Publications
218 results found
Ganeshapillai D, Woo LWL, Thomas MP, et al., 2018, C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors, ACS OMEGA, Vol: 3, Pages: 10748-10772, ISSN: 2470-1343
Synthetic routes to potent bicyclic nonsteroidal sulfamate-based active-site-directed inhibitors of the enzyme steroid sulfatase (STS), an emerging target in the treatment of postmenopausal hormone-dependent diseases, including breast cancer, are described. Sulfamate analogs 9–27 and 28–46 of the core in vivo active two-ring coumarin template, modified at the 4- and 3-positions, respectively, were synthesized to expand structure–activity relationships. α-Alkylacetoacetates were used to synthesize coumarin sulfamate derivatives with 3-position modifications, and the bicyclic ring of other parent coumarins was primarily constructed via the Pechmann synthesis of hydroxyl coumarins. Compounds were examined for STS inhibition in intact MCF-7 breast cancer cells and in placental microsomes. Low nanomolar potency STS inhibitors were achieved, and some were found to inhibit the enzyme in MCF-7 cells ca. 100–500 more potently than the parent 4-methylcoumarin-7-O-sulfamate 3, with the best compounds close in potency to the tricyclic clinical drug Irosustat. 3-Hexyl-4-methylcoumarin-7-O-sulfamate 29 and 3-benzyl-4-methylcoumarin-7-O-sulfamate 41 were particularly effective inhibitors with IC50 values of 0.68 and 1 nM in intact MCF-7 cells and 8 and 32 nM for placental microsomal STS, respectively. They were docked into the STS active site for comparison with estrone 3-O-sulfamate and Irosustat, showing their sulfamate group close to the catalytic hydrated formylglycine residue and their pendant group lying between the hydrophobic sidechains of L103, F178, and F488. Such highly potent STS inhibitors expand the structure–activity relationship for these coumarin sulfamate-based agents that possess therapeutic potential and may be worthy of further development.
Stengel C, Newman SP, Leese MP, et al., 2015, The In Vitro and In Vivo Activity of the Microtubule Disruptor STX140 Is Mediated by Hif-1 Alpha and CAIX Expression, ANTICANCER RESEARCH, Vol: 35, Pages: 5249-5261, ISSN: 0250-7005
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- Citations: 12
Stengel C, Newman SP, Day JM, et al., 2014, In vivo and in vitro properties of STX2484: a novel non-steroidal anti-cancer compound active in taxane-resistant breast cancer, BRITISH JOURNAL OF CANCER, Vol: 111, Pages: 300-308, ISSN: 0007-0920
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- Citations: 9
Elliott KM, Dent J, Stanczyk FZ, et al., 2014, Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer, BRITISH JOURNAL OF SURGERY, Vol: 101, Pages: 939-948, ISSN: 0007-1323
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- Citations: 12
Leese MP, Jourdan FL, Major MR, et al., 2014, Synthesis, Anti-tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones, CHEMMEDCHEM, Vol: 9, Pages: 798-812, ISSN: 1860-7179
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- Citations: 17
Dohle W, Leese MP, Jourdan FL, et al., 2014, Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1-Substituted Tetrahydroisoquinolines, CHEMMEDCHEM, Vol: 9, Pages: 350-370, ISSN: 1860-7179
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- Citations: 14
Meyer-Losic F, Newman SP, Day JM, et al., 2013, STX140, but Not Paclitaxel, Inhibits Mammary Tumour Initiation and Progression in C3(1)/SV40T/t-Antigen Transgenic Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 16
Woo LWL, Wood PM, Bubert C, et al., 2013, Synthesis and Structure-Activity Relationship Studies of Derivatives of the Dual Aromatase-Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate, CHEMMEDCHEM, Vol: 8, Pages: 779-799, ISSN: 1860-7179
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- Citations: 23
Day JM, Foster PA, Tutill HJ, et al., 2013, STX2171, a 17 beta-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model, ENDOCRINE-RELATED CANCER, Vol: 20, Pages: 53-64, ISSN: 1351-0088
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- Citations: 16
Woo LWL, Leblond B, Purohit A, et al., 2012, Synthesis and evaluation of analogues of estrone-3-O-sulfamate as potent steroid sulfatase inhibitors, BIOORGANIC & MEDICINAL CHEMISTRY, Vol: 20, Pages: 2506-2519, ISSN: 0968-0896
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- Citations: 42
Meyer-Losic F, Fiore A, Carlson M, et al., 2012, Safety profile and therapeutic potential in breast cancer of STX140, an original tubulin binding agent, CANCER RESEARCH, Vol: 72, ISSN: 0008-5472
Purohit A, Foster PA, 2012, Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers, JOURNAL OF ENDOCRINOLOGY, Vol: 212, Pages: 99-110, ISSN: 0022-0795
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- Citations: 104
