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1.
Med Sci Monit ; 26: e920389, 2020 Feb 09.
Article En | MEDLINE | ID: mdl-32036379

BACKGROUND This study aimed to investigate the effects of the 6-nitroindazole compound and amino analog of ludartin, (11R)-13-(6-nitroindazole)-11,13-dihydroludartin (NDHL), on human prostate carcinoma cells in vitro and in mouse tumor xenografts in vivo. MATERIAL AND METHODS DU-145 and LNCaP human prostate carcinoma cells were cultured with increasing concentrations of NDHL. Cell viability was measured using the MTT assay, and cell apoptosis was measured by fluorescence flow cytometry. Mouse tumor xenografts were created by implanting 2×106 of DU-145 cells subcutaneously in the left flank. On the second day following DU-145 cell implantation, the mice in the treatment groups were injected intraperitoneally with 2, 5, and 10 mg/kg of NDHL. RESULTS Treatment of DU-145 and LNCaP cells with NDHL (range, 2.5-20.0 µM) significantly reduced cell proliferation in vitro (P<0.05). The proliferation rate of DU-145 and LNCaP cells was reduced to 27% and 24%, respectively, following treatment with 20.0 µM of NDHL. Treatment with NDHL significantly increased cell apoptosis and the formation of reactive oxygen species (ROS) formation in DU-145 cells at 48 h (P<0.05). NDHL significantly increased the proportion of DU-145 cells in the G1 phase of the cell cycle and significantly increased the expression of cyclin D1 and p21 (P<0.05). Treatment of the mice in the xenograft tumor model with NDHL significantly increased survival and suppressed tumor growth (P<0.02). CONCLUSIONS NDHL inhibited cell proliferation, increased apoptosis, and caused cell cycle arrest in human prostate carcinoma cells in vitro and inhibited mouse tumor xenograft growth in vivo.


Indazoles/pharmacology , Prostatic Neoplasms/pathology , Santonin/analogs & derivatives , Xenograft Model Antitumor Assays , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin D1/metabolism , Cyclin-Dependent Kinase Inhibitor p21 , Humans , Male , Mice , Reactive Oxygen Species/metabolism , Santonin/pharmacology
2.
Eur J Med Chem ; 149: 90-97, 2018 Apr 10.
Article En | MEDLINE | ID: mdl-29499490

A series of α-santonin-derived compounds as potentially anti-hepatoma agents were designed and synthesized in an effort to find novel therapeutic agents. Among them, derivative 5h was more potent than the positive control 5-fluorouracil (5-Fu) on HepG-2, QGY-7703 and SMMC-7721 with IC50 values of 7.51, 3.06 and 4.08 µM, respectively. The structure-activity relationships (SARs) of these derivatives were discussed. In addition, flow cytometry and western blot assay revealed that the derivatives induced hepatoma cells apoptosis by facilitating apoptosis-related proteins expressions. Our findings suggested that these α-santonin-derived analogues hold promise as chemotherapeutic agents for the treatment of human hepatocellular cancer.


Antineoplastic Agents/chemical synthesis , Liver Neoplasms/drug therapy , Santonin/analogs & derivatives , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Drug Design , Humans , Inhibitory Concentration 50 , Santonin/chemical synthesis , Santonin/pharmacology , Structure-Activity Relationship
3.
Org Biomol Chem ; 15(31): 6500-6510, 2017 Aug 09.
Article En | MEDLINE | ID: mdl-28745382

Allelochemicals are safer, more selective and more active alternatives than synthetic agrochemicals for weed control. However, the low solubility of these compounds in aqueous media limits their use as agrochemicals. Herein, we propose the application of α-, ß- and γ-cyclodextrins to improve the physicochemical properties and biological activities of three sesquiterpene lactones: dehydrocostuslactone, costunolide and (-)-α-santonin. Complexation was achieved by kneading and coprecipitation methods. Aqueous solubility was increased in the range 100-4600% and the solubility-phase diagrams suggested that complex formation had been successful. The results of the PM3 semiempirical calculations were consistent with the experimental results. The activities on etiolated wheat coleoptiles, Standard Target Species and parasitic weeds were improved. Cyclodextrins preserved or enhanced the activity of the three sesquiterpene lactones. Free cyclodextrins did not show significant activity and therefore the enhancement in activity was due to complexation. These results are promising for applications in agrochemical design.


