Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors
Copyright © 2021 Elsevier Masson SAS. All rights reserved..
Ligustrazine is the principle bioactive alkaloid in the widely-used Chinese herb Chuan Xiong rhizome. Herein, a series of novel derivatives has been designed as human carbonic anhydrases inhibitors (hCAIs) starting from the natural product Ligustrazine inserted as a tail instead of the 4-fluorophenyl tail of SLC-0111, a front-runner selective hCA IX inhibitor currently in clinical trials as antitumor/antimetastatic agent. Other derivatives were designed via incorporation of different linkers, of amide and ester type, or incorporation of different zinc anchoring groups such as secondary sulfamoyl and carboxylic acid functionalities. The newly designed molecules were prepared following different synthetic pathways, and were assessed for their inhibitory actions against four isoforms: the widespread cytosolic (hCA I and II), and the transmembrane tumor-related (hCA IX and XII). The primary sulfonamides efficiently inhibited the target hCA IX and hCA XII in the nanomolar range (KIs: 6.2-951.5 nM and 3.3-869.3 nM, respectively). The most selective hCA IX inhibitors 6c and 18 were assessed for their potential anticancer effects, and displayed anti-proliferative activity against MCF-7 cancer cell line with IC50s of 11.9 and 36.7 μM, respectively. Molecular modelling studies unveiled the relationship between structural features and inhibitory profiles against the off-target hCA II and the target, tumor-related isoforms hCA IX and XII.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:228 |
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| Enthalten in: |
European journal of medicinal chemistry - 228(2022) vom: 15. Jan., Seite 114008 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Elimam, Diaaeldin M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.01.2022 Date Revised 26.01.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2021.114008 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334085446 |
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| 245 | 1 | 0 | |a Natural inspired ligustrazine-based SLC-0111 analogues as novel carbonic anhydrase inhibitors |
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| 500 | |a Date Revised 26.01.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a Ligustrazine is the principle bioactive alkaloid in the widely-used Chinese herb Chuan Xiong rhizome. Herein, a series of novel derivatives has been designed as human carbonic anhydrases inhibitors (hCAIs) starting from the natural product Ligustrazine inserted as a tail instead of the 4-fluorophenyl tail of SLC-0111, a front-runner selective hCA IX inhibitor currently in clinical trials as antitumor/antimetastatic agent. Other derivatives were designed via incorporation of different linkers, of amide and ester type, or incorporation of different zinc anchoring groups such as secondary sulfamoyl and carboxylic acid functionalities. The newly designed molecules were prepared following different synthetic pathways, and were assessed for their inhibitory actions against four isoforms: the widespread cytosolic (hCA I and II), and the transmembrane tumor-related (hCA IX and XII). The primary sulfonamides efficiently inhibited the target hCA IX and hCA XII in the nanomolar range (KIs: 6.2-951.5 nM and 3.3-869.3 nM, respectively). The most selective hCA IX inhibitors 6c and 18 were assessed for their potential anticancer effects, and displayed anti-proliferative activity against MCF-7 cancer cell line with IC50s of 11.9 and 36.7 μM, respectively. Molecular modelling studies unveiled the relationship between structural features and inhibitory profiles against the off-target hCA II and the target, tumor-related isoforms hCA IX and XII | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anticancer agents | |
| 650 | 4 | |a Carbonic anhydrase inhibitors | |
| 650 | 4 | |a Ligustrazine | |
| 650 | 4 | |a SLC-0111 analogues | |
| 650 | 4 | |a Tail approach | |
| 650 | 4 | |a Ureido benzenesulfonamides | |
| 650 | 7 | |a Antineoplastic Agents, Phytogenic |2 NLM | |
| 650 | 7 | |a Biological Products |2 NLM | |
| 650 | 7 | |a Carbonic Anhydrase Inhibitors |2 NLM | |
| 650 | 7 | |a Isoenzymes |2 NLM | |
| 650 | 7 | |a Phenylurea Compounds |2 NLM | |
| 650 | 7 | |a Pyrazines |2 NLM | |
| 650 | 7 | |a SLC-0111 |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a Carbonic Anhydrases |2 NLM | |
| 650 | 7 | |a EC 4.2.1.1 |2 NLM | |
| 650 | 7 | |a tetramethylpyrazine |2 NLM | |
| 650 | 7 | |a V80F4IA5XG |2 NLM | |
| 700 | 1 | |a Eldehna, Wagdy M |e verfasserin |4 aut | |
| 700 | 1 | |a Salem, Rofaida |e verfasserin |4 aut | |
| 700 | 1 | |a Bonardi, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Nocentini, Alessio |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Rashood, Sara T |e verfasserin |4 aut | |
| 700 | 1 | |a Elaasser, Mahmoud M |e verfasserin |4 aut | |
| 700 | 1 | |a Gratteri, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Supuran, Claudiu T |e verfasserin |4 aut | |
| 700 | 1 | |a Allam, Heba Abdelrasheed |e verfasserin |4 aut | |
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