Synthesis, cytotoxicity and inhibition of NO production of ivangustin enantiomer analogues.
The eight novel ivangustin enantiomer analogues possessing α-methylene-γ-butyrolactone moiety have been synthesized using (4S6R, 4S6S)-4-tert-butyldimethylsilyloxy-6-methylcyclohex-2-en-1-one (1) as starting material. These transformations were mainly carried out by aldol condensation reaction and one-pot annelation procedure. The stereochemistry of these synthesized analogues was determined by NOE analysis. Their cytoxicity was evaluated against the human cancer cell lines HCT-116 (colon), HL-60 (leukemia), QGY-7701 (liver), SMMC-7721 (liver), A549 (lung), MCF-7 (breast). The results showed that these analogues were more selective against the cell lines HL-60 and QGY-7701. Analogue 17 exhibited potent cytotoxicity and high selectivity toward HL-60 cell line with IC50 value of 1.02 μM, which suggested that it might be a promising anti-cancer lead compound. The inhibitory activities against NO production and the cytotoxicities in RAW 264.7 macrophages were determined at the same time. All of the analogues significantly inhibited the NO production with IC50 value in the range of 3.44-6.99 μM. Analogues 17, 22, 23 and 7 showed higher cytotoxicities, indicated their inhibitory activities against NO production may be influenced by the cytotoxicities.
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Xiang-Yang
XY
Qin
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Bing-Yang
BY
Chen
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Jian-Jun
JJ
Fu
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
Lei
L
Shan
National Institute of Biological Sciences, Beijing (NIBS), Changping District, Beijing 102206, China.
Xiao-Guang
XG
Lei
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: wdzhangy@hotmail.com.
Wei-Dong
WD
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D007783:Lactones; D009569:Nitric Oxide
Cytotoxicity; Inhibition of NO production; Ivangustin; Natural product analogues; Sesquiterpene lactone