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Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo
17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17α-hydroxylase/C 17,20-lyase with IC 50 values ranging from 7 to 90 nM, and K i values from 1.2 to 41 nM. VN/8...
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| Published in: | The Journal of steroid biochemistry and molecular biology 1999-12, Vol.71 (3), p.145-152 |
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| container_issue | 3 |
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| container_title | The Journal of steroid biochemistry and molecular biology |
| container_volume | 71 |
| creator | Nnane, I.P. Njar, V.C.O. Liu, Y. Lu, Q. Brodie, A.M.H. |
| description | 17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17α-hydroxylase/C
17,20-lyase with IC
50 values ranging from 7 to 90 nM, and
K
i values from 1.2 to 41 nM.
VN/85-1 and
VN/108-1 were the most potent inhibitors against this enzyme with IC
50 value of 8 nM (
K
i of 1.2 nM) and 7 nM (
K
i of 1.9 nM), respectively.
VN/107-1,
VN/108-1 and
VN/109-1 also showed moderate inhibition of 5α-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1–2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly (
p |
| doi_str_mv | 10.1016/S0960-0760(99)00129-6 |
| format | article |
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17,20-lyase with IC
50 values ranging from 7 to 90 nM, and
K
i values from 1.2 to 41 nM.
VN/85-1 and
VN/108-1 were the most potent inhibitors against this enzyme with IC
50 value of 8 nM (
K
i of 1.2 nM) and 7 nM (
K
i of 1.9 nM), respectively.
VN/107-1,
VN/108-1 and
VN/109-1 also showed moderate inhibition of 5α-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1–2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly (
p<0.05) lower in rats treated with the novel 17-azolyl steroids by more than 50% compared to the control group. Similarly, the concentration of DHT in the serum and prostates was significantly (
p<0.05) diminished in rats treated with the 17-azolyl steroids by 39–80% compared to the control group. Furthermore, the wet weights of the prostates and seminal vesicles were significantly (
p<0.05) reduced by several of the novel steroids. Although only one dose was evaluated in these studies,
VN/85-1 was the most effective compound and reduced prostatic androgen levels by more than 80% and the wet weights of the prostate and seminal vesicles in rats by about 50%. These findings suggest that these novel compounds may provide useful leads for the research and development of suitable agents for the treatment of androgen dependent prostate cancer.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/S0960-0760(99)00129-6</identifier><identifier>PMID: 10659703</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>17-Azolyl steroids ; 17α-hydroxylase/C 17,20-Lyase ; 5α-Reductase ; Androgens ; Androgens - biosynthesis ; Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Azoles - chemistry ; Azoles - pharmacology ; Biological and medical sciences ; Dihydrotestosterone - blood ; Dihydrotestosterone - metabolism ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Genitalia, Male - drug effects ; Genitalia, Male - metabolism ; Gynecology. Andrology. Obstetrics ; Humans ; In Vitro Techniques ; Kinetics ; Male ; Male genital diseases ; Medical sciences ; Prostate - drug effects ; Prostate - metabolism ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Rats ; Rats, Sprague-Dawley ; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors ; Steroids - chemistry ; Steroids - pharmacology ; Testis - drug effects ; Testis - metabolism ; Testosterone - blood ; Testosterone - metabolism ; Tumors</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 1999-12, Vol.71 (3), p.145-152</ispartof><rights>2000</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-ff60e92317c05480c5a7977599cd05d27f0407dbd4d008e9d361f9a52fac418f3</citedby><cites>FETCH-LOGICAL-c390t-ff60e92317c05480c5a7977599cd05d27f0407dbd4d008e9d361f9a52fac418f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1240902$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10659703$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nnane, I.P.</creatorcontrib><creatorcontrib>Njar, V.C.O.</creatorcontrib><creatorcontrib>Liu, Y.</creatorcontrib><creatorcontrib>Lu, Q.</creatorcontrib><creatorcontrib>Brodie, A.M.H.</creatorcontrib><title>Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17α-hydroxylase/C
17,20-lyase with IC
50 values ranging from 7 to 90 nM, and
K
i values from 1.2 to 41 nM.
