3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety
[Display omitted] Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreat...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2022-04, Vol.61, p.128591-128591, Article 128591 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Sun, Jufeng Ambrus, Joey I. Baker, Jennifer R. Russell, Cecilia C. Cossar, Peter J. Sakoff, Jennette A. Scarlett, Christopher J. McCluskey, Adam |
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Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total.
Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition. |
| doi_str_mv | 10.1016/j.bmcl.2022.128591 |
| format | Article |
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Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total.
Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4–30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2022.128591</identifier><identifier>PMID: 35114371</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - pathology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2022-04, Vol.61, p.128591-128591, Article 128591</ispartof><rights>2022</rights><rights>Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-f394965c1ed4745210ea7ae3023db47c16c09c43dd7e14a51fa82e1b3b4bc173</citedby><cites>FETCH-LOGICAL-c356t-f394965c1ed4745210ea7ae3023db47c16c09c43dd7e14a51fa82e1b3b4bc173</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2022.128591$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27925,27926,45996</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35114371$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Jufeng</creatorcontrib><creatorcontrib>Ambrus, Joey I.</creatorcontrib><creatorcontrib>Baker, Jennifer R.</creatorcontrib><creatorcontrib>Russell, Cecilia C.</creatorcontrib><creatorcontrib>Cossar, Peter J.</creatorcontrib><creatorcontrib>Sakoff, Jennette A.</creatorcontrib><creatorcontrib>Scarlett, Christopher J.</creatorcontrib><creatorcontrib>McCluskey, Adam</creatorcontrib><title>3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total.
Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4–30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFu1DAQhi1ERbeFF-CAfGylJnhsx9lIXKCitFIlLj1wsxx7wnrlxIvtrLQ3Hr1ZtnDk5Dl8_z-ej5D3wGpgoD5u6360oeaM8xr4uungFVmBVLISkjWvyYp1ilXrTv44Jxc5bxkDyaR8Q85FAyBFCyvyW9w01Refr0ryQ5hjiiOWzSFc7zY4HUKewxAnM3qH-YYaOsU9Brozk01oirfULiMmamzxe6QBjavpw7THXPzPBYgTjQMtG6QF0-gnE6hZVvyJjtFjObwlZ4MJGd-9vJfk6e7r0-199fj928Pt58fKikaVahCd7FRjAZ1sZcOBoWkNCsaF62VrQVnWWSmcaxGkaWAwa47Qi172FlpxSa5OtbsUf83L9_Tos8UQzIRxzporrhjrQB1RfkJtijknHPQu-dGkgwamj-L1Vh_F66N4fRK_hD689M_9iO5f5K_pBfh0AnA5cu8x6Ww9LvKcT2iLdtH_r_8ZIV2WQg</recordid><startdate>20220401</startdate><enddate>20220401</enddate><creator>Sun, Jufeng</creator><creator>Ambrus, Joey I.</creator><creator>Baker, Jennifer R.</creator><creator>Russell, Cecilia C.</creator><creator>Cossar, Peter J.</creator><creator>Sakoff, Jennette A.</creator><creator>Scarlett, Christopher J.</creator><creator>McCluskey, Adam</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></search><sort><creationdate>20220401</creationdate><title>3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety</title><author>Sun, Jufeng ; Ambrus, Joey I. ; Baker, Jennifer R. ; Russell, Cecilia C. ; Cossar, Peter J. ; Sakoff, Jennette A. ; Scarlett, Christopher J. ; McCluskey, Adam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-f394965c1ed4745210ea7ae3023db47c16c09c43dd7e14a51fa82e1b3b4bc173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Jufeng</creatorcontrib><creatorcontrib>Ambrus, Joey I.</creatorcontrib><creatorcontrib>Baker, Jennifer R.</creatorcontrib><creatorcontrib>Russell, Cecilia C.</creatorcontrib><creatorcontrib>Cossar, Peter J.</creatorcontrib><creatorcontrib>Sakoff, Jennette A.</creatorcontrib><creatorcontrib>Scarlett, Christopher J.</creatorcontrib><creatorcontrib>McCluskey, Adam</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Jufeng</au><au>Ambrus, Joey I.</au><au>Baker, Jennifer R.</au><au>Russell, Cecilia C.</au><au>Cossar, Peter J.</au><au>Sakoff, Jennette A.</au><au>Scarlett, Christopher J.</au><au>McCluskey, Adam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2022-04-01</date><risdate>2022</risdate><volume>61</volume><spage>128591</spage><epage>128591</epage><pages>128591-128591</pages><artnum>128591</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Virtual screening identified N-(6-((4-bromobenzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzenesulfonamide (1) a lead compound that bound to the S100A2-p53 binding groove. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. It is a validated pancreatic cancer drug target. Lead 1, inhibited the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 = 2.97 μM). Focused compound libraries were developed to explore the SAR of this compound class with 4 libraries and 43 compounds total.
Focused library (Library 1) development identified lipophillic sulfonamides as preferred for MiaPaCa-2 activity, with -CF3 and -C(CH3)3 substituents well tolerated (MiaPaCa-2 GI50 < 6 μM). Contraction of the hexylamino spacer to ethyl (Library 2) and propyl (Library 3) proved beneficial to activity against a broad spectrum panel of cancer cell lines: HT29 (lung), MCF-7 (breast), A2780 (ovarian), H460 (colon), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), U87 and SJ-G2 (glioblastoma) (cohort-1); and a pancreatic cancer cell line panel: MiaPaCa-2, BxPC-3, AsPC-1, Capan-2, HPAC and PANC-1 (cohort-2). With a marked preference for a propyl linker the observed GI50 values ranged from 1.4 to 30 μM against cohort-1 and 1.4–30 μM against cohort-2 cell lines. In Library 4 the terminal aromatic moiety was explored with 4-substituted analogues preferred (with activity of 48 (4-Cl) > 47 (3-Cl) > 46 (2-Cl)) against the cell lines examined. The introduction of bulky aromatic moieties was well tolerated, e.g. dihydrobenzo[b][1,4]dioxine (51) returned cohort-2 GI50 values of 1.2–3.4 μM. In all instances the observed docked binding poses and binding scores were consistent with the observed cytotoxicity. This in turn supports, but does not prove, that these analogues function via S100A2-p53 binding groove inhibition.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35114371</pmid><doi>10.1016/j.bmcl.2022.128591</doi><tpages>1</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Evaluation, Preclinical Drug Screening Assays, Antitumor Humans Molecular Structure Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - pathology Structure-Activity Relationship |
| title | 3,5-Bis(trifluoromethyl)phenylsulfonamides, a novel pancreatic cancer active lead. Investigation of the terminal aromatic moiety |
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