Source:http://linkedlifedata.com/resource/pubmed/id/18472187
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
2009-2-23
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pubmed:abstractText |
Androgens are well known to play a predominant role in prostate cancer and other androgen-dependent diseases. To decrease the level of androgen testosterone in the prostate, we are interested in developing inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5). This enzyme expressed in the prostate is one of the two enzymes able to convert 4-androstene-3,17-dione into testosterone. From a screening study, it was found that a series of steroid derivatives bearing a lactone on D-ring demonstrated potent inhibition of 17beta-HSD5 over-expressed in HEK-293 cells. The results of enzymatic assays using intact cells indicated that a C18-steroid (estradiol or 3-deoxyestradiol) backbone and a spiro-delta-lactone (six-member ring) are important for a strong inhibitory activity. Moreover, the presence of a dimethyl group at the alpha-position of the lactone carbonyl increases the selectivity of the inhibitor toward 17beta-HSD5. Compound 26, a 3-deoxyestradiol derivative with a dimethylated spiro-delta-lactone at position 17, possesses the most potent inhibitory activity for 17beta-HSD5 (IC(50)=2.9 nM). It showed no binding affinity for estrogen, androgen, progestin and glucocorticoid receptors (ER, AR, PR and GR). A weak proliferative effect was, however, observed on ZR-75-1 (ER+) cells in culture at high concentration (1 microM), but not at 0.03 microM. Interestingly, no significant proliferative effect was detected on Shionogi (AR+) cells in culture in the presence of 0.1 and 1 microM of lactone 26.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/17-Hydroxysteroid Dehydrogenases,
http://linkedlifedata.com/resource/pubmed/chemical/3 (or 17)-beta-hydroxysteroid...,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Lactones,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Androgen,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Estrogen,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Glucocorticoid,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Progesterone,
http://linkedlifedata.com/resource/pubmed/chemical/Steroids
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1768-3254
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:volume |
44
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
632-44
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pubmed:meshHeading |
pubmed-meshheading:18472187-17-Hydroxysteroid Dehydrogenases,
pubmed-meshheading:18472187-Cell Line,
pubmed-meshheading:18472187-Cell Proliferation,
pubmed-meshheading:18472187-Enzyme Inhibitors,
pubmed-meshheading:18472187-Humans,
pubmed-meshheading:18472187-Lactones,
pubmed-meshheading:18472187-Male,
pubmed-meshheading:18472187-Prostatic Diseases,
pubmed-meshheading:18472187-Receptors, Androgen,
pubmed-meshheading:18472187-Receptors, Estrogen,
pubmed-meshheading:18472187-Receptors, Glucocorticoid,
pubmed-meshheading:18472187-Receptors, Progesterone,
pubmed-meshheading:18472187-Steroids,
pubmed-meshheading:18472187-Structure-Activity Relationship
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pubmed:year |
2009
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pubmed:articleTitle |
Steroidal lactones as inhibitors of 17beta-hydroxysteroid dehydrogenase type 5: chemical synthesis, enzyme inhibitory activity, and assessment of estrogenic and androgenic activities.
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pubmed:affiliation |
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and University Laval, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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