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1.
Bioorg Med Chem Lett ; 21(16): 4879-83, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21757349

ABSTRACT

4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was previously identified as an antileukemic agent exhibiting no evident toxicity toward normal hematopoietic cells. An SAR study has been carried out to examine the effect of varying the C-2 and C-4- substituents on the thiadiazolidinone ring of TDZD-8 on antileukemic activity. These studies resulted in the identification of more druglike analogs that exhibited comparable potency to TDZD-8 in killing acute myelogenous leukemia (AML) cells in culture. Surprisingly, the cell death kinetics induced by several of these novel analogs on MV-411 cells were extremely fast, with commitment to death occurring within 30 min. At a concentration of 10 µM, 3f (LD(50)=3.5 µM) completely eradicated cell viability of MV-411 cells within 2h, while analog 3e (LD(50)=2.0 µM) decimated cell viability within 30 min at a concentration of 10 µM and effectively abolished cell viability at 5 µM within 1-2h.


Subject(s)
Drug Discovery , Leukemia, Myeloid, Acute/drug therapy , Thiadiazoles/pharmacology , Cell Death/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Kinetics , Leukemia, Myeloid, Acute/pathology , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Tumor Cells, Cultured
2.
Bioorg Med Chem ; 19(4): 1515-9, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21273084

ABSTRACT

Melampomagnolide B has been identified as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was designed and synthesized in order to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Leukemia/drug therapy , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Cell Survival/drug effects , Humans , Molecular Structure , Tumor Cells, Cultured
3.
Bioorg Med Chem Lett ; 20(24): 7450-3, 2010 Dec 15.
Article in English | MEDLINE | ID: mdl-21055931

ABSTRACT

A series of 3-O-phosphorylated analogs (4-10) of a novel bone-targeting estradiol analog (3) were synthesized after a thorough study of the reaction of 3 with a selection of phosphoryl chlorides under a variety of reaction conditions. Evaluation of these novel phosphate analogs for affinity for hydroxyapatite revealed that they bind with equal or higher affinity when compared to the bone tissue accumulator, tetracycline.


Subject(s)
Bone and Bones/chemistry , Estradiol/analogs & derivatives , Estrenes/chemistry , Phosphates/chemistry , Durapatite/chemistry , Esters , Estradiol/chemical synthesis , Estradiol/pharmacology , Tetracycline/chemistry
4.
Bioorg Med Chem Lett ; 19(15): 4346-9, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19505822

ABSTRACT

A series of aminoparthenolide analogs (6-37) were synthesized and evaluated for their anti-leukemic activity. Eight compounds exhibited good anti-leukemic activity with LD(50)'s in the low microM range (1.5-3.0microM). Compounds 16, 24 and 30 were the most potent compounds in the series, causing greater than 90% cell death at 10microM concentration against primary AML cells in culture, with LD(50) values of 1.7, 1.8 and 1.6microM.


Subject(s)
Antineoplastic Agents/chemical synthesis , Leukemia, Myeloid, Acute/drug therapy , NF-kappa B/metabolism , Sesquiterpenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Cell Death , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Drug Screening Assays, Antitumor/methods , Humans , Lactones/chemistry , Models, Chemical , Rats , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Solubility , Water/chemistry
5.
Planta Med ; 74(12): 1492-5, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18816429

ABSTRACT

A new dihydroflavonol, songaricol ( 1) and seven known flavonoids, ayamenin A ( 2), irisflavone A ( 3), 5,7-dihydroxy-2',6-dimethoxyisoflavone ( 4), irilin B ( 5), 5,3'-dihydroxy-7,8,2'-trimethoxyisoflavone ( 6) and irisoid A ( 7) were isolated from rhizome and roots of IRIS SONGARICA. Structure elucidation of 1 was achieved through extensive NMR and circular dichroism techniques. Compounds 1, 5 and 7 showed antioxidant activity in HL-60 cells (IC50 values of 21, 11 and 3.8 microg/mL), whereas 2, 5 and the previously isolated irisone B were able to show estrogenic response (EC50 values of 305.5, 159.7 and 322.0 microg/mL) in yeast cells expressing human estrogen receptor (ER-alpha).


Subject(s)
Antioxidants/pharmacology , Estrogens/pharmacology , Flavonoids/pharmacology , Iris Plant/chemistry , Antioxidants/chemistry , Antioxidants/isolation & purification , Circular Dichroism , Estrogens/chemistry , Estrogens/isolation & purification , Flavonoids/chemistry , Flavonoids/isolation & purification , HL-60 Cells , Humans , Nuclear Magnetic Resonance, Biomolecular , Plant Roots/chemistry , Rhizome/chemistry , Spectrometry, Mass, Electrospray Ionization , Toxicity Tests
6.
Bioorg Med Chem Lett ; 18(14): 3870-3, 2008 Jul 15.
Article in English | MEDLINE | ID: mdl-18590961

ABSTRACT

A series of aminoparthenolide analogs have been synthesized through a diastereoselective conjugate addition of several primary and secondary amines to the alpha-methylene-gamma-butyrolactone function of the very lipophilic sesquiterpene lactone, parthenolide. Seventeen of the above amines derivatives were evaluated in a full panel of 60 cancer cell lines for anticancer activity. Compound 12, derived from tyramine, was found to be cytostatic as well as cytotoxic toward acute lymphoblastic leukemia cells (ALL, CCRF-CEM) at nanomolar concentrations, while the (R)-(1,2,3,4-tetrahydro-1-naphthyl)amino derivative 9 was found to be cytostatic toward human anaplastic large T-cell lymphoma (SR) cells at concentrations below 10 nM.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Lymphoma, Large-Cell, Anaplastic/drug therapy , Models, Chemical
7.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 3): o639, 2008 Feb 29.
Article in English | MEDLINE | ID: mdl-21201970

ABSTRACT

THE TITLE COMPOUND [SYSTEMATIC NAME: (12R)-4,8-dimethyl-12-[(1'R)-1',2',3',4'-tetrahydro-1'-naphthyl)aminomethyl]-3,14-dioxatricyclo[9.3.0.0(2,4)]tetradec-7-en-13-one}, C(25)H(33)NO(3), was formed from the reaction of (1R)-1-amino-tetra-lin with parthenolide in methano-lic solution. X-ray crystal structure analysis determined that the configuration of the new chiral center in the title compound was R.

8.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 3): o644, 2008 Feb 29.
Article in English | MEDLINE | ID: mdl-21201974

ABSTRACT

THE TITLE COMPOUND (SYSTEMATIC NAME: 12-{[2-(4-hydroxyphenyl)ethyl]aminomethyl}-4,8-dimethyl-3,14-dioxatricyclo[9.3.0.0(2,4)]tetradec-7-en-13-one monohydrate), C(23)H(31)NO(4)·H(2)O, was obtained by the reaction of tyramine with parthenolide. The configuration of the new chiral center in the title compound is R, establishing the stereospecificity of the amination reaction. The water molecule is disordered over three positions; the site occupancy factors are 0.45, 0.40 and 0.15.

9.
J Pharm Biomed Anal ; 45(1): 120-124, 2007 Sep 21.
Article in English | MEDLINE | ID: mdl-17706392

ABSTRACT

Several studies on dipyridyl isomers have suggested that they are neurotoxic and that chronic exposure to these compounds could be a potential human health hazard. A reversed phase HPLC method was developed for the simultaneous quantitation of 2,2'-dipyridyl and its four positional isomers, 2,3'-, 2,4'-, 3,4'- and 4,4'-dipyridyl in human plasma. Plasma samples were basified, extracted with 1-chlorobutane, evaporated, the residue reconstituted in mobile phase, and an aliquot part was analyzed by HPLC. Chromatographic separations were performed on a C(18) reversed phase Sunfire column eluted with a mobile phase composed of potassium phosphate (pH 3.5; 25 mM)-acetonitrile (80:20, v/v). Isomers were separated with good resolution, and quantification was determined utilizing an internal standard of quinoxaline. The method has been validated over a range from 30 to 2000 ng/ml with correlation coefficients higher than 0.995. Extraction recoveries for the dipyridyl isomers averaged from 65 to 92%. Limit of detection and limit of quantitation for the dipyridyl isomers ranged from 15 to 70 ng/ml and 30 to 90 ng/ml, respectively. The inter- and intra-day variation did not exceed 7% with an accuracy range of 96-102%. The described analytical method was successfully utilized for the determination of dipyridyl isomers in human plasma and suggested the need for more routine monitoring of tobacco smokers and other individuals who are involuntarily exposed to environmental source of dipyridyl isomers.


Subject(s)
2,2'-Dipyridyl/isolation & purification , Environmental Pollutants/blood , Neurotoxicity Syndromes/blood , 2,2'-Dipyridyl/chemistry , Calibration , Chromatography, High Pressure Liquid/methods , Drug Stability , Environmental Pollutants/chemistry , Humans , Isomerism , Molecular Structure , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Smoking/blood
10.
Nat Prod Res ; 18(5): 465-71, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15248616

ABSTRACT

Two new isoflavones 1 and 2 along with eleven known compounds 3-13, have been isolated for the first time from the rhizomes of Iris soforana. The structures of these compounds were determined on the basis of spectroscopic methods and found to be 5,3'-dihydroxy-4'-methoxy-6,7-methylenedioxyisoflavone (1) (Soforanarin A), and 5,7,5'-trimethoxy-6,3',4'-trihydroxyisoflavone (2) (Soforanarin B).


Subject(s)
Iris , Isoflavones/chemistry , Phytotherapy , Plant Extracts/chemistry , Humans , Magnetic Resonance Spectroscopy , Plant Roots
11.
Phytother Res ; 17(5): 575-7, 2003 May.
Article in English | MEDLINE | ID: mdl-12749005

ABSTRACT

In vitro biological activities including bactericidal, fungicidal and insecticidal activities as well as phytotoxicity and brine shrimp toxicity of the petroleum ether, chloroform and ethyl acetate extracts of Iris germanica L. were determined. The bactericidal activity of the extracts was assayed by the agar well diffusion test. In the fungicidal test, the agar tube dilution method was used. The insecticidal activity was determined by the exposure method. The toxicity of the extracts was evaluated by the phytotoxicity test as well as the brine shrimp toxicity test. The chloroform and ethyl acetate extracts of I. germanica rhizomes exhibited bactericidal activity, while the petroleum ether extract did not exhibit any bactericidal, fungicidal and insecticidal activities. It was also inactive in the brine shrimp toxicity test, whereas it showed significant phytotoxicity against the plant Lemna aequinoctialis Welv. Two known isoflavones were isolated from the chloroform extract of the plant.


Subject(s)
Bacteria/drug effects , Benzopyrans/pharmacology , Dioxoles/pharmacology , Fungi/drug effects , Iris Plant , Isoflavones/pharmacology , Rhizome/chemistry , Animals , Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Araceae/drug effects , Artemia/drug effects , Benzopyrans/chemistry , Benzopyrans/isolation & purification , Dioxoles/chemistry , Dioxoles/isolation & purification , Dose-Response Relationship, Drug , Herbicides/pharmacology , Insecta/drug effects , Insecticides/pharmacology , Isoflavones/chemistry , Isoflavones/isolation & purification , Molecular Structure , Plant Extracts/pharmacology , Toxicity Tests
12.
J Ethnopharmacol ; 86(2-3): 177-80, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12738083

ABSTRACT

The anti-inflammatory activity of nine isoflavonoids 5,7-dihydroxy-3-(3'-hydroxy-4',5'dimethoxy)-8-methoxy-4H-1-benzopyran-4-one 1, 5,7-dihydroxy-3-(3'-hydroxyl-4', 5'-dimethoxy)-6-methoxy-4H-1-benzopyran-4-one 2, 5, 7-dihydroxy-3-(4'-hydroxy)-6-methoxy-4H-1-benzopyrane-4-one 3, 5-hydroxy-3-(4'-hydroxy)-6,7-methylenedioxy-4H-1-benzopyran-4-one 4, 5-hydroxy-3-(4'-methoxy)-6,7-methylenedioxy-4H-1-benzopyran-4-one 5, 5-methoxy-3-(4'-hydroxy)-6,7-methyenedioxy-4H-1-benzopyran-4-one 6, 5,7-dihydroxy-3-(3'-hydroxy-4'-methoxy)-6-methoxy-4H-1-benzopyran-4-one 7, 5,7-dihydroxy-3-(3'-methoxy-4'-hydroxy)-6-methoxy-4H-1-benzopyran-4-one 8, and isopeonol 9 determined by a spectrophotometric assay using the activated human neutrophils. These isoflavonoids were isolated from an important folkloric medicinal plant Irsa (Iris germanica L.), a member of the family Iridaceae. Structures of these compounds were identified by spectral comparison with the reported data and active members of this group adds into the growing number of non-steroidal anti-inflammatory agents.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Iris Plant , Isoflavones , Medicine, Traditional , Plant Preparations , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Humans , Isoflavones/chemistry , Isoflavones/isolation & purification , Isoflavones/pharmacology , Neutrophils/drug effects , Plant Preparations/chemistry , Plant Preparations/isolation & purification , Plant Preparations/pharmacology , Rhizome , Spectrophotometry , Structure-Activity Relationship
13.
Chem Pharm Bull (Tokyo) ; 50(8): 1100-2, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12192144

ABSTRACT

Four isoflavone glycosides were isolated from the rhizomes of Iris germanica. Compounds 1 and 2 are new, while compounds 3 and 4 are known isoflavone glycosides. These compounds were identified as iriskashmirianin 4'-O-beta-D-glucoside (1), nigricin 4'-O-beta-D-glucoside (2), irilone 4'-O-beta-D-glucoside (3) and iridin (4). Their structures were determined with the help of spectroscopic methods.


Subject(s)
Glycosides/isolation & purification , Iris Plant/chemistry , Isoflavones/isolation & purification , Rhizome , Glycosides/chemistry , Isoflavones/chemistry , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Rhizome/chemistry
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