The Synthesis and Pharmacologic Evaluation of a Series of 8-Alkylthio-Thiated Theophyllines<sup>1</sup>

Dietz, Albert G. H.; Burgison, Raymond M.

doi:10.1021/jm00322a013

Cited by 11 publications

(6 citation statements)

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“…Here we used FAMA to conduct HTS and identified a small molecule, theophylline, 8-[(benzylthio)methyl]-(7CI,8CI) (TPBM, an 8-alkylthiothiated theophylline) (31,32), that specifically inhibits E 2 -induced, ER␣-mediated, gene expression in intact cells, without significantly inhibiting PR-and GR-mediated gene expression. TPBM also inhibits E 2 and 4-hydroxytamoxifen (OHT, the active metabolite of Tam) induction of an endogenous gene in Tam-resistant breast cancer cells expressing elevated levels of ER␣.…”

Section: Estrogen Receptor ␣ (Er␣)mentioning

confidence: 99%

A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

Mao

Patterson

Cherian

et al. 2008

Journal of Biological Chemistry

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Estrogen receptor ␣ (ER␣)3 is a member of the steroid/nuclear receptor family of transcription regulators and mediates cell growth and metastasis and resistance to apoptosis and immunosurveillance (1-5). ER␣ is activated by binding of 17␤-estradiol (E 2 ), or by the epidermal growth factor-activated extracellular signal-regulated kinase pathway and other signal transduction pathways (6). ER␣-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer (5,7,8). A role for ER action in ovarian cancer is supported by the recent finding that endocrine therapy is effective against relapsed ER-containing ovarian cancers (9, 10). Aromatase inhibitors that inhibit estrogen production and tamoxifen (Tam) and other selective estrogen receptor modulators (SERMs) are mainstays in treatment of estrogen-dependent cancers and have played an important role in developing our understanding of ER action (5,7,11,12). Tam and other SERMs work by competing with estrogens for binding in the ligand binding pocket of ER. Over time, tumors usually become resistant to tamoxifen and other SERMs (13-15), requiring new strategies to inhibit ER␣ action.In the best characterized model for ER action, ER␣ activates gene transcription by binding to palindromic estrogen response element (ERE) DNA and ERE half sites (4,16, 17). Thus, an alternative to current approaches that primarily target ER action at the level of ligand binding is to target ER␣ at the level of its interaction with ERE DNA. Although targeting protein binding to DNA is attractive, until recently this approach was questioned, because small molecules may not disrupt the large interaction surfaces of protein⅐DNA and protein⅐protein complexes (18). However, several recent studies support the feasi-

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Section: Estrogen Receptor ␣ (Er␣)mentioning

confidence: 99%

A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

Mao

Patterson

Cherian

et al. 2008

Journal of Biological Chemistry

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“…Compounds 2-55 were synthesized as described by Dietz and Burgison [11,12], and obtained from the NCI Developmental Therapeutics Program. Solid compounds were dissolved in dimethyl sulfoxide (DMSO) and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

“…In a high-throughput screen, our laboratory identified a small molecule inhibitor of steroid receptor transactivation [10], 8-benzylsulfanylmethyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (TPBM), that belongs to a family of theophylline derivatives originally synthesized by Dietz & Burgison [11,12]. A second small molecule characterized from this set, 8-((4-(4-fluorophenyl)-4-oxobutyl)thio)-1,3-dimethyl-6-thioxo-6,7-dihydro-1 H -purin-2(3 H )-one (TPSF), showed increased potency and a different mode of action than TPBM [13].…”

Section: Introductionmentioning

confidence: 99%

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

et al. 2012

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The progesterone receptor (PR) plays a key role in reproduction and is important in cancers of the reproductive tract. Current PR antagonists usually compete for progestin binding in the PR ligand-binding pocket and often exhibit cross-binding with other members of the steroid receptor family. Using stably transfected cells expressing reporter genes, a set of ~150 theophylline analogues were screened for their ability to inhibit progesterone, estrogen, glucocorticoid and androgen signaling. The structure-activity studies presented here identify branched 8-alkylthio-6-thio-substitutions of theophylline as selective PR inhibitors. 6-thio-8-(2-ethylbutyl)thiotheophylline (51), the most extensively studied derivative, does not act by competing with progestins for binding in the ligand-binding pocket of PR. It demonstrated the ability to inhibit the mouse mammary tumor virus (MMTV)-luciferase reporter and endogenous PR-regulated alkaline phosphatase activity in T47D breast cancer cells. Compound 51 is the lead member of a novel class of PR inhibitors that act outside the PR ligand-binding pocket, thus serving as a novel probe to investigate PR action and a lead for further development.

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“…These sedative substituted xanthines include several 8-alkylthiothiated theophyllines (Dietz and Burgison 1966) and some 8-alkyl-and 8-cycloaNytheophyllines (Goodsell etal. 1971).…”

mentioning

confidence: 99%

“…1971). However, in the experiments of Dietz and Burgison (1966) and Goodsell et al (1971) only gross behavioral measures of sedation (e.g. ataxia, postural changes, loss of righting reflex, and hexobarbital sleeping time potentiation) were employed.…”

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confidence: 99%

Dose-response effects of 8-cyclopropyltheophylline on sleep and wakefulness in rats

Radulovački

Virus

1988

Psychopharmacology

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The dose-response effects of the substituted xanthine 8-cyclopropyltheophylline (CPRT) on sleep and wakefulness (W) after intraperitoneal administration to rats were examined by means of simultaneous electroencephalographic (EEG) and electromyographic (EMG) recordings. Doses of 20 and 40 mg/kg CPRT increased W and decreased slow wave sleep (SWS) in rats, indicating CNS stimulant effects. The greatest CNS stimulation was produced by the lowest (20 mg/kg) dose of CPRT examined, which also increased the latency to SWS. In addition, the 20 mg/kg dose of CPRT also significantly decreased the amount of total sleep (TS), as compared to the vehicle group, during all time periods examined. In contrast, the 80 mg/kg dose of CPRT decreased W and increased both SWS and TS. However, this apparent hypnotic effect of the 80 mg/kg CPRT may be due to toxicity, since 80% of rats treated with this dose of the drug died within 48 h of injection.

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The Synthesis and Pharmacologic Evaluation of a Series of 8-Alkylthio-Thiated Theophyllines¹

Cited by 11 publications

References 0 publications

A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

Dose-response effects of 8-cyclopropyltheophylline on sleep and wakefulness in rats

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The Synthesis and Pharmacologic Evaluation of a Series of 8-Alkylthio-Thiated Theophyllines1

Cited by 11 publications

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A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells

8-Alkylthio-6-thio-substituted theophylline analogues as selective noncompetitive progesterone receptor antagonists

Dose-response effects of 8-cyclopropyltheophylline on sleep and wakefulness in rats

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The Synthesis and Pharmacologic Evaluation of a Series of 8-Alkylthio-Thiated Theophyllines¹