VN/85-1 and
VN/108-1 were the most potent inhibitors against this enzyme with IC
50 value of 8 nM (
K
i of 1.2 nM) and 7 nM (
K
i of 1.9 nM), respectively.
VN/107-1,
VN/108-1 and
VN/109-1 also showed moderate inhibition of 5α-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1–2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly (
p<0.05) lower in rats treated with the novel 17-azolyl steroids by more than 50% compared to the control group. Similarly, the concentration of DHT in the serum and prostates was significantly (
p<0.05) diminished in rats treated with the 17-azolyl steroids by 39–80% compared to the control group. Furthermore, the wet weights of the prostates and seminal vesicles were significantly (
p<0.05) reduced by several of the novel steroids. Although only one dose was evaluated in these studies,
VN/85-1 was the most effective compound and reduced prostatic androgen levels by more than 80% and the wet weights of the prostate and seminal vesicles in rats by about 50%. These findings suggest that these novel compounds may provide useful leads for the research and development of suitable agents for the treatment of androgen dependent prostate cancer.</description><subject>17-Azolyl steroids</subject><subject>17α-hydroxylase/C 17,20-Lyase</subject><subject>5α-Reductase</subject><subject>Androgens</subject><subject>Androgens - biosynthesis</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Azoles - chemistry</subject><subject>Azoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Dihydrotestosterone - blood</subject><subject>Dihydrotestosterone - metabolism</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Genitalia, Male - drug effects</subject><subject>Genitalia, Male - metabolism</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Male</subject><subject>Male genital diseases</subject><subject>Medical sciences</subject><subject>Prostate - drug effects</subject><subject>Prostate - metabolism</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Steroid 17-alpha-Hydroxylase - antagonists & inhibitors</subject><subject>Steroids - chemistry</subject><subject>Steroids - pharmacology</subject><subject>Testis - drug effects</subject><subject>Testis - metabolism</subject><subject>Testosterone - blood</subject><subject>Testosterone - metabolism</subject><subject>Tumors</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNqFkE1LAzEQhoMoWqs_QdmDiB5WJ_uR7JxExC8oeFDPIeZDI9ukJttC_fVu3aLePA3DPDPz8hByQOGMAmXnj4AMcuAMThBPAWiBOdsgI9pwzGlRwCYZ_SA7ZDeldwAoS8q3yQ4FViOHckQerq01qktZsJkPC9NmlOfyM7TLNlNhOgtzr_uhz6TXMbwan6Wl795McilzPlu4LobVbGgWYY9sWdkms7-uY_J8c_10dZdPHm7vry4nuSoRutxaBgaLPo2CumpA1ZIj5zWi0lDrgluogOsXXWmAxqAuGbUo68JKVdHGlmNyPNydxfAxN6kTU5eUaVvpTZgnwbCiVUPrHqwHUMWQUjRWzKKbyrgUFMTKpPg2KVaaBKL4NilYv3e4fjB_mRr9Z2tQ1wNHa0AmJVsbpVcu_XJFBQhFj10MmOltLJyJIilnvDLaxV680MH9k-QL9myOvw</recordid><startdate>19991215</startdate><enddate>19991215</enddate><creator>Nnane, I.P.</creator><creator>Njar, V.C.O.</creator><creator>Liu, Y.</creator><creator>Lu, Q.</creator><creator>Brodie, A.M.H.</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19991215</creationdate><title>Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo</title><author>Nnane, I.P. ; Njar, V.C.O. ; Liu, Y. ; Lu, Q. ; Brodie, A.M.H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-ff60e92317c05480c5a7977599cd05d27f0407dbd4d008e9d361f9a52fac418f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>17-Azolyl steroids</topic><topic>17α-hydroxylase/C 17,20-Lyase</topic><topic>5α-Reductase</topic><topic>Androgens</topic><topic>Androgens - biosynthesis</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Azoles - chemistry</topic><topic>Azoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Dihydrotestosterone - blood</topic><topic>Dihydrotestosterone - metabolism</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Genitalia, Male - drug effects</topic><topic>Genitalia, Male - metabolism</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Male</topic><topic>Male genital diseases</topic><topic>Medical sciences</topic><topic>Prostate - drug effects</topic><topic>Prostate - metabolism</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Steroid 17-alpha-Hydroxylase - antagonists & inhibitors</topic><topic>Steroids - chemistry</topic><topic>Steroids - pharmacology</topic><topic>Testis - drug effects</topic><topic>Testis - metabolism</topic><topic>Testosterone - blood</topic><topic>Testosterone - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nnane, I.P.</creatorcontrib><creatorcontrib>Njar, V.C.O.</creatorcontrib><creatorcontrib>Liu, Y.</creatorcontrib><creatorcontrib>Lu, Q.</creatorcontrib><creatorcontrib>Brodie, A.M.H.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nnane, I.P.</au><au>Njar, V.C.O.</au><au>Liu, Y.</au><au>Lu, Q.</au><au>Brodie, A.M.H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>1999-12-15</date><risdate>1999</risdate><volume>71</volume><issue>3</issue><spage>145</spage><epage>152</epage><pages>145-152</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17α-hydroxylase/C
17,20-lyase with IC
50 values ranging from 7 to 90 nM, and
K
i values from 1.2 to 41 nM.
VN/85-1 and
VN/108-1 were the most potent inhibitors against this enzyme with IC
50 value of 8 nM (
K
i of 1.2 nM) and 7 nM (
K
i of 1.9 nM), respectively.
VN/107-1,
VN/108-1 and
VN/109-1 also showed moderate inhibition of 5α-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1–2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly (
p<0.05) lower in rats treated with the novel 17-azolyl steroids by more than 50% compared to the control group. Similarly, the concentration of DHT in the serum and prostates was significantly (
p<0.05) diminished in rats treated with the 17-azolyl steroids by 39–80% compared to the control group. Furthermore, the wet weights of the prostates and seminal vesicles were significantly (
p<0.05) reduced by several of the novel steroids. Although only one dose was evaluated in these studies,
VN/85-1 was the most effective compound and reduced prostatic androgen levels by more than 80% and the wet weights of the prostate and seminal vesicles in rats by about 50%. These findings suggest that these novel compounds may provide useful leads for the research and development of suitable agents for the treatment of androgen dependent prostate cancer.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>10659703</pmid><doi>10.1016/S0960-0760(99)00129-6</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-0760 |
| ispartof | The Journal of steroid biochemistry and molecular biology, 1999-12, Vol.71 (3), p.145-152 |
| issn | 0960-0760 1879-1220 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69414815 |
| source | Elsevier |
| subjects | 17-Azolyl steroids 17α-hydroxylase/C 17,20-Lyase 5α-Reductase Androgens Androgens - biosynthesis Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Azoles - chemistry Azoles - pharmacology Biological and medical sciences Dihydrotestosterone - blood Dihydrotestosterone - metabolism Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Genitalia, Male - drug effects Genitalia, Male - metabolism Gynecology. Andrology. Obstetrics Humans In Vitro Techniques Kinetics Male Male genital diseases Medical sciences Prostate - drug effects Prostate - metabolism Prostate cancer Prostatic Neoplasms - drug therapy Rats Rats, Sprague-Dawley Steroid 17-alpha-Hydroxylase - antagonists & inhibitors Steroids - chemistry Steroids - pharmacology Testis - drug effects Testis - metabolism Testosterone - blood Testosterone - metabolism Tumors |
| title | Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo |
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