Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX
Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemica...
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Audrius Zakšauskas Edita Čapkauskaitė Vaida Paketurytė-Latvė Alexey Smirnov Janis Leitans Andris Kazaks Elviss Dvinskis Laimonas Stančaitis Aurelija Mickevičiūtė Jelena Jachno Linas Jezepčikas Vaida Linkuvienė Andrius Sakalauskas Elena Manakova Saulius Gražulis Jurgita Matulienė Kaspars Tars Daumantas Matulis |
| author_facet | Audrius Zakšauskas Edita Čapkauskaitė Vaida Paketurytė-Latvė Alexey Smirnov Janis Leitans Andris Kazaks Elviss Dvinskis Laimonas Stančaitis Aurelija Mickevičiūtė Jelena Jachno Linas Jezepčikas Vaida Linkuvienė Andrius Sakalauskas Elena Manakova Saulius Gražulis Jurgita Matulienė Kaspars Tars Daumantas Matulis |
| author_sort | Audrius Zakšauskas |
| collection | DOAJ |
| description | Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound <b>4b</b>, which exhibited an extremely high <i>observed</i> binding affinity to CAIX; the <i>K<sub>d</sub></i> was 0.12 nM. The <i>intrinsic</i> dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound <b>3b</b> bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes. |
| first_indexed | 2024-03-10T03:39:42Z |
| format | Article |
| id | doaj.art-84acb04d62b848db9affb4f5bc5e5838 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:39:42Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-84acb04d62b848db9affb4f5bc5e58382023-11-23T11:35:09ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0123113010.3390/ijms23010130Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IXAudrius Zakšauskas0Edita Čapkauskaitė1Vaida Paketurytė-Latvė2Alexey Smirnov3Janis Leitans4Andris Kazaks5Elviss Dvinskis6Laimonas Stančaitis7Aurelija Mickevičiūtė8Jelena Jachno9Linas Jezepčikas10Vaida Linkuvienė11Andrius Sakalauskas12Elena Manakova13Saulius Gražulis14Jurgita Matulienė15Kaspars Tars16Daumantas Matulis17Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaLatvian Biomedical Research and Study Centre, Ratsupites 1 k-1, LV-1067 Riga, LatviaLatvian Biomedical Research and Study Centre, Ratsupites 1 k-1, LV-1067 Riga, LatviaLatvian Biomedical Research and Study Centre, Ratsupites 1 k-1, LV-1067 Riga, LatviaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Protein—DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Protein—DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaLatvian Biomedical Research and Study Centre, Ratsupites 1 k-1, LV-1067 Riga, LatviaDepartment of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio al. 7, LT-10257 Vilnius, LithuaniaAmong the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound <b>4b</b>, which exhibited an extremely high <i>observed</i> binding affinity to CAIX; the <i>K<sub>d</sub></i> was 0.12 nM. The <i>intrinsic</i> dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound <b>3b</b> bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.https://www.mdpi.com/1422-0067/23/1/130methyl 5-sulfamoyl-benzoatehuman carbonic anhydrase<i>intrinsic</i> binding thermodynamicsenzyme inhibitorX-ray crystallographyfluorescent thermal shift assay |
| spellingShingle | Audrius Zakšauskas Edita Čapkauskaitė Vaida Paketurytė-Latvė Alexey Smirnov Janis Leitans Andris Kazaks Elviss Dvinskis Laimonas Stančaitis Aurelija Mickevičiūtė Jelena Jachno Linas Jezepčikas Vaida Linkuvienė Andrius Sakalauskas Elena Manakova Saulius Gražulis Jurgita Matulienė Kaspars Tars Daumantas Matulis Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX International Journal of Molecular Sciences methyl 5-sulfamoyl-benzoate human carbonic anhydrase <i>intrinsic</i> binding thermodynamics enzyme inhibitor X-ray crystallography fluorescent thermal shift assay |
| title | Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX |
| title_full | Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX |
| title_fullStr | Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX |
| title_full_unstemmed | Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX |
| title_short | Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX |
| title_sort | methyl 2 halo 4 substituted 5 sulfamoyl benzoates as high affinity and selective inhibitors of carbonic anhydrase ix |
| topic | methyl 5-sulfamoyl-benzoate human carbonic anhydrase <i>intrinsic</i> binding thermodynamics enzyme inhibitor X-ray crystallography fluorescent thermal shift assay |
| url | https://www.mdpi.com/1422-0067/23/1/130 |
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