Cyclodextrins/chemistry , Lactones/chemistry , Plant Weeds/drug effects , Santonin/analogs & derivatives , Sesquiterpenes/chemistry , Cyclodextrins/chemical synthesis , Cyclodextrins/toxicity , Lactones/chemical synthesis , Lactones/toxicity , Models, Molecular , Santonin/chemical synthesis , Santonin/toxicity , Sesquiterpenes/chemical synthesis , Sesquiterpenes/toxicity , Solubility
4.
J Med Chem ; 60(16): 6828-6852, 2017 08 24.
Article En | MEDLINE | ID: mdl-28696694

As a therapeutic target for antitumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogues were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by Western blotting and NF-κB luciferase assay. Further BIAcore, in-gel fluorescence imaging, and immunoprecipitation assays demonstrated that compound 6d exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound 1 (IJ-5). Mechanistic investigations revealed that compound 6d preferentially bound to and inactivated UbcH5c by forming a covalent adduct with its active site Cys85. Furthermore, compound 6d exhibited potent anti-inflammatory activity against complete Freund's adjuvant-induced adjuvant arthritis in vivo. These findings suggest that the novel α-santonin-derived UbcH5c inhibitor 6d is a promising lead compound for the development of new antirheumatoid arthritis (RA) agent.


Benzofurans/pharmacology , Santonin/analogs & derivatives , Santonin/pharmacology , Ubiquitin-Conjugating Enzymes/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzofurans/chemical synthesis , Benzofurans/pharmacokinetics , Drug Stability , Fibroblasts/metabolism , HeLa Cells , Humans , I-kappa B Kinase/metabolism , Male , Mice , Microsomes, Liver/metabolism , NF-kappa B/metabolism , Rats, Sprague-Dawley , Santonin/chemical synthesis , Santonin/pharmacokinetics , Signal Transduction , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism , Ubiquitination
5.
Pest Manag Sci ; 72(3): 580-4, 2016 Mar.
Article En | MEDLINE | ID: mdl-25914183

BACKGROUND: Faced with the need to develop herbicides with different modes of action on account of weed resistance to existing herbicides, the sesquiterpene lactones can be the starting point in the search for new bioactive compounds. Lumisantonin and five novel amides have been evaluated against two monocotyledons and three dicotyledons. RESULTS: An efficient and versatile synthesis of lumisantonin and the five novel amides has been accomplished from readily available α-santonin. These compounds were subjected to evaluation for their biological activity against Sorghum bicolor (sorghum), Allium cepa (onion), Cucumis sativus (cucumber), Solanum lycopersicum (tomato) and Bidens pilosa (beggartick). Lumisantonin has inhibited the development of the aerial parts of sorghum and onion by 76 and 67% at 1000 µM respectively. One of the novel amides has prevented the growth of shoots and radicles of sorghum by 80 and 71% at 1000 µM respectively. CONCLUSION: All of the tested compounds have been found to exhibit promising seed germination inhibition. We can conclude that lumisantonin was on average the most lethal against all plant species evaluated; however, two of the novel amides have exhibited inhibition selectivity against monocotyledons when compared with dicotyledons. © 2015 Society of Chemical Industry.


Adamantane/pharmacology , Aminobenzoates/pharmacology , Anilides/pharmacology , Crops, Agricultural/drug effects , Herbicides/pharmacology , Plants/drug effects , Amides/chemistry , Amides/pharmacology , Santonin/analogs & derivatives , Santonin/chemistry , Santonin/pharmacology
6.
Zhonghua Wei Chang Wai Ke Za Zhi ; 18(8): 832-4, 2015 Aug.
Article Zh | MEDLINE | ID: mdl-26303697

OBJECTIVE: To evaluate the feasibility of endoscopic gastrostomy combined with magnetic compression techniques in dogs. METHODS: The magnetic compression device consisted of a couple of cylindrical magnets with a hole in the center. A 14-French gastric tube was inserted through the hole and fixed on the parent magnets. Four male mongrel dogs were selected randomly for the operation. The daughter magnet was placed into the dog's gastric body by a Zebra Guidewire under endoscopy, then a skin incision was performed on the left upper abdomen, through which the subcutaneous tissues and muscle were isolated up to the peritoneum. The parent magnet was placed on the surface of the peritoneum, which attracted the daughter magnet inside the gastric cavity automatically to compress the gastric wall and peritoneum. A needle was inserted through the gastric tube and punctured the tissue in the hole of the magnets repeatedly to form a fistula. After removing the needle, the gastrostomy was complete. The fistula was observed and its specimen was taken two weeks later under laparotomy. RESULTS: All the four operations were successfully performed, and the operation time was 11-15 minutes. The stoma was matured immediately, through which early enteral nutrition support was administered. The gastric wall and peritoneum were observed with well healing and no adhesion in the abdominal cavity under laparotomy two weeks after the operation. CONCLUSION: The gastrostomy performed by magnetic compression technique combined with endoscopy is convenient, minimally invasive and safe, which may be used in future clinical practice.


