2-Substituted Estradiol Bis-sulfamates, Multitargeted Antitumor Agents:  Synthesis, In Vitro SAR, Protein Crystallography, and In Vivo Activity

Leese, Mathew P.; Leblond, Bertrand; Smith, Andrew C.; Newman, Simon P.; Fiore, Anna Di; Simone, Giuseppina De; Supuran, Claudiu T.; Purohit, Atul; Reed, Michael J.; Potter, Barry V. L.

doi:10.1021/jm060705x

Cited by 100 publications

(178 citation statements)

References 49 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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“…Among the most promising were 2-ethylestradiol-3,17-O,O-bis-sulfamate (compound 14), 2-ethylestrone 3-O-sulfamate (compound 15), and 2-ethylestradiol 3-Osulfamate (compound 16) (Fig. 1) [12][13][14]. Compound 14 was shown to be a highly effective anti-proliferative agent in vitro with a mean 50% growth inhibition concentration (GI 50 ) of 0.018 μM across the National Cancer Institute's (NCI) 60 cancer cell line panel and in vivo in both breast and prostate cancer xenografted mice [12,14].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds

Sippel¹,

Stander²,

Tu³

et al. 2011

LDDD

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“…As an alternative approach to modification of either the steroid nucleus or the C2 position of 2-MeOE2, the C3/C17 hydroxy groups were sulphamoylated to give 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE, Figures 1, 2) (Howarth et al, 1994;Purohit et al, 1995a, b;Raobaikady et al, 2003;Newman et al, 2004;Leese et al, 2006). In addition, a C17 analogue of 2-MeOE2bisMATE, cyanomethyl derivative (2-methoxy-3-O-sulphamoyl-17b-cyanomethyloestra-1,3,5(10)-triene,17-Cym-2-MeOE2-MATE, Figures 1, 3) was also synthesised (Utsumi et al, 2005).…”

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confidence: 99%

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

et al. 2007

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Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg À1 significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg À1 was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg À1 and 38% regression at 20 mg kg À1 . 17-Cym-2-MeOE2MATE (20 mg kg À1 ) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.

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2-Substituted Estradiol Bis-sulfamates, Multitargeted Antitumor Agents: Synthesis, In Vitro SAR, Protein Crystallography, and In Vivo Activity

Cited by 100 publications

References 49 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

Characterization of Carbonic Anhydrase Isozyme Specific Inhibition by Sulfamated 2-Ethylestra Compounds

In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol

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