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Exploration of Benzo[b]carbazole-6,11-diones as anticancer agents: Synthesis and studies of hTopoIIα inhibition and apoptotic effects.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Oct 01; Vol. 49, pp. 128274. Date of Electronic Publication: 2021 Jul 22. - Publication Year :
- 2021
-
Abstract
- Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κβ signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Antineoplastic Agents chemical synthesis
Antineoplastic Agents toxicity
Carbazoles chemical synthesis
Carbazoles toxicity
Cell Line, Tumor
Cell Proliferation drug effects
Drug Screening Assays, Antitumor
HEK293 Cells
Humans
Naphthoquinones chemical synthesis
Naphthoquinones toxicity
S Phase Cell Cycle Checkpoints drug effects
Signal Transduction drug effects
Topoisomerase II Inhibitors chemical synthesis
Topoisomerase II Inhibitors toxicity
Antineoplastic Agents pharmacology
Apoptosis drug effects
Carbazoles pharmacology
DNA Topoisomerases, Type II metabolism
Naphthoquinones pharmacology
Poly-ADP-Ribose Binding Proteins metabolism
Topoisomerase II Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 49
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34303812
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.128274