Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved..
We previously discovered a novel family of antimicrotubule agents designated as phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required to inhibit cell growth by 50% (IC50) of 3,5-PFB-SOs is over 1000 nM while most of 2,6-PFB-SOs exhibit IC50 in the nanomolar range (23-900 nM). Furthermore, the most potent 2,6-PFB-SOs 19, 26 and 27 arrest the cell cycle progression in G2/M phase, induce cytoskeleton disruption and impair microtubule polymerization. Docking studies also show that the most potent 2,6-PFB-SOs 19, 21, 24, 26 and 27 have binding affinity toward the colchicine-binding site (C-BS). Moreover, their antiproliferative activity is not affected by antimicrotubule- and multidrug-resistant cell lines. Besides, they exhibit improved in vitro hepatic stability in the mouse, rat and human microsomes compared to their non-fluorinated counterparts. They also showed theoretical pharmacokinetic, physicochemical and drug-like properties suited for further in vivo assays. In addition, they exhibit low to no systemic toxicity toward chick embryos. Finally, our study evidences that PIB-SOs must be fluorinated in specific positions on ring A to maintain both their antiproliferative activity and their biological activity toward microtubules.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:146 |
|---|---|
| Enthalten in: |
Bioorganic chemistry - 146(2024) vom: 26. Apr., Seite 107299 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bouzriba, Chahrazed [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 15.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bioorg.2024.107299 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370372484 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370372484 | ||
| 003 | DE-627 | ||
| 005 | 20240415233601.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240330s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bioorg.2024.107299 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1376.xml |
| 035 | |a (DE-627)NLM370372484 | ||
| 035 | |a (NLM)38547722 | ||
| 035 | |a (PII)S0045-2068(24)00204-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bouzriba, Chahrazed |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.04.2024 | ||
| 500 | |a Date Revised 15.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a We previously discovered a novel family of antimicrotubule agents designated as phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required to inhibit cell growth by 50% (IC50) of 3,5-PFB-SOs is over 1000 nM while most of 2,6-PFB-SOs exhibit IC50 in the nanomolar range (23-900 nM). Furthermore, the most potent 2,6-PFB-SOs 19, 26 and 27 arrest the cell cycle progression in G2/M phase, induce cytoskeleton disruption and impair microtubule polymerization. Docking studies also show that the most potent 2,6-PFB-SOs 19, 21, 24, 26 and 27 have binding affinity toward the colchicine-binding site (C-BS). Moreover, their antiproliferative activity is not affected by antimicrotubule- and multidrug-resistant cell lines. Besides, they exhibit improved in vitro hepatic stability in the mouse, rat and human microsomes compared to their non-fluorinated counterparts. They also showed theoretical pharmacokinetic, physicochemical and drug-like properties suited for further in vivo assays. In addition, they exhibit low to no systemic toxicity toward chick embryos. Finally, our study evidences that PIB-SOs must be fluorinated in specific positions on ring A to maintain both their antiproliferative activity and their biological activity toward microtubules | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 2 | |
| 650 | 4 | |a 6-PFB-SOs | |
| 650 | 4 | |a 6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates | |
| 650 | 4 | |a Anticancer agents | |
| 650 | 4 | |a Antimicrotubule agents | |
| 650 | 4 | |a Fluorination | |
| 650 | 4 | |a PIB-SOs | |
| 650 | 4 | |a Phenyl 2 | |
| 650 | 4 | |a Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates | |
| 650 | 7 | |a Benzenesulfonates |2 NLM | |
| 650 | 7 | |a Colchicine |2 NLM | |
| 650 | 7 | |a SML2Y3J35T |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Tubulin |2 NLM | |
| 650 | 7 | |a Tubulin Modulators |2 NLM | |
| 700 | 1 | |a Gagné-Boulet, Mathieu |e verfasserin |4 aut | |
| 700 | 1 | |a Chavez Alvarez, Atziri Corin |e verfasserin |4 aut | |
| 700 | 1 | |a Ouellette, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Laverdière, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Fortin, Sébastien |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic chemistry |d 1986 |g 146(2024) vom: 26. Apr., Seite 107299 |w (DE-627)NLM012846570 |x 1090-2120 |7 nnns |
| 773 | 1 | 8 | |g volume:146 |g year:2024 |g day:26 |g month:04 |g pages:107299 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bioorg.2024.107299 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 146 |j 2024 |b 26 |c 04 |h 107299 | ||