Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase

2004 ◽  
Vol 12 (10) ◽  
pp. 2759-2772 ◽  
Author(s):  
Hatem A.M Hejaz ◽  
L.W.Lawrence Woo ◽  
Atul Purohit ◽  
Michael J Reed ◽  
Barry V.L Potter
Keyword(s):  
Steroid Sulfatase

scholarly journals Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

2011 ◽  
Vol 212 (2) ◽  
pp. 99-110 ◽  
Author(s):  
Atul Purohit ◽  
Paul A Foster
Keyword(s):  
Clinical Trials ◽  
Dehydroepiandrosterone Sulfate ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Developmental History ◽  
Estrone Sulfate ◽  
Therapy Targets ◽  
History Of

Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

scholarly journals No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies

2005 ◽  
Vol 90 (6) ◽  
pp. 3600-3605 ◽  
Author(s):  
Fabian Hammer ◽  
Sandra Subtil ◽  
Philipp Lux ◽  
Christiane Maser-Gluth ◽  
Paul M. Stewart ◽  
...  
Keyword(s):  
Sex Steroids ◽  
Hepg2 Cells ◽  
Young Men ◽  
In Vitro Studies ◽  
Steroid Sulfatase ◽  
No Conversion ◽  
Storage Pool ◽  
Androstanediol Glucuronide

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS interconvert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependant conversion of DHEA (0.1–2 μm) to DHEAS but no conversion of DHEAS (0.1–2 μm). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.

Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

ChemMedChem ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. 1708-1730 ◽  
Author(s):  
Christian Bubert ◽  
L. W. Lawrence Woo ◽  
Oliver B. Sutcliffe ◽  
Mary F. Mahon ◽  
Surinder K. Chander ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Aromatase Inhibitors ◽  
Steroid Sulfatase

Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography

2008 ◽  
Vol 7 (8) ◽  
pp. 2435-2444 ◽  
Author(s):  
L.W. Lawrence Woo ◽  
Delphine S. Fischer ◽  
Christopher M. Sharland ◽  
Melanie Trusselle ◽  
Paul A. Foster ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Second Generation ◽  
Protein Crystallography ◽  
Steroid Sulfatase ◽  
Generation Agent

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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