9-Aminoacridine (Aminacrine)

9-Aminoacridine Inhibits Ribosome Biogenesis by Targeting Both Transcription and Processing of Ribosomal RNA

Int J Mol Sci 2022 Jan 23;23(3):1260.35163183 PMC8836032

Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the mechanisms behind their biological effects are not fully elucidated, they are most often attributed to the acridines' ability to intercalate into DNA. Here, we characterized the effects of 9-Aminoacridine (9AA) on pre-rRNA metabolism in cultured mammalian cells. Our results demonstrate that 9AA inhibits both transcription of the ribosomal RNA precursors (pre-rRNA) and processing of the already synthesized pre-rRNAs, thereby rapidly abolishing ribosome biogenesis. Using a fluorescent intercalator displacement assay, we further show that 9AA can bind to RNA in vitro, which likely contributes to its ability to inhibit post-transcriptional steps in pre-rRNA maturation. These findings extend the arsenal of small-molecule compounds that can be used to block ribosome biogenesis in mammalian cells and have implications for the pharmacological development of new ribosome biogenesis inhibitors.

Synthesis of 9-Aminoacridine Derivatives as Anti-Alzheimer Agents

Am J Alzheimers Dis Other Demen 2016 May;31(3):263-9.26385945 10.1177/1533317515603115

In the present study, some 9-Aminoacridine derivatives have been synthesized by condensation of 9-Aminoacridine with substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimer's disease. All derivatives showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine, a well-known acridine derivative used for the treatment of Alzheimer's disease.

Liposomal 9-Aminoacridine for Treatment of Ischemic Stroke: From Drug Discovery to Drug Delivery

Nano Lett 2020 Mar 11;20(3):1542-1551.32039606 10.1021/acs.nanolett.9b04018

Neuroinflammation plays a pivotal part in the pathogenesis of stroke. Orphan nuclear receptor NR4A1 is involved in the inflammatory response of microglia and macrophages. In this study, we discovered an old drug, 9-Aminoacridine (9-AA), as a novel NR4A1 activator from our in-house FDA-approved drug library, which exhibited anti-inflammatory activities through an NR4A1/IL-10/SOCS3 signaling pathway and modulated the microglia activation. To improve the druggability of 9-AA, different liposomal formulations were screened and investigated. 9-AA-loaded liposome (9-AA/L) was prepared to reduce the adverse effect of 9-AA. Furthermore, 9-AA-loaded PEG/cRGD dual-modified liposome (9-AA/L-PEG-cRGD) was obtained, which displayed prolonged circulation, improved biodistribution, and increased brain accumulation. In the transient middle cerebral artery occlusion (tMCAO) rat model, 9-AA/L-PEG-cRGD significantly reduced brain infarct area, ameliorated ischemic brain injury, and promoted long-term neurological function recovery. This "from drug discovery to drug delivery" methodology provides a potential therapeutic strategy using the liposomal 9-AA, the NR4A1 activator to suppress neuroinflammation for treatment of ischemic stroke.

Reproductive toxicology. 9-Aminoacridine hydrochloride

Environ Health Perspect 1997 Feb;105 Suppl 1(Suppl 1):269-70.9114319 PMC1470281

9-Aminoacridine as a fluorescent probe of the electrical diffuse layer associated with the membranes of plant mitochondria

Biochem J 1981 Jan 1;193(1):37-46.7305932 PMC1162573

1. Mitochondria from Jerusalem artichoke (Helianthus tuberosus) tubers and Arum maculatum spadices caused a quenching of the fluorescence of 9-Aminoacridine when mixed in a low-cation medium (approximately 1 mM-K+) and addition of chelators further decreased the fluorescence. Salts released the quenching of the 9-Aminoacridine fluorescence and the efficiency of the release appeared to be mainly dependent on the valency of the cation (C3+ greater than C2+ greater than C+). 2. The results are consistent with the theory of charge screening and demonstrate that 9-Aminoacridine is a convenient probe of the behaviour of cations on the membranes of mitochondria and in the diffuse layer associated with these membranes. 3. The concentration of salt required to achieve half-maximal release of quenching of 9-Aminoacridine fluorescence was proportional to the concentration of mitochondria in the solution and theoretical considerations show this effect to be inherent in the Gouy-Chapman theory. 4. 9-Aminoacridine was removed from the bulk of the solution by the mitochondria to a far greater extent than was Na+ or K+, which is suggested to be due to the formation of bi- and poly-valent cations by aggregation of 9-Aminoacridine molecules in the diffuse layer. This would have implications for the use of 9-Aminoacridine to determine delta pH across membranes. 5. Jerusalem-artichoke mitochondria removed from 9-Aminoacridine and Ca2+ from the bulk of the solution and required more ions to screen the membranes than did an equal concentration (mg of protein/ml) of Arum mitochondria, indicating that Jerusalem-artichoke mitochondria contain more negative charges per mg of protein.