ABSTRACT
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.
Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/toxicity , Lactones/pharmacology , Lactones/toxicity , Macrophages/drug effects , Nitric Oxide/biosynthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Lactones/chemical synthesis , Lactones/chemistry , Mice , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of new α-methylene-γ-lactone carbamates were synthesized by an asymmetric synthetic route. The activities on inhibiting nitric oxide (NO) release of these compounds were evaluated in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. The results indicated that most of the compounds except one exhibited potent NO inhibitory effect with IC50 value more than 2 µΜ. The cytotoxicities of these compounds were estimated via MTT assays. The results suggested that six compounds were accompanied by low cytotoxicity. The structure-activity relationships were also discussed. The S configuration of C3 on lactones ring would be more helpful to NO inhibitory effect.
Subject(s)
Carbamates/chemistry , Carbamates/pharmacology , Lactones/chemistry , Lipopolysaccharides/adverse effects , Macrophages/drug effects , Nitric Oxide/biosynthesis , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Carbamates/chemical synthesis , Chemistry Techniques, Synthetic , Mice , RAW 264.7 CellsABSTRACT
A guaiane framework was scaffolded by photochemical rearrangement reactions using α-santonin 1 as a starting material. Then, using a series of reactions, we synthesized the guaiane-type sesquiterpene lactone 5 in high yield. The inhibitory activities of compound 5 and of a series of derivatives on nitric oxide (NO) release were evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 6g, 7h, 7i, 7k and 8g, exhibited significant inhibitory effects on NO production, with IC50 values of 14.8, 22.3, 18.3, 17.4 and 7.0 µM, respectively. Their cytotoxicities were also estimated using an MTT assay. The structure-activity relationships of these compounds were also discussed.
Subject(s)
Lactones/chemistry , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Nitric Oxide/biosynthesis , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/pharmacology , Animals , Cell Line , Chemistry Techniques, Synthetic , Mice , Sesquiterpenes, Guaiane/chemical synthesis , Sesquiterpenes, Guaiane/toxicity , Structure-Activity RelationshipABSTRACT
A series of novel derivatives of phenyl substituted tetramethoxy xanthone were synthesized and evaluated for their in vitro cytotoxicity against human hepatocellular carcinoma (HCC) and non-tumor hepatic cells. Among these derivatives, compound 6 was more potent than positive control 5-fluorouracil (5-Fu) on QGY-7703 and SMMC-7721 cells with IC50 values of 6.27 µM, 7.50 µM and 15.56 µM, 14.55 µM, respectively. Furthermore, compounds 6, 14, 16, and 29 exhibited much better selectivity toward the normal hepatic cell line QSG-7701 than 5-Fu. Additionally, compound 6 significantly induced cell apoptosis in QGY-7703 cells. Our findings suggested that these phenylxanthone derivatives may hold promise as chemotherapeutic agents for the treatment of human HCC.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Xanthones/chemistry , Xanthones/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Liver Neoplasms/pathology , Molecular Structure , Structure-Activity Relationship , Tumor Cells, Cultured , Xanthones/chemical synthesisABSTRACT
The inhibitory activity of 4,4'-dihydroxy-α-truxillic acid and its derivatives (5-1a-5-35a) on nitric oxide (NO) release was evaluated in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Compounds 5-3a, 5-4a, 5-5a, 5-10a, 5-24a, 5-26a and 5-30a exhibited significant inhibitory effects on NO production, with IC50 values of 19.8, 21.1, 16.4, 17.5, 20.8, 22.6 and 17.6 µM, respectively. Their cytotoxicities were also estimated using a CCK-8 assay. Among them, compound 5-10a showed no cytotoxic effect on cells up to a concentration of 50 µM. The structure-activity relationships of the compounds are also discussed.
