Small-Molecule Inhibitors of 25-Hydroxyvitamin D‑24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation
The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivit...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-09, Vol.57 (18), p.7702-7715 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ferla, Salvatore Aboraia, Ahmed S Brancale, Andrea Pepper, Christopher J Zhu, Jinge Ochalek, Justin T DeLuca, Hector F Simons, Claire |
| description | The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation. |
| doi_str_mv | 10.1021/jm5009314 |
| format | Article |
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Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm5009314</identifier><identifier>PMID: 25148392</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Catalytic Domain ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemistry Techniques, Synthetic ; Cytochrome P-450 Enzyme Inhibitors - chemical synthesis ; Cytochrome P-450 Enzyme Inhibitors - chemistry ; Cytochrome P-450 Enzyme Inhibitors - metabolism ; Cytochrome P-450 Enzyme Inhibitors - pharmacology ; Heme - metabolism ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - metabolism ; Imidazoles - pharmacology ; Inhibitory Concentration 50 ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Models, Molecular ; Sequence Homology, Amino Acid ; Structure-Activity Relationship ; Vitamin D3 24-Hydroxylase - antagonists & inhibitors ; Vitamin D3 24-Hydroxylase - chemistry</subject><ispartof>Journal of medicinal chemistry, 2014-09, Vol.57 (18), p.7702-7715</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a350t-ff050be356a1b3dff786b1e8739ff3c144356a0cbc050531046f83ef21b1880e3</citedby><cites>FETCH-LOGICAL-a350t-ff050be356a1b3dff786b1e8739ff3c144356a0cbc050531046f83ef21b1880e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm5009314$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm5009314$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27074,27922,27923,56736,56786</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25148392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferla, Salvatore</creatorcontrib><creatorcontrib>Aboraia, Ahmed S</creatorcontrib><creatorcontrib>Brancale, Andrea</creatorcontrib><creatorcontrib>Pepper, Christopher J</creatorcontrib><creatorcontrib>Zhu, Jinge</creatorcontrib><creatorcontrib>Ochalek, Justin T</creatorcontrib><creatorcontrib>DeLuca, Hector F</creatorcontrib><creatorcontrib>Simons, Claire</creatorcontrib><title>Small-Molecule Inhibitors of 25-Hydroxyvitamin D‑24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Catalytic Domain</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemistry Techniques, Synthetic</subject><subject>Cytochrome P-450 Enzyme Inhibitors - chemical synthesis</subject><subject>Cytochrome P-450 Enzyme Inhibitors - chemistry</subject><subject>Cytochrome P-450 Enzyme Inhibitors - metabolism</subject><subject>Cytochrome P-450 Enzyme Inhibitors - pharmacology</subject><subject>Heme - metabolism</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - metabolism</subject><subject>Imidazoles - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Models, Molecular</subject><subject>Sequence Homology, Amino Acid</subject><subject>Structure-Activity Relationship</subject><subject>Vitamin D3 24-Hydroxylase - antagonists & inhibitors</subject><subject>Vitamin D3 24-Hydroxylase - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtOwkAUQCdGI4gu_AEzGxNYVO-8SnGHiEKi0QRduGqmZUaGTDvYaYns_AV_0S-xhMfK1U3uPTnJPQidE7giQMn1PBMAPUb4AWoSQSHgEfBD1ASgNKAhZQ104v0cABih7Bg1qCA8Yj3aRItJJq0NnpxVaWUVHuczk5jSFR47jakIRqtp4b5WS1PKzOT47vf7h_Ld1kqvcHvw_kJ5n3Ru8GSVlzPljccyn-Jb46z7MKm0eLiUtpKlcfkpOtLSenW2nS30dj98HYyCx-eH8aD_GEgmoAy0BgGJYiKUJGFTrbtRmBAVdVlPa5YSztcnSJO05gQjwEMdMaUpSUgUgWIt1N54F4X7rJQv48z4VFkrc-UqH5OQCsbDqBa1UGeDpoXzvlA6XhQmk8UqJhCvA8f7wDV7sdVWSaame3JXtAYuN4BMfTx3VZHXX_4j-gMSaIC_</recordid><startdate>20140925</startdate><enddate>20140925</enddate><creator>Ferla, Salvatore</creator><creator>Aboraia, Ahmed S</creator><creator>Brancale, Andrea</creator><creator>Pepper, Christopher J</creator><creator>Zhu, Jinge</creator><creator>Ochalek, Justin T</creator><creator>DeLuca, Hector F</creator><creator>Simons, Claire</creator><general>American Chemical Society</general><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>20140925</creationdate><title>Small-Molecule Inhibitors of 25-Hydroxyvitamin D‑24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation</title><author>Ferla, Salvatore ; 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Med. Chem</addtitle><date>2014-09-25</date><risdate>2014</risdate><volume>57</volume><issue>18</issue><spage>7702</spage><epage>7715</epage><pages>7702-7715</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25148392</pmid><doi>10.1021/jm5009314</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Catalytic Domain Cell Line, Tumor Cell Proliferation - drug effects Chemistry Techniques, Synthetic Cytochrome P-450 Enzyme Inhibitors - chemical synthesis Cytochrome P-450 Enzyme Inhibitors - chemistry Cytochrome P-450 Enzyme Inhibitors - metabolism Cytochrome P-450 Enzyme Inhibitors - pharmacology Heme - metabolism Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - metabolism Imidazoles - pharmacology Inhibitory Concentration 50 Leukemia, Lymphocytic, Chronic, B-Cell - pathology Models, Molecular Sequence Homology, Amino Acid Structure-Activity Relationship Vitamin D3 24-Hydroxylase - antagonists & inhibitors Vitamin D3 24-Hydroxylase - chemistry |
| title | Small-Molecule Inhibitors of 25-Hydroxyvitamin D‑24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation |
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