Two new interesting modes of action of quinacrine have been discovered. The first concerns a dose-related inhibition of uptake of [8-(3)H] adenosine into host cells of parasitized blood. Second, the drug inhibits the incorporation of tritiated adenosine triphosphate primarily into RNA but also into DNA of the erythrocyte-free malarial parasite Plasmodium berghei.

http://science.sciencemag.org/content/sci/169/3944/492.full.pdf

Quinacrine: mechanisms of antimalarial action.

Acridines interact with both nucleic acids and proteins. The targeting of these biopolymers is broadly applied in cancer therapy and gene delivery. Interestingly, due to direct interactions of acridines with various enzymes, acridines can be suitable drugs for treatment of neurodegenerative diseases, inflammation, immunological disorders, protozoal diseases, etc.General introduction to the field of acridines is provided including scope and limitations of the field. Some important structures, which are used as drugs, are highlighted. Acridines are heteroaromatic compounds (Figs. 1.1 and 2.1) that were applied for treatment of many diseases since the beginning of 20th century [1]. Namely, aminoacridines possessing higher solubility in physiological liquids were used as antiprotozoal and antibacterial drugs. The growth of transplanted tumor was suppressed by acriflavine (mixture of 3,6-diamino-10-methylacridinium chloride and 3,6-diaminoacridine) in the thirties [2]. In the past, anti-tumor activity of acridines was attributed to their interactions with nucleic acids; however, the more recent studies favor an explanation based on direct interaction of acridines with biologically important proteins [3–10]. According to search in RCSB PDB database conduced in August 2015, there were 48 structures containing acridine skeleton and 30 structures containing 1,2,3,4-tetrahydroacridine, respectively. From these 78 structures only 32 correspond to acridine binding to nucleic acids including one complex between amsacrine-nucleic acids and enzyme topoisomerase II. Thus, more than half of the structures represents direct binding of acridines to proteins. The development of human society has incorporated acridine drugs to daily life of millions of individuals worldwide [6, 10–28]. For selected acridine drugs see Fig. 1.1. Due to high toxicity, compounds 1–4 are applied only as local antiseptic agents. m-Amsacrine (6) is very active against malignant lymphomas and acute leukemia. Asulacrine (7), which combines the substructures of m-amsacrine (6) and DACA (5), has improved pharmacokinetic profile and broader scope of applications against leukemia, Lewis lung tumors, and many solid tumors. Nitracrine (8) serves for treatment of mammary and ovarian tumors. BRACO19 (9) is powerful binder of quadruplexes. Pt-ACRAMTU (10) is mimicking anticancer cisplatin; however, it has different mode of action. Quinacrine (11) can be viewed as a universal medicine for © Springer International Publishing AG 2017 J. Ježek et al., Biomedical Applications of Acridines, Progress in Drug Research 72, DOI 10.1007/978-3-319-63953-6_1 1

Biomedical Applications of Acridines

Plasmodium berghei: Inhibited incorporation of AMP-8-3H into nucleic acids of erythrocyte-free malarial parasites by acridines, phenanthridines, and 8-aminoquinolines

Air-dried blood smears and erythrocyte suspension from patients infected with Plasmodium falciparum, stained under optimal conditions with acridine orange, permit easy detection of plasmodia with fluorescence microscopy together with a clear cytochemical colour differentiation of nuclear DNA (green or green-yellow) and cytoplasmic RNA (orange-red fluorescence). Judging from fluorescence characteristics of nuclei (DNase sensitive and RNase resistant green or green-yellow), the plasmodial DNA appears to be double-stranded.

Cytochemical significance of acridine orange staining of human plasmodia with some comments on double-stranded DNA.

Chapter v – applications of synthetic dyes to biological problems

Acridine orange in daily doses of 1, 2 and 4 mg for 4 days was given to chicks averaging 50 gm in weight. Dosage was started 1, 2 and 3 days after infection with Plasmodium gallinaceum. Such doses were sufficient to stain the parasite in vivo, as shown by its bright fluorescence in UV light, but did not exhibit any antimalarial action. Staining of fresh blood samples from infected chicks with 0.01% acridine orange in Krebs–Ringer containing 0.1 M phosphate buffer (pH 6.0-6.2) resulted in differential fluorescence of the nucleic acids of the plasmodia, to show nuclear DNA bright green and cytoplasmic RNA orange-red. After optimum acid hydrolysis, as used for the Feulgen reaction, staining with 0.1% acridine orange produced intense red fluorescence of the nuclear DNA in the plasmodia. Nuclear DNA of the chick erythrocytes showed bright fluorescence both in vivo and in vitro.

Dutta Gp

Papers

Acridine Orange Staining and Fluorescence of Nucleic Acids in Plasmodia and Associated Host Erythrocytes