Niche for acridine derivatives in anticancer therapy.

During the last 4 decades, intensive research has focussed on the effect of small organic molecules with antitumour activity that are able to intercalate into DNA and inhibit topoisomerase and telomerase enzymes. In this review, we describe some of the chemical and biological properties of acridine, which is a chemotherapeutic agent that has been used for cancer treatment since 1970. In addition, we summarise the progress that has been made in the development of anticancer agents based on the clinical in vivo/in vitro studies that have been conducted for 13 classes of natural and synthetic acridines.

Pre-clinical pharmacokinetics of the acridine antitumour candidate AC04 and its 1-oxo-metabolite plasma profile.

This work aimed to investigate plasma pharmacokinetics and tissue distribution of a new acridine derivative 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) and its 1-oxo-AC04 metabolite disposition in Wistar rats. After a single AC04 1.5 mg/kg intravenous (i.v.) bolus dose, blood samples were taken up to 120 h. Plasma samples were deproteinization, and AC04 and metabolite were quantified by validated liquid chromatography in tandem with mass spectrometry method. Protein binding was determined by ultrafiltration. AC04 tissue disposition was evaluated after i.v. bolus dose. Individual AC04 concentration-time profiles were best fitted by a two-compartment model showing CL(tot) of 3.4 ± 3.4 L/h/kg, Vd(SS) of 137.9 ± 91.4 L/kg, AUC(0-∞) of 788 ± 483 ng·h/mL and a t(1/2) of 45.5 ± 31.5 h. Protein binding was 98.1 ± 1.6%. AC04 showed higher penetration into the lung, spleen and liver, with AUC(0-96) of 798,443, 263,211 and 303,722 ng·h/mL, respectively. The 1-oxo-AC04 metabolite represented 10% of AC04 plasma concentration, showing a t(1/2) of 23.2 ± 10.4 h. These results suggest that, despite the small free plasma fraction, AC04 penetrates extensively reaching high concentrations in most tissues residing for a long time, which is important for its activity on solid tumours. All results combined indicate that AC04 is potentially a good antitumour candidate.

Dyes, trypanosomiasis and DNA: a historical and critical review.

Trypanosomiasis, a group of diseases including sleeping sickness in humans and Nagana in cattle in Africa, and Chagas' disease in South America, remains a considerable problem in the 21(st) century. The therapies that are available, however, usually have their roots in the "dye therapy" of a century ago, knowledge gained at the microscope from parasite staining procedures and converted to chemotherapy based on compounds closely related to the laboratory reagents. Dyes such as trypan red and trypan blue led to the development of suramin, while cationic nitrogen heterocyclic dyes furnished examples of the phenanthridinium class, such as ethidium (homidium) and isometamidium. Both suramin and isometamidium remain in use. Owing to mutagenicity issues, the presence of ethidium among the phenanthridinium dyes has led to concerns over the clinical use of related derivatives. There are several mechanisms for dye-DNA interaction, however, including possible hydrogen bonding of dye to the polymer, and these are discussed together with structure-activity relations and cellular localization of the phenanthridine and isomeric acridines involved. Better understanding of nucleic acid binding properties has allowed the preparation of more effective phenanthridinium analogues intended for use as anticancer/antiviral therapy.

Antischistosomal activity of acridanone-hydrazones in Cebus monkeys experimentally infected with the SJ strain of Schistosoma mansoni

In this study, four compounds where utilized at the dose of 12.5mg/kg body weight, p.o., to treat Cebus monkeys experimentally infected with about 200 cercariae of Schistosoma mansoni (SJ strain), via transcutaneous route. The oograms performed with rectal snips, as well as stool examinations carried out periodically, showed no viable eggs of the parasite, from day 29 to 226 post-treatment. The perfusion undertaken after killing the animals showed absence of worms in the treated monkeys, whereas 83 worms were recovered from the control, thus corroborating the results obtained by means of oograms and coproscopy. These results confirm the efficacy of 9-acridanonehydrazones previously tested against the LE strain of S. mansoni. The low curative dose and apparent absence of toxicity render these drugs an important therapeutic reserve, taking into consideration the reports on the resistance of S. mansoni to the modern drugs oxamiziquine and praziquantel.

Antischistosomal activity of acridanone-hydrazones in Cebus monkeys experimentally infected with the SJ strain of Schistosoma mansoni.

In this study, four compounds were utilized at the dose of 12.5 mg/kg body weight, p.o., to treat Cebus monkeys experimentally infected with about 200 cercariae of Schistosoma mansoni (SJ strain), via transcutaneous route. The oograms performed with rectal snips, as well as stool examinations carried out periodically, showed no viable eggs of the parasite, from day 29 to 226 post-treatment. The perfusion undertaken after killing the animals showed absence of worms in the treated monkeys, whereