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10-(4-Phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and related compounds: Synthesis, antiproliferative activity and inhibition of tubulin polymerization
- Source :
- Bioorganicmedicinal chemistry letters. 32
- Publication Year :
- 2020
-
Abstract
- As part of our continuing search for potent inhibitors of tubulin polymerization, two novel series of 42 10-(4-phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and N-benzoylated acridones were synthesized on the basis of a retrosynthetic approach. All newly synthesized compounds were tested for antiproliferative activity and interaction with tubulin. Several analogs potently inhibited tumor cell growth. Among the compounds tested, 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)acridin-9(10H)-one (17c) exhibited excellent growth inhibitory effects on 93 tumor cell lines, with an average GI50 value of 5.4 nM. We were able to show that the strong cytotoxic effects are caused by disruption of tubulin polymerization, as supported by the EBI (N,N'-Ethylenebis(iodoacetamide)) assay and the fact that the most potent inhibitors of cancer cell growth turned out to be the most efficacious tubulin polymerization inhibitors. Potencies were nearly comparable or superior to those of the antimitotic reference compounds. Closely related to this, the most active analogs inhibited cell cycling at the G2/M phase at concentrations down to 30 nM and induced apoptosis in K562 leukemia cells. We believe that our work not only proves the excellent suitability of the acridone scaffold for the design of potent tubulin polymerization inhibitors but also enables synthetic access to further potentially interesting N-acylated acridones.
- Subjects :
- Stereochemistry
Clinical Biochemistry
Cell
Molecular Conformation
Pharmaceutical Science
Phenylpiperazine
Antineoplastic Agents
macromolecular substances
01 natural sciences
Biochemistry
Piperazines
chemistry.chemical_compound
Structure-Activity Relationship
Tubulin
Drug Discovery
medicine
Humans
Molecular Biology
Cell Proliferation
Binding Sites
biology
010405 organic chemistry
Organic Chemistry
Tubulin Modulators
0104 chemical sciences
Acridone
G2 Phase Cell Cycle Checkpoints
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
medicine.anatomical_structure
chemistry
Apoptosis
Cancer cell
biology.protein
Iodoacetamide
Molecular Medicine
Acridines
M Phase Cell Cycle Checkpoints
K562 Cells
K562 cells
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 32
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....cdfb3d2b9afa4f3caa96636319982f20