Acridine and Acridone Derivatives, Anticancer Properties and Synthetic Methods: Where Are We Now?

Abstract

Acridine derivatives are interesting chemotherapeutic agents that were first used as antibacterial and antiparasite agents. In this review we wish to concentrate our attention on the anticancer properties of acridines used in clinics since the 1970's. Based on recent results, an outlook on antitumour acridine chemotherapy will be proposed. The biological activity of acridines is mainly attributed to the planarity of these aromatic structures, which can intercalate within the double-stranded DNA structure, thus interfering with the cellular machinery. Recent understanding of the mode of action of acridines leads to continuous and exciting research in this heterocyclic family. Indeed, biological targets such as topoisomerases I and II, telomerase/telomere and protein kinases emerge and allow the design of novel acridine-based patterns. This review further pinpoints the latest progress in the development of anticancer agents based on naturally occurring and synthetic acridines (e.g. acridones, pyridoacridines); for this matter in vitro/in vivo studies and clinical trial results will be discussed. The DNA-affinic property of acridine is also useful to vectorise drugs into cell nuclei and some applications in hypoxia-selective treatment, platinum or N-mustard derived conjugates will be reported. Some other properties including inhibition of multidrug resistance or potential impact on Alzheimer disease will be treated. It is noteworthy that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity observed. So, we wish also to disclose a summary of recent synthetic methodologies developed for acridine synthesis.

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

“…C-1311 and other acridine-based compounds display nuclear and perinuclear accumulation and exert their cytotoxic activity via direct interaction with DNA as well as with DNA-modifying enzymes including topoisomerase I or II (Topcu, 2001;Belmont et al, 2007). To exclude the possibility that differential subcellular accumulation of IAs is the basis of the observed difference in cytotoxicity and cellular fluorescence, A549/K1.5 cells were incubated with 10 M concentrations of selected IAs from groups A and B in the presence or absence of FTC and subjected to fluorescence microscopy.…”

Study of the synthesis of novel trisubstituted acridines

“…1,2 In a more recent study, it has been reported that quadruplex-binding trisubstituted acridines have exhibited rapid anti-tumor effects involving several parallel mechanisms, including telomere uncapping, direct or indirect telomerase inhibition with the characteristic induction of senescence and apoptosis. [3][4][5][6][7][8] Recent research has also shown that G-quadruplexes selectively target both telomerase and telomere in cancer cells.…”

Molecular‐Recognition‐Assisted pKa Shifts and Metal‐Ion‐Induced Fluorescence Regeneration in p‐Sulfonatocalix[6]arene‐Encapsulated Acridine

“…[14,15] Acridine and related derivatives are potent DNA-intercalating anticancer agents. [16,17] Recently, Sedlacek et al have demonstrated pH-controlled activation of polymer-conjugated acridine-based anticancer drugs in cancer cells. [17] This was possible because acridine exists in water in two prototropic forms (pK a % 5.3), [14,18] one being neutral (Ac) and the second being protonated (AcH + , cf.…”