Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors
Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors wit...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-12, Vol.55 (23), p.10551-10563 |
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| container_title | Journal of medicinal chemistry |
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| creator | Shukla, Krupa Ferraris, Dana V. Thomas, Ajit G. Stathis, Marigo Duvall, Bridget Delahanty, Greg Alt, Jesse Rais, Rana Rojas, Camilo Gao, Ping Xiang, Yan Dang, Chi V. Slusher, Barbara S. Tsukamoto, Takashi |
| description | Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure–activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model. |
| doi_str_mv | 10.1021/jm301191p |
| format | Article |
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Med. Chem</addtitle><description>Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure–activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.</description><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glutaminase - antagonists & inhibitors</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Models, Molecular</subject><subject>Sulfides - chemical synthesis</subject><subject>Sulfides - chemistry</subject><subject>Sulfides - pharmacology</subject><subject>Thiadiazoles - chemical synthesis</subject><subject>Thiadiazoles - chemistry</subject><subject>Thiadiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1u1DAURi0EokNhwQsgb5BmpDFc23F-lm0ZSqVKVJqyjm5iu_HIsYc4QQrvwruSakpXrO5dHJ3F-Qh5z-ETB8E_H3oJnFf8-IKsuBLAshKyl2QFIAQTuZBn5E1KBwCQXMjX5ExIrjiUakX-fDHJPYQt3c9h7JY_bSkGTe86HHpso48PrkVPd7_QTzi6GGi09NIlJthasWNnwuyxNSP2TkfGt2KbsbFzqB3-jn6hZr8xYzd7up-8ddpQSdeXd_e7_YZeBFz8iWKi1356VARMht6EzjVujEN6S15Z9Mm8e7rn5MfX3f3VN3b7_frm6uKWoVQwsipvLHBlFWiTN20mi0xIVFXZWNkUhbamLDKwvKmEVnmucmNVprJGloUWrQF5TtYn73GIPyeTxrp3qTXeYzBxSvVSrYIcoCoXdHNC2yGmNBhbHwfX4zDXHOrHNernNRb2w5N2anqjn8l_-Rfg4wnANtWHOA1LkPQf0V-UEo_R</recordid><startdate>20121213</startdate><enddate>20121213</enddate><creator>Shukla, Krupa</creator><creator>Ferraris, Dana V.</creator><creator>Thomas, Ajit G.</creator><creator>Stathis, Marigo</creator><creator>Duvall, Bridget</creator><creator>Delahanty, Greg</creator><creator>Alt, Jesse</creator><creator>Rais, Rana</creator><creator>Rojas, Camilo</creator><creator>Gao, Ping</creator><creator>Xiang, Yan</creator><creator>Dang, Chi V.</creator><creator>Slusher, Barbara S.</creator><creator>Tsukamoto, Takashi</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>20121213</creationdate><title>Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors</title><author>Shukla, Krupa ; Ferraris, Dana V. ; Thomas, Ajit G. ; Stathis, Marigo ; Duvall, Bridget ; Delahanty, Greg ; Alt, Jesse ; Rais, Rana ; Rojas, Camilo ; Gao, Ping ; Xiang, Yan ; Dang, Chi V. ; Slusher, Barbara S. ; Tsukamoto, Takashi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a350t-96bf015f50de6bc437423a598bf3b77dfe8740f1b92d56656ef5454b387d2ce03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glutaminase - antagonists & inhibitors</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Models, Molecular</topic><topic>Sulfides - chemical synthesis</topic><topic>Sulfides - chemistry</topic><topic>Sulfides - pharmacology</topic><topic>Thiadiazoles - chemical synthesis</topic><topic>Thiadiazoles - chemistry</topic><topic>Thiadiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shukla, Krupa</creatorcontrib><creatorcontrib>Ferraris, Dana V.</creatorcontrib><creatorcontrib>Thomas, Ajit G.</creatorcontrib><creatorcontrib>Stathis, Marigo</creatorcontrib><creatorcontrib>Duvall, Bridget</creatorcontrib><creatorcontrib>Delahanty, Greg</creatorcontrib><creatorcontrib>Alt, Jesse</creatorcontrib><creatorcontrib>Rais, Rana</creatorcontrib><creatorcontrib>Rojas, Camilo</creatorcontrib><creatorcontrib>Gao, Ping</creatorcontrib><creatorcontrib>Xiang, Yan</creatorcontrib><creatorcontrib>Dang, Chi V.</creatorcontrib><creatorcontrib>Slusher, Barbara S.</creatorcontrib><creatorcontrib>Tsukamoto, Takashi</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shukla, Krupa</au><au>Ferraris, Dana V.</au><au>Thomas, Ajit G.</au><au>Stathis, Marigo</au><au>Duvall, Bridget</au><au>Delahanty, Greg</au><au>Alt, Jesse</au><au>Rais, Rana</au><au>Rojas, Camilo</au><au>Gao, Ping</au><au>Xiang, Yan</au><au>Dang, Chi V.</au><au>Slusher, Barbara S.</au><au>Tsukamoto, Takashi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| subjects | Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Glutaminase - antagonists & inhibitors Magnetic Resonance Spectroscopy Models, Molecular Sulfides - chemical synthesis Sulfides - chemistry Sulfides - pharmacology Thiadiazoles - chemical synthesis Thiadiazoles - chemistry Thiadiazoles - pharmacology |
| title | Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl Sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors |
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