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4 β -amidotriazole linked podophyllotoxin congeners: DNA topoisomerase-IIα inhibition and potential anticancer agents for prostate cancer
- Source :
- European Journal of Medicinal Chemistry. 144:595-611
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Topoisomerases (topo-I and topo-II) have occupied a significant role in DNA replication, transcription, and are a promising set of antitumor targets. In the present approach, a series of new 4 beta-amidotriazole linked podophyllotoxin derivatives (10a-i and 11a-k) were designed, synthesized by employing the click chemistry and their biological activities were evaluated. The majority of derivatives showed promising antiproliferative activity with IC50 values ranging from 1 to 10 mu M on the six human cancer cell lines; cervical (HeLa), breast (MCF-7), prostate (DU-145), lung (A549), liver (HepG2) and colon (HT-29). Among them, some of the congeners 10b, 10g and 10i have shown remarkable cytotoxicity with IC50 values of, < 1 mu M against the tested cancer cell lines and found to be more active than etoposide. Topoisomerase-mediated DNA relaxation assay results showed that the derivatives could efficiently inhibit the activity of topoisomerase-II. In addition, flow cytometry analysis on DU-145 cells revealed that these compounds arrest G2/M phase of cell cycle. Further apoptotic studies were also performed on these DU-145 cells, which showed that this class of compounds could induce apoptosis effectively
- Subjects :
- Male
0301 basic medicine
Antineoplastic Agents
Apoptosis
HeLa
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
Drug Discovery
Tumor Cells, Cultured
medicine
Humans
Topoisomerase II Inhibitors
Cytotoxicity
Etoposide
Cell Proliferation
Podophyllotoxin
Membrane Potential, Mitochondrial
Pharmacology
Dose-Response Relationship, Drug
Molecular Structure
biology
Chemistry
Topoisomerase
Cell Cycle
Organic Chemistry
DNA replication
Prostatic Neoplasms
General Medicine
Triazoles
Cell cycle
biology.organism_classification
Molecular Docking Simulation
DNA Topoisomerases, Type II
030104 developmental biology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 144
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....a4d4499946700250ba593ae8da655810