24039-89-2Relevant academic research and scientific papers
Synthesis and reactivity of the catechol metabolites from the equine estrogen, 8,9-dehydroestrone
Zhang,Yao,Hua,Van Breemen,Bolton
, p. 754 - 763 (2001)
The risk factors for women developing breast and endometrial cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy in particular has been correlated with an increased cancer risk. Previously, we showed that the equine estrogens equilin and equilenin, which are major components of the widely prescribed estrogen replacement formulation Premarin, are metabolized to highly cytotoxic quinoids which caused oxidative stress and alkylation of DNA in vitro [Bolton, J. L., Pisha, E., Zhang, F., and Qiu, S. Chem. Res. Toxicol. 1998, 11, 1113-1127]. In this study, we have synthesized 8,9-dehydroestrone (a third equine estrogen component of Premarin) and its potential catechol metabolites, 4-hydroxy-8,9-dehydroestrone and 2-hydroxy-8,9-dehydroestrone. Both 2-hydroxy-8,9-dehydroestrone and 4-hydroxy-8,9-dehydroestrone were oxidized by tyrosinase or rat liver microsomes to o-quinones which reacted with GSH to give one mono-GSH conjugate and two di-GSH conjugates. Like endogenous estrogens, 8,9-dehydroestrone was primarily converted by rat liver microsomes to the 2-hydroxylated rather than the 4-hydroxylated o-quinone GSH conjugates; the ratio of 2-hydroxy-8,9-dehydroestrone versus 4-hydroxy-8,9-dehydroestrone was 6:1. Also in contrast to experiments with equilin, 4-hydroxyequilenin was not observed in microsomal incubations with 8,9-dehydroestrone or its catechols. The behavior of 2-hydroxy-8,9-dehydroestrone was found to be more complex than 4-hydroxy-8,9-dehydroestrone as GSH conjugates resulting from 2-hydroxy-8,9-dehydroestrone were detected even without oxidative enzyme catalysis. Under physiological conditions, 2-hydroxy-8,9-dehydroestrone isomerized to 2-hydroxyequilenin to form the very stable 2-hydroxyequilenin catechol; however, 4-hydroxy-8,9-dehydroestrone was found to be stable under similar conditions. Finally, preliminary studies conducted with the human breast tumor S-30 cell lines demonstrated that the catechol metabolites of 8,9-dehydroestrone were much less toxic than 4-hydroxyequilenin (20-40-fold). These results suggest that the catechol metabolites of 8,9-dehydroestrone may have the ability to cause cytotoxicity in vivo primarily through formation of o-quinones; however, most of the adverse effects of Premarin estrogens are likely due to formation of 4-hydroxyequilenin o-quinone from equilin and equilenin.
BETA-2 SELECTIVE ADRENERGIC RECEPTOR AGONISTS
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, (2019/06/23)
Aspects of the present disclosure include conformationally restricted analogs of catecholamine type compounds (e.g., isoprenaline, adrenaline, noradrenaline) which activate β2AR with high selectivity over β1AR. The subject beta-2 selective adrenergic rece
Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction
Mahalingam, Poornachandran,Takrouri, Khuloud,Chen, Ting,Sahoo, Rupam,Papadopoulos, Evangelos,Chen, Limo,Wagner, Gerhard,Aktas, Bertal H.,Halperin, Jose A.,Chorev, Michael
, p. 5094 - 5111 (2014/07/08)
The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro ch
Mapping the catechol binding site in dopamine D1 receptors: Synthesis and evaluation of two parallel series of bicyclic dopamine analogues
Bonner, Lisa A.,Laban, Uros,Chemel, Benjamin R.,Juncosa, Jose I.,Lill, Markus A.,Watts, Val J.,Nichols, David E.
, p. 1024 - 1040 (2012/01/06)
A novel class of isochroman dopamine analogues, originally reported by Abbott Laboratories, have >100-fold selectivity for D1-like over D2-like receptors. We synthesized a parallel series of chroman compounds and showed that repositioning the oxygen atom in the heterocyclic ring decreases potency and confers D2-like receptor selectivity to these compounds. Insilico modeling supports the hypothesis that the altered pharmacology for the chroman series is due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxy group of the catechol moiety. This interaction realigns the catechol hydroxy groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds. Our results suggest that if the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity are restored. What a difference an H bond makes: Structurally related chromans, isochromans, and their carbocyclic analogues were assessed for dopamine D1 and D2 receptor affinity. Isochromans and carbocyclic analogues had high D1 receptor affinity. Poor affinity for the chromans was attributed to an intramolecular hydrogen bond, which disrupts the ligand-receptor hydrogen bonding network.
Facile synthesis of octahydrobenzo[h]isoquinolines: Novel and highly potent D1 dopamine agonists
Bonner, Lisa A.,Chemel, Benjamin R.,Watts, Val J.,Nichols, David E.
experimental part, p. 6763 - 6770 (2010/10/20)
The octahydrobenzo[h]isoquinoline scaffold is of interest as a conformationally-restricted phenethylamine that may be useful for constructing biologically active products. Surprisingly, however, no tractable synthesis of this ring system has been reported
OCTAHYDROBENZOISOQUINOLINE MODULATORS OF DOPAMINE RECEPTORS AND USES THEREFOR
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Page/Page column 31-32, (2010/11/05)
Octahydrobenzoisoquinoline modulators of dopamine receptors are described herein. Methods for using octahydrobenzoisoquinoline modulators of dopamine receptors in the treatment of dopamine dysfunction are also described herein.
Synthesis and evaluation of the bioactivity of simplified analogs of the seco-pseudopterosins; progress toward determining a pharmacophore
Tanis, Virginia M.,Moya, Claudia,Jacobs,Little, R. Daniel
, p. 10649 - 10663 (2008/12/23)
The pseudopterosins are marine natural products that display significant anti-inflammatory and wound healing properties. We describe the synthesis of six structural analogs of the seco-pseudopterosin-like core that are devoid of all but one of the stereoc
5- substituted tetralones as inhibitors of ras farnesyl trransferase
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, (2008/06/13)
The present invention provides novel 5-substituted tetralones of Formulas (I), (II), (III) and (IV) and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof, which are useful for treating and preventing uncontrolled or abnormal proliferation of tissues, such as cancer, atherosclerosis, restenosis, and psoriasis. Specifically, the present invention relates to compounds that inhibit the farnesyl transferase enzyme.
Facile synthesis of 5,6-dimethoxy-1-tetralone
Lahiri, Saswata,Ramarao,Rao, B. Venkateswara,Rao, A.V. Rama,Chorghade, Mukund S.
, p. 71 - 72 (2013/09/08)
A facile synthesis of 5,6-dimethoxy-1-tetralone, a key intermediate in the synthesis of an antidepressant compound, ABT-200, was developed from the inexpensive starting material guaiacol.
Synthesis and in vitro antibacterial activities of novel conformationally restricted hygromycin A analogues
Cooper, Christopher B.,Blair, Kyle T.,Jones, Christopher S.,Minich, Martha L.
, p. 1747 - 1752 (2007/10/03)
The preparation of semisynthetic conformationally restricted hygromycin A analogues are described. Antibacterial results from these compounds suggest active conformations for this class of agents.
