Discovery of β-carboline-(phenylsulfonyl)furoxan hybrids as potential anti-breast cancer agents.

Abstract

The cytotoxicity properties of the β-carboline alkaloids have been broadly investigated. However, the potential application of β-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty β-carboline-(phenylsulfonyl)furoxan hybrids (11a-j, 12a-j and 13a-j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 μM) and MDA-MB-231 (IC50 = 0.62 μM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.

• Authors: Xu Hu, Xiang Gao, Gang Gao, Yanbing Wang, Hao Cao, Dahong Li, Huiming Hua
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 40 Pg. 127952 (05 15 2021) ISSN: 1464-3405 [Electronic] England
• PMID: 33744443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Carbolines
• Nitric Oxide Donors
• Oxadiazoles
• Reactive Oxygen Species
• Sulfones
• furoxans
• DNA

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Carbolines (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• Drug Design
• Drug Screening Assays, Antitumor
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Molecular Structure
• Nitric Oxide Donors (chemical synthesis, pharmacology)
• Oxadiazoles (chemical synthesis, pharmacology)
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship
• Sulfones (chemical synthesis, pharmacology)