On the tumor cell growth limiting potential of newly synthesized acridine-1,8-dione derivatives

A series of acridine derivatives, namely 10-(4-substituted benzyl)-9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-tetrahydroacridine-1,8(2H,5H)-diones, was synthesized via the Hantzsch-type multicomponent reaction between dimedone, 4-hydroxybenzaldehyde and 4-substituted benzylamine. The cytotoxic potential of these compounds was evaluated against human ovarian (A2780), melanoma (A375), colon (HCT 116) and breast cancer (MCF-7) cell lines, as well as normal human lung fibroblasts (MRC-5) and keratinocytes (HaCaT). Tested cell lines displayed different but moderate sensitivity to the investigated compounds, with the exception of compounds with a methyl (2) and a bromo group on the benzyl ring (6). These two compounds were almost equally effective against all cancer cell lines tested, suggesting that their activity is more general and less dependent on cell-specific characteristics. Compound 2 showed satisfying solubility, thus appeared to be the most acceptable for further examination and the A375 cell line was selected as the platform for evaluating the compound as the most sensitive to the applied treatment. This compound was shown to induce cell cycle arrest in G2/M phase, accelerating aging manifested through development of differentiated as well as senescent-like phenotype and subsequent fragmentation of genetic material. All aforementioned effects were accompanied with strong increment in production of reactive oxygen/nitrogen species (ROS/RNS). Docking studies against topoisomerase IIβ, hypoxia-inducible factor (HIF) 2α and mitogen-activated extracellular signal-regulated kinase (MEK) 1 revealed that treatment with tested compound might interfere with key signaling pathways involved in cell proliferation, and metabolic features of crucial importance for tumor progression. The obtained results contribute to the expansion of biologically relevant chemical space, thus providing guidelines for the assessment of new candidates for anticancer drugs.