Wood PM, Woo LWL, Thomas MP, et al., 2011, Aromatase and Dual Aromatase-Steroid Sulfatase Inhibitors from the Letrozole and Vorozole Templates, CHEMMEDCHEM, Vol: 6, Pages: 1423-1438, ISSN: 1860-7179
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- Citations: 53
Jourdan F, Leese MP, Dohle W, et al., 2011, Structure-Activity Relationships of C-17-Substituted Estratriene-3-O-sulfamates as Anticancer Agents, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 54, Pages: 4863-4879, ISSN: 0022-2623
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- Citations: 17
Purohit A, Woo LWL, Potter BVL, 2011, Steroid sulfatase: A pivotal player in estrogen synthesis and metabolism, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 340, Pages: 154-160, ISSN: 0303-7207
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- Citations: 50
Woo LWL, Purohit A, Potter BVL, 2011, Development of steroid sulfatase inhibitors, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 340, Pages: 175-185, ISSN: 0303-7207
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- Citations: 50
Geisler J, Sasano H, Chen S, et al., 2011, Steroid sulfatase inhibitors: Promising new tools for breast cancer therapy?, JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, Vol: 125, Pages: 39-45, ISSN: 0960-0760
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- Citations: 47
Stanway SJ, Palmieri C, Stanczyk FZ, et al., 2011, Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer, ANTICANCER RESEARCH, Vol: 31, Pages: 1367-1372, ISSN: 0250-7005
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- Citations: 6
Woo LWL, Bubert C, Purohit A, et al., 2011, Hybrid Dual Aromatase-Steroid Sulfatase Inhibitors with Exquisite Picomolar Inhibitory Activity, ACS MEDICINAL CHEMISTRY LETTERS, Vol: 2, Pages: 243-247, ISSN: 1948-5875
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- Citations: 30
Woo LWL, Ganeshapillai D, Thomas MP, et al., 2011, Structure-Activity Relationship for the First-in-Class Clinical Steroid Sulfatase Inhibitor Irosustat (STX64, BN83495), ChemMedChem: chemistry enabling drug discovery, Vol: 6, Pages: 2019-2034
Wood PM, Woo LWL, Labrosse J-R, et al., 2010, Bicyclic Derivatives of the Potent Dual Aromatase-Steroid Sulfatase Inhibitor 2-Bromo-4-{[(4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenylsulfamate: Synthesis, SAR, Crystal Structure, and in vitro and in vivo Activities, CHEMMEDCHEM, Vol: 5, Pages: 1577-1593, ISSN: 1860-7179
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- Citations: 22
Day JM, Foster PA, Tutill HJ, et al., 2010, STX2171, a 17 beta-Hydroxysteroid Dehydrogenase Type 3 (17 beta-HSD3) Inhibitor, Is Efficacious In Vivo in a Novel Hormone-Dependent Prostate Cancer Model., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Day JM, Tutill HJ, Purohit A, 2010, 17 beta-Hydroxysteroid dehydrogenase inhibitors, MINERVA ENDOCRINOLOGICA, Vol: 35, Pages: 87-108, ISSN: 0391-1977
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- Citations: 18
Jourdan F, Leese MP, Dohle W, et al., 2010, Synthesis, Antitubulin, and Antiproliferative SAR of Analogues of 2-Methoxyestradiol-3,17-O,O-bis-sulfamate, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 53, Pages: 2942-2951, ISSN: 0022-2623
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- Citations: 38
Woo LWL, Jackson T, Putey A, et al., 2010, Highly Potent First Examples of Dual Aromatase-Steroid Sulfatase Inhibitors based on a Biphenyl Template, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 53, Pages: 2155-2170, ISSN: 0022-2623
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- Citations: 69
Stengel C, Newman SP, Leese MP, et al., 2010, Class III beta-tubulin expression and in vitro resistance to microtubule targeting agents, BRITISH JOURNAL OF CANCER, Vol: 102, Pages: 316-324, ISSN: 0007-0920
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- Citations: 133
Leese MP, Jourdan F, Kimberley MR, et al., 2010, Chimeric microtubule disruptors, CHEMICAL COMMUNICATIONS, Vol: 46, Pages: 2907-2909, ISSN: 1359-7345
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- Citations: 24
Foster PA, Ho YT, Newman SP, et al., 2009, STX140 and STX641 Cause Apoptosis via the Intrinsic Mitochondrial Pathway and Down-regulate Survivin and XIAP Expression in Ovarian and Prostate Cancer Cells, ANTICANCER RESEARCH, Vol: 29, Pages: 3751-3757, ISSN: 0250-7005
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- Citations: 8
Stengel C, Newman S, Foster P, et al., 2009, Anti-cancer activity of a new non-steroidal anti-angiogenic microtubule disruptor in breast cancer, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
Stengel C, Newman S, Foster P, et al., 2009, Anti-cancer activity of a new non-steroidal anti-angiogenic microtubule disruptor in breast cancer, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472
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