Gastrostomy , Abdomen , Animals , Catheterization , Dogs , Enteral Nutrition , Gastroscopy , Laparotomy , Magnetics , Male , Santonin/analogs & derivatives , Stomach , Surgical Stomas , Wound Healing
7.
Eur J Med Chem ; 101: 769-79, 2015 Aug 28.
Article En | MEDLINE | ID: mdl-26222449

A series of Michael-type analogues were generated on the C-ring of α-santonin (α-methylene-γ-butyrolactone) upon reaction with various thiols. All the thiol adducts synthesized were evaluated for their anticancer activity against four human cancer cell lines (PC-3, HCT-15, A-549 and MCF-7). Bioassay results indicated that even though most of the synthesized compounds exhibited a good anticancer activity against various cancer cells in vitro, some of the compounds like 9e, 9g and 9q were found to be the most promising analogues in this series, with compound 9e showing IC50 values of 1.5 µM, 0.6 µM, 2.4 µM and 1.2 µM on PC-3, MCF-7, A-549 and HCT-116 cell lines respectively. Further, flow cytometry studies showed that MCF-7 cells treated with the compounds 9e, 9g and 9q were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. These lead molecules were further studied for NF-κB, p65 transcription factor inhibitory activity which confirmed concentration dependent inhibition against NF-κB, p65 with analogue 9e showing 57% inhibition at 2 µM, 9g showing 62% inhibition at 3 µM and 9q showing 54% inhibition at 2 µM concentration.


Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Santonin/analogs & derivatives , Sulfhydryl Compounds/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Santonin/chemical synthesis , Santonin/chemistry , Santonin/pharmacology , Structure-Activity Relationship , Sulfhydryl Compounds/pharmacology
8.
Toxicol In Vitro ; 27(5): 1458-66, 2013 Aug.
Article En | MEDLINE | ID: mdl-23542210

Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2 µM, respectively)]. However, after 48 h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents.


Cytotoxins/pharmacology , Santonin/analogs & derivatives , Santonin/pharmacology , Apoptosis/drug effects , Caspase 3/metabolism , Caspase 7/metabolism , Cell Cycle Checkpoints/drug effects , Cell Proliferation/drug effects , DNA Fragmentation , G2 Phase , HL-60 Cells , Humans , Membrane Potential, Mitochondrial/drug effects
9.
Biosci Biotechnol Biochem ; 76(12): 2360-3, 2012.
Article En | MEDLINE | ID: mdl-23221713

(11S)-2α-Bromo-3-oxoeudesmano-12,6α-lactone, designated santonin-related compound 2 (SRC2), only weakly affected IκBα degradation after tumor necrosis factor-α (TNF-α) stimulation, but strongly blocked the nuclear translocation of nuclear factor κB (NF-κB) subunit p65. Replacement of Cys-38 of p65 with serine abolished the inhibitory effect of SRC2 on this TNF-α-induced nuclear translocation. These results indicate that SRC2 inhibits the nuclear translocation of p65 by targeting Cys-38.


Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cysteine , Santonin/analogs & derivatives , Santonin/pharmacology , Signal Transduction/drug effects , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Active Transport, Cell Nucleus/drug effects , Cell Line, Tumor , Humans , Transcription Factor RelA/chemistry
10.
J Phys Chem A ; 115(26): 7815-22, 2011 Jul 07.
Article En | MEDLINE | ID: mdl-21627307

The CASSCF and CASPT2 methodologies have been used to explore the potential energy surfaces of lumisantonin in the ground and low-lying triplet states along the photoisomerization pathways. Calculations indicate that the (1)(nπ*) state is the accessible low-lying singlet state with a notable oscillator strength under an excitation wavelength of 320 nm and that it can effectively decay to the (3)(ππ*) state through intersystem crossing in the region of minimum surface crossings with a notable spin-orbital coupling constant. The (3)(ππ*) state, derived from the promotion of an electron from the π-type orbital mixed with the σ orbital localized on the C-C bond in the three-membered alkyl ring to the π* orbital of conjugation carbon atoms, plays a critical role in C-C bond cleavage. Based on the different C-C bond rupture patterns, the reaction pathways can be divided into paths A and B. Photolysis along path A arising from C1-C5 bond rupture is favorable because of the dynamic and thermodynamic preferences on the triplet excited-state PES. Path B is derived from the cleavage of the C5-C6 bond, leading first to a relatively stable species, compared to intermediate A-INT formed on the ground state PES. Accordingly, path B is relatively facile for the pyrolytic reaction. The present results provide a basis to interpret the experimental observations.


Santonin/analogs & derivatives , Models, Molecular , Photochemistry , Santonin/chemistry
11.
Arch Pharm Res ; 34(2): 191-8, 2011 Feb.
Article En | MEDLINE | ID: mdl-21380800

Induction of differentiation is a new and promising approach to leukemia therapy, well illustrated by the treatment of acute promyelocytic leukemia with 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] or all-trans retinoic acid (ATRA). Using combination of either 1,25-(OH)(2)D(3) or ATRA and chemotherapy, adverse effects 1,25-(OH)(2)D(3) or ATRA such as hypercalcemic effects have decreased, and long-term survival has improved. In a previous study, we demonstrated that santonin could be chemically modified into a diacetoxy acetal derivative of santonin with strong differentiation-inducing activity. In this study, we further synthesized C(6)-epimer derivatives of diacetoxy acetal derivative of santonin and tested their effects on HL-60 cell differentiation. Some of the C(6)-epimer derivatives themselves induced increases in cell differentiation. Especially, (11S)-3,3-(ethylenedioxy) eudesmano-13-ol-6ß-acetate (7) was demonstrated to induce differentiation with larger than 80% of the cells attaining a differentiated phenotype. Importantly, 7 strongly enhanced differentiation of HL-60 cells in a dose-dependent manner when combined with either low doses of 1,25-(OH)(2)D(3) or ATRA. The ability to enhance the differentiation potential of 1,25-(OH)(2)D(3) or ATRA by 7 may improve outcomes in the therapy of acute promyelocytic leukemia.


Acetals/chemical synthesis , Acetals/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Leukemia, Promyelocytic, Acute/drug therapy , Santonin/analogs & derivatives , Acetals/analysis , Antineoplastic Agents/analysis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Drug Synergism , HL-60 Cells , Humans , Santonin/chemical synthesis , Santonin/chemistry , Santonin/pharmacology , Tretinoin/pharmacology , Vitamin D/analogs & derivatives , Vitamin D/pharmacology
12.
Eur J Med Chem ; 45(12): 6045-51, 2010 Dec.
Article En | MEDLINE | ID: mdl-20971532

Ten novel α-santonin derivatives have been synthesized as cytotoxic agents. The in vitro antitumor activity of these compounds has been evaluated against cancer cells lines. Structure-activity relationships indicate that α-methylene-γ-lactone and endoperoxide functionalities play important roles in conferring cytotoxicity. The compounds 2-4, possessing the α-methylene-γ-lactone group showed IC50 values between 5.70 and 16.40 µM. Mixture of isomers 5 and 6, with the α-methylene-γ-lactone and endoperoxide functionalities, displayed the greatest activity, with IC50 values between 1.45 and 4.35 µM. The biological assays conducted with normal cells revealed that the compounds 2, 5 and 6 are selective against cancer cells lines tested. Bioactive lactones described herein and in our previous report did not cause disruption of the cell membrane in mouse erythrocytes.


Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Santonin/chemical synthesis , Santonin/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Molecular Structure , Santonin/analogs & derivatives , Stereoisomerism , Structure-Activity Relationship
13.
Eur J Med Chem ; 44(9): 3739-45, 2009 Sep.
Article En | MEDLINE | ID: mdl-19406535

Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC(50) values in the range of 0.36-14.5 microM, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development.


Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/toxicity , Lactones/chemistry , Lactones/toxicity , Santonin/analogs & derivatives , Santonin/toxicity , Antineoplastic Agents, Phytogenic/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Lactones/chemical synthesis , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Santonin/chemical synthesis
14.
Arch Pharm Res ; 31(3): 300-4, 2008 Mar.
Article En | MEDLINE | ID: mdl-18409041

DAAS is the diacetoxy acetal derivative of a-santonin and induces HL-60 cell differentiation into granulocytes. In this report, we investigated the structure-activity relationship (SAR) of DAAS derivatives in the differentiation of human HL-60 leukemia cells. Although its derivatives themselves had less effect on HL-60 cell differentiation than DAAS, the monoacetyl derivative, 2, mainly induced HL-60 cell differentiation. Moreover, compound 2 synergistically enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation when combined with 50 nM ATRA, a well-known differentiation inducer. This enhancing effect is similar to that of DAAS in ATRA-induced differentiation.


Antineoplastic Agents/pharmacology , Cell Differentiation/drug effects , Leukemia/drug therapy , Santonin/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Dose-Response Relationship, Drug , Drug Synergism , HL-60 Cells , Humans , Leukemia/pathology , Molecular Structure , Santonin/chemical synthesis , Santonin/pharmacology , Santonin/therapeutic use , Structure-Activity Relationship , Tretinoin/pharmacology
15.
J Asian Nat Prod Res ; 8(4): 317-26, 2006 Jun.
Article En | MEDLINE | ID: mdl-16864442

One fungus, Abisidia coerulea IFO 4011, and suspended cell cultures of one plant, Asparagus officinalis, were employed to bioconvert alpha- and 6beta-santonin. Incubation of alpha-santonin with the cell cultures of the fungus afforded two products, 11beta-hydroxy-alpha-santonin (1, in 76.5% yield) and 8alpha-hydroxy-alpha-santonin (2, in 2.0% yield). And from 6beta-santonin, four major products (3, 4, 5 and 6) and four minor products (7, 8, 9 and 10) were obtained, including 8alpha-hydroxylated products in trace yields. Very interestingly, a skeletal rearrangement occurred and a guaiane product (13) formed in a very low yield when alpha-santonin incubating with A.officinalis cell cultures, while not in the case of 6beta-santonin as substrate. Among the obtained 15 products, 2, 7, 8, 9, 10 and 12 are new compounds. The fact of 8alpha hydroxylation of santonin enables the formation of 8,12-eudesmanolide instead of 6,12-eudesmanolide and some useful modification at C-8 position. In addition, these reactions would provide evidence for the biogenesis between different types of eudesmane and/or guaiane compounds in the plants in nature.


Asparagus Plant/metabolism , Fungi/metabolism , Santonin/analogs & derivatives , Santonin/metabolism , Asparagus Plant/cytology , Biotransformation , Cells, Cultured , Fungi/cytology , Molecular Structure , Santonin/chemistry
16.
J Biol Chem ; 281(19): 13117-13125, 2006 May 12.
Article En | MEDLINE | ID: mdl-16554308

Many sesquiterpene lactone compounds either induce or enhance the cell differentiation of human leukemia cells. However, we reported in a previous study that santonin, a eudesmanolide sesquiterpene lactone, exerts no effects on the differentiation of leukemia cells. In this report, to evaluate the possibility of chemically modifying santonin into its derivatives with differentiation inducing activity, we synthesized a series of santonin derivatives, and determined their effects on cellular differentiation in the human promyelocytic leukemia HL-60 cell system. A diacetoxy acetal derivative of santonin (DAAS) was found to induce significant HL-60 cell differentiation in a dose-dependent manner, whereas santonin in its original form did not. The HL-60 cells were differentiated into a granulocytic lineage when exposed to DAAS. In addition, the observed induction in cell differentiation closely correlated with the levels of NF-kappaB DNA binding activity inhibited by DAAS. Both Western blot analyses and kinase inhibitor studies determined that protein kinase C, ERK, and phosphatidylinositol 3-kinase were upstream components of the DAAS-mediated inhibition of NF-kappaB binding activity in HL-60 leukemia cells. The results of this study indicate that santonin can, indeed, be chemically modified into a derivative with differentiation inducing abilities, and suggest that DAAS might prove useful in the treatment of neoplastic diseases.


Cell Differentiation/drug effects , Down-Regulation/drug effects , Granulocyte Precursor Cells/drug effects , Leukemia/pathology , NF-kappa B/metabolism , Santonin/chemistry , Santonin/pharmacology , DNA/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation , Granulocyte Precursor Cells/pathology , HL-60 Cells , Humans , Leukemia/metabolism , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding/drug effects , Protein Kinase C/metabolism , Santonin/analogs & derivatives
17.
Arch Pharm Res ; 29(1): 40-5, 2006 Jan.
Article En | MEDLINE | ID: mdl-16491841

Several diacetoxy acetal analogues have been synthesized from santonin and assessed for their ability of inducing or enhancing the differentiation of human HL-60 leukemia cells. The compounds themselves had little effect on HL-60 cell differentiation. However, three analogues, 2a, 3a, and 5b, synergistically enhanced 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced HL-60 cell differentiation when combined with 5 nM of dihydroxyvitamin D3 [1,25-(OH)2D3], a well-known differentiation inducer. Especially, the compound 5b profoundly enhanced the 1,25-(OH)2D3]-induced HL-60 cell differentiation.


Calcitriol/pharmacology , Cell Differentiation/drug effects , Santonin/analogs & derivatives , Santonin/pharmacology , Vitamins/pharmacology , Drug Synergism , HL-60 Cells , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Nitroblue Tetrazolium , Santonin/chemical synthesis
18.
Yao Xue Xue Bao ; 40(9): 834-7, 2005 Sep.
Article En | MEDLINE | ID: mdl-16342687

AIM: To obtain more valuable derivatives for the further structural modification of 6beta-santonin (1) via biotransformation by using cell suspension cultures of Phytolacca acinosa. METHODS: The substrate 1 was incubated with cell suspension cultures of P. acinosa, the products were obtained by chromatography, and identified on the basis of their physical and spectral data (HRMS, 1D NMR, 2D NMR, NOE and IR). RESULTS: After incubation with cell suspension cultures of P. acinosa, 1 was converted into five products. Among them, 3 is a new compound. CONCLUSION: 6beta-santonin could be selectively reduced and hydroxylated by the cell suspension cultures of P. acinosa, which would provide valuable intermediates for its further structural modification.


Phytolacca/metabolism , Plants, Medicinal/metabolism , Santonin/analogs & derivatives , Santonin/metabolism , Biotransformation , Cell Culture Techniques/methods , Cells, Cultured , Molecular Structure , Phytolacca/cytology , Plants, Medicinal/cytology , Santonin/chemistry
19.
J Nat Prod ; 65(11): 1703-6, 2002 Nov.
Article En | MEDLINE | ID: mdl-12444708

Starting from 2 and 3, obtained from santonin (1), we have synthesized natural guaianolides 4-7. Chemoselective epoxidation of 2 gave (+)-11betaH,13-dihydroestafiatin (4), and epoxidation of 3 followed by regioselective elimination of the hydroxyl group afforded (+)-11betaH,13-dihydroludartin (5). Sharpless' mild regioselective ring-opening of 4 and 5 followed by hydrogenolysis yielded (-)-compressanolide (6) and (-)-11betaH,13-dihydromicheliolide (7), respectively.


Lactones/chemical synthesis , Santonin/chemistry , Santonin/chemical synthesis , Catalysis , Cyclization , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Santonin/analogs & derivatives , Stereoisomerism
20.
Immunopharmacology ; 48(2): 129-35, 2000 Jul 20.
Article En | MEDLINE | ID: mdl-10936510

Santonin-related compounds (SRCs) were synthesized from the starting material L-alpha-santonin and tested for the biological activity on the expression of intercellular adhesion molecule-1 (ICAM-1) in response to IL-1 stimulation on human adenocarcinoma cells. One of the bromoketone derivatives termed SRC2 [11S-2 alpha-bromo-3-oxoeudesmanno-13,6 alpha-lactone] strongly inhibited the ICAM-1 expression at an IC(50) value of 5.9 microM, whereas L-alpha-santonin itself was totally inactive up to 100 microM. The blockage of ICAM-1 expression by SRC2 was not due to the direct inhibition of de novo RNA and protein synthesis. The nuclear translocation of NF-kappaB subunit p65 was markedly prevented by SRC2. Moreover, I kappa B alpha degradation upon IL-1 stimulation was strongly inhibited by SRC2. These observations suggest that SRC2 blocks the IL-1 signaling pathway upstream of I kappa B degradation.


I-kappa B Proteins/antagonists & inhibitors , Intercellular Adhesion Molecule-1/biosynthesis , Interleukin-1/physiology , Santonin/pharmacology , Signal Transduction/drug effects , Biological Transport/drug effects , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Humans , I-kappa B Proteins/metabolism , Intercellular Adhesion Molecule-1/genetics , Interleukin-1/antagonists & inhibitors , NF-kappa B/metabolism , RNA/antagonists & inhibitors , RNA/biosynthesis , Santonin/analogs & derivatives , Signal Transduction/immunology , Transcription Factor RelA , Tumor Cells, Cultured
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