Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
[Display omitted] Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structur...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2021-08, Vol.44, p.116307-116307, Article 116307 |
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| container_title | Bioorganic & medicinal chemistry |
| container_volume | 44 |
| creator | Fairweather, Alisa E.R. Goetz, Daniel B. Schroeder, Chloe M. Bhuiyan, Nazmul H. Varney, Michelle L. Wiemer, David F. Holstein, Sarah A. |
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Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity. |
| doi_str_mv | 10.1016/j.bmc.2021.116307 |
| format | Article |
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Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2021.116307</identifier><identifier>PMID: 34298413</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Bisphosphonate ; Diphosphonates - chemical synthesis ; Diphosphonates - chemistry ; Diphosphonates - pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Farnesyltranstransferase - antagonists & inhibitors ; Farnesyltranstransferase - metabolism ; Geranylgeranyl diphosphate synthase ; Humans ; Inhibition ; Isoprenoid biosynthesis ; Molecular Structure ; Myeloma ; Structure-Activity Relationship ; Triazole ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry, 2021-08, Vol.44, p.116307-116307, Article 116307</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-aaecf93a3daca6ec9b05f9f5da1abcc9aeae4cdf90796bb32ee7a8589bbb931c3</citedby><cites>FETCH-LOGICAL-c451t-aaecf93a3daca6ec9b05f9f5da1abcc9aeae4cdf90796bb32ee7a8589bbb931c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2021.116307$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34298413$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fairweather, Alisa E.R.</creatorcontrib><creatorcontrib>Goetz, Daniel B.</creatorcontrib><creatorcontrib>Schroeder, Chloe M.</creatorcontrib><creatorcontrib>Bhuiyan, Nazmul H.</creatorcontrib><creatorcontrib>Varney, Michelle L.</creatorcontrib><creatorcontrib>Wiemer, David F.</creatorcontrib><creatorcontrib>Holstein, Sarah A.</creatorcontrib><title>Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity.</description><subject>Bisphosphonate</subject><subject>Diphosphonates - chemical synthesis</subject><subject>Diphosphonates - chemistry</subject><subject>Diphosphonates - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Farnesyltranstransferase - antagonists & inhibitors</subject><subject>Farnesyltranstransferase - metabolism</subject><subject>Geranylgeranyl diphosphate synthase</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Isoprenoid biosynthesis</subject><subject>Molecular Structure</subject><subject>Myeloma</subject><subject>Structure-Activity Relationship</subject><subject>Triazole</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - pharmacology</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhiMEotvCA3BBPnLJYseJNxYSEqqgVKrEBc7W2Jk0s0rsxfauurwVL8IzkVWWCi4crDn83_y2_BXFK8HXggv1dru2k1tXvBJrIZTkmyfFStSqLqXU4mmx4lq1JW-1uiguU9pyzqtai-fFhawr3dZCroqH22kHLrPQs18_yyl01JODTMEnFjzLA7I5pgPl44nJkeBHGJFZSrshnI6HjIlBYvcYwR_H82AdLcAcs3T0eYCEjPxAlnKI6UXxrIcx4cvzvCq-ffr49fpzeffl5vb6w13p6kbkEgBdryXIDhwodNryptd904EA65wGBKxd12u-0cpaWSFuoG1aba3VUjh5Vbxfend7O2Hn0OcIo9lFmiAeTQAy_yaeBnMfDqaVG85lNRe8ORfE8H2PKZuJksNxBI9hn0zVNI3gSio1o2JBXQwpRewfrxHcnIyZrZmNmZMxsxibd17__b7HjT-KZuDdAuD8SwfCaJIj9A47iuiy6QL9p_43t-St4w</recordid><startdate>20210815</startdate><enddate>20210815</enddate><creator>Fairweather, Alisa E.R.</creator><creator>Goetz, Daniel B.</creator><creator>Schroeder, Chloe M.</creator><creator>Bhuiyan, Nazmul H.</creator><creator>Varney, Michelle L.</creator><creator>Wiemer, David F.</creator><creator>Holstein, Sarah A.</creator><general>Elsevier Ltd</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><scope>5PM</scope></search><sort><creationdate>20210815</creationdate><title>Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors</title><author>Fairweather, Alisa E.R. ; Goetz, Daniel B. ; Schroeder, Chloe M. ; Bhuiyan, Nazmul H. ; Varney, Michelle L. ; Wiemer, David F. ; Holstein, Sarah A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-aaecf93a3daca6ec9b05f9f5da1abcc9aeae4cdf90796bb32ee7a8589bbb931c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Bisphosphonate</topic><topic>Diphosphonates - chemical synthesis</topic><topic>Diphosphonates - chemistry</topic><topic>Diphosphonates - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Farnesyltranstransferase - antagonists & inhibitors</topic><topic>Farnesyltranstransferase - metabolism</topic><topic>Geranylgeranyl diphosphate synthase</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Isoprenoid biosynthesis</topic><topic>Molecular Structure</topic><topic>Myeloma</topic><topic>Structure-Activity Relationship</topic><topic>Triazole</topic><topic>Triazoles - chemical synthesis</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fairweather, Alisa E.R.</creatorcontrib><creatorcontrib>Goetz, Daniel B.</creatorcontrib><creatorcontrib>Schroeder, Chloe M.</creatorcontrib><creatorcontrib>Bhuiyan, Nazmul H.</creatorcontrib><creatorcontrib>Varney, Michelle L.</creatorcontrib><creatorcontrib>Wiemer, David F.</creatorcontrib><creatorcontrib>Holstein, Sarah A.</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fairweather, Alisa E.R.</au><au>Goetz, Daniel B.</au><au>Schroeder, Chloe M.</au><au>Bhuiyan, Nazmul H.</au><au>Varney, Michelle L.</au><au>Wiemer, David F.</au><au>Holstein, Sarah A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2021-08-15</date><risdate>2021</risdate><volume>44</volume><spage>116307</spage><epage>116307</epage><pages>116307-116307</pages><artnum>116307</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34298413</pmid><doi>10.1016/j.bmc.2021.116307</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Bisphosphonate Diphosphonates - chemical synthesis Diphosphonates - chemistry Diphosphonates - pharmacology Dose-Response Relationship, Drug Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Farnesyltranstransferase - antagonists & inhibitors Farnesyltranstransferase - metabolism Geranylgeranyl diphosphate synthase Humans Inhibition Isoprenoid biosynthesis Molecular Structure Myeloma Structure-Activity Relationship Triazole Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology |
| title | Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors |
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