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Application of hydrazino and hydrazido linkers to connect benzenesulfonamides with hydrophilic/phobic tails for targeting the middle region of human carbonic anhydrases active site: Selective inhibitors of hCA IX.
- Source :
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European journal of medicinal chemistry [Eur J Med Chem] 2019 Oct 01; Vol. 179, pp. 547-556. Date of Electronic Publication: 2019 Jun 28. - Publication Year :
- 2019
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Abstract
- Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO <subscript>2</subscript> hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following K <subscript>I</subscript> ranges: 76.8-357.4 nM for hCA I, 8.2-94.6 nM for hCA II, 2.0-46.3 nM for hCA XI, and 8.3-88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC <subscript>50</subscript> values equal 3.32 ± 0.06 and 8.53 ± 0.32 μM, respectively, which are comparable to the reference drug doxorubicin (IC <subscript>50</subscript> = 2.36 ± 0.04 and 8.39 ± 0.25 μM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Benzene chemistry
Carbonic Anhydrase IX metabolism
Carbonic Anhydrase Inhibitors chemical synthesis
Carbonic Anhydrase Inhibitors chemistry
Catalytic Domain drug effects
Cell Cycle drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hydrazines chemical synthesis
Hydrazines chemistry
Hydrophobic and Hydrophilic Interactions
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship
Sulfonamides chemistry
Antineoplastic Agents pharmacology
Benzene pharmacology
Carbonic Anhydrase IX antagonists & inhibitors
Carbonic Anhydrase Inhibitors pharmacology
Hydrazines pharmacology
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 179
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31276899
- Full Text :
- https://doi.org/10.1016/j.ejmech.2019.06.081