxic activities with IC50values ranging from 0.62 to 7.51 μM. Among the eight hybrids, compound 11b, with an ethyl amino and a dien-pregn moieties showed the highest potency, with an IC50values of 0.87 μM and 0.53 μM for 293T cell lines and Hela cell lines, respectively. Some structure-activity relationships among the groups of the twenty-seven derivatives are discussed and identify several determinants important for the activity of these compounds. What's more, further molecular mechanism studies suggested that 11b one of the most potent derivatives caused Hela cell lines apoptosis and arrested the cell cycle at S phase in a concentration dependent manner.
authors.affiliation: Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Crop Stress Biology in Arid Area, College of Life Science Northwest Agriculture and Forestry University, Yangling 712100, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Huo
authors.affiliation: Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Key Laboratory of Botanical Pesticide R & D in Shaanxi Province, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, University of California, 1156 High Street, Santa Cruz, CA 95064, United States.
authors.forename: Longbo
authors.initials: L
authors.lastname: Li
authors.affiliation: Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Dan
authors.affiliation: Key Laboratory of Botanical Pesticide R & D in Shaanxi Province, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Botanical Pesticide R & D in Shaanxi Province, Northwest A&F University, Yangling 712100, Shaanxi, China; Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Botanical Pesticide R & D in Shaanxi Province, Northwest A&F University, Yangling 712100, Shaanxi, China. Electronic address: shibaojun@nwsuaf.edu.cn.
authors.forename: Baojun
authors.initials: B
authors.lastname: Shi
mesh_terms: D000731:Androstanes / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000731:Androstanes; D000970:Antineoplastic Agents; D011720:Pyrazoles; D013256:Steroids
keywords: 5,16-Pregnadienolone; Antiproliferative activity; Apoptosis; Isopregnanolone; Steroidal phenylpyrazoles; Vilsmeier reaction