Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates

Leese, Mathew P.; Leblond, Bertrand; Newman, Simon P.; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1016/j.jsbmb.2005.01.005

Cited by 42 publications

(41 citation statements)

References 31 publications

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“…2-Methoxyoestradiol-3,17-O,O-bis-sulfamate (STX140, Figure 1 compound II) and 2-ethyloestradiol-3,17-O,O-bis-sulfamate (STX243, Figure 1 compound III) were synthesised by reaction of the appropriate 2-substituted oestradiol in dimethyl acetamide solution with sulphamoyl chloride (Leese et al, 2005b(Leese et al, , 2006. 2-Methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide (ENMD1198, IRC110160, Figure 1 compound VI) was synthesised as described in US2005/ 203075 .…”

Section: Drug Synthesismentioning

confidence: 99%

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

et al. 2009

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BACKGROUND: Class III b-tubulin overexpression is a marker of resistance to microtubule disruptors in vitro, in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to develop a new model of class III b-tubulin expression, avoiding the toxicity associated with chronic overexpression of class III b-tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model. METHODS: MCF-7 (ER þ ve) and MDA-MB-231 (ERÀve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT -PCR and immunoblotting were used to monitor the changes in class III b-tubulin mRNA and protein expression. RESULTS: The model allowed for subtle changes in class III b-tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III b-tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III b-tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III b-tubulin expression. CONCLUSION: These data indicate that the effect of class III b-tubulin overexpression may depend on where the drug's binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.

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Section: Drug Synthesismentioning

confidence: 99%

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

et al. 2009

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“…Modification of the C17 position not only imparts improved resistance to metabolism but can also increase the potency of 2-MeOE2-like compounds (37). Furthermore, Utsumi et al (13) showed that 2-MeOE2bisMATE and another C17 positionmodified compound, 2-methoxyestradiol-17h-cyanomethyl-3-Osulfamate, inhibited both in vitro cell proliferation (MCF-7 and MDA-MB-231 cells) and caused significant tumor regression (20 mg/kg p.o.)…”

Section: Discussionmentioning

confidence: 99%

The Role of 17β-Hydroxysteroid Dehydrogenases in Modulating the Activity of 2-Methoxyestradiol in Breast Cancer Cells

et al. 2006

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The bis -sulfamoylated derivative of 2-methoxyestradiol (2-MeOE2), 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2-MeOE2bisMATE), has shown potent antiproliferative and antiangiogenic activity in vitro and inhibits tumor growth in vivo. 2-MeOE2bisMATE is bioavailable, in contrast to 2-MeOE2 that has poor bioavailability. In this study, we have examined the role of 17B-hydroxysteroid dehydrogenase (17B-HSD) type 2 in the metabolism of 2-MeOE2. In MDA-MB-231 cells, which express high levels of 17B-HSD type 2, and in MCF-7 cells transfected with 17B-HSD type 2, highperformance liquid chromatography analysis showed that a significant proportion of 2-MeOE2 was metabolized to inactive 2-methoxyestrone. Furthermore, MCF-7 cells transfected with 17B-HSD type 2 were protected from the cytotoxic effects of 2-MeOE2. In contrast, no significant metabolism of 2-MeOE2bisMATE was detected in transfected cells and 17B-HSD type 2 transfection did not offer protection against 2-MeOE2bisMATE cytotoxicity. This study may go some way to explaining the poor bioavailability of 2-MeOE2, as the gastrointestinal mucosa expresses high levels of 17B-HSD type 2. In addition, this study shows the value of synthesizing sulfamoylated derivatives of 2-MeOE2 with C17-position modifications as these compounds have improved bioavailability and potency both in vitro and in vivo. (Cancer Res 2006; 66(1): 324-30)

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“…Inhibitor design based on the estrane core is nonetheless limited, because they must be devoid of estrogenic activity [13][14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17b-hydroxysteroid dehydrogenase type 1 isozyme (17b-HSD1) were investigated. The transformation of estrone to 17b-estradiol was studied by an in vitro radiosubstrate incubation method. 13a-Estrone inhibited the enzyme activity effectively with an IC 50 value of 1.2 mM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13b derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13a and 3-ether counterparts. The 3-hydroxy13b-D-secoalcohol and the 3-hydroxy-13a-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy13b-D-secooxime has an IC 50 value of 0.070 mM and is one of the most effective 17b-HSD1 inhibitors reported to date in the literature.

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Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates

Cited by 42 publications

References 31 publications

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

The Role of 17β-Hydroxysteroid Dehydrogenases in Modulating the Activity of 2-Methoxyestradiol in Breast Cancer Cells

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

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