Synthesis and Biological Evaluation of Acridine/Acridone Analogs as Potential Anticancer Agents

Author(s): Monika Gensicka-Kowalewska, Mirosława Cichorek, Anna Ronowska, Milena Deptuła, Ilona Klejbor, Krystyna Dzierzbicka*

Journal Name: Medicinal Chemistry

Volume 15 , Issue 7 , 2019

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Graphical Abstract:


Background: The lack of efficacious therapy for advanced melanoma and neuroblastoma makes new approaches necessary. Therefore, many scientists seek new, more effective, more selective and less toxic anticancer drugs.

Objective: We propose the synthesis of the new functionalized analogs of 1-nitroacridine/4- nitroacridone connected to tuftsin/retro-tuftsin derivatives as potential anticancer agents.

Methods: Acridine and acridone analogues were prepared by Ullmann condensation and then cyclization reaction. As a result of nucleophilic substitution reaction 1-nitro-9-phenoxyacridine or 1- chloro-4-nitro-9(10H)-acridone with the corresponding peptides, the planned acridine derivatives (10a-c, 12, 17-a-d, 19) have been obtained. The cytotoxic activity of the newly obtained analogs were evaluated against melanotic (Ma) and amelanotic (Ab) melanoma cell lines and neuroblastoma SH-SY5Y by using the XTT method. Apoptosis and cell cycle were analyzed by flow cytometry.

Results: Among the investigated analogs compound 12 exhibited the highest potency comparable to dacarbazine action for amelanotic Ab melanoma cells. FLICA test (flurochrome-labeled inhibitors of caspases) showed that this analog significantly increased the content of cells with activated caspases (C+) among both neuroblastoma lines and only Ab melanoma line. Using phosphatidylserine (PS) externalization assay, 12 induced changes in the Ab melanoma plasma membrane structure as the externalization of phosphatidylserine (An+ cells). These changes in neuroblastoma cells were less pronounced.

Conclusion: Analog 12 could be proposed as the new potential chemotherapeutic against amelanotic melanoma form especially.

Keywords: Acridine, acridone, tuftsin, retro-tuftsin, melanoma, neuroblastoma.

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Article Details

Year: 2019
Published on: 15 October, 2018
Page: [729 - 737]
Pages: 9
DOI: 10.2174/1573406414666181015145120
Price: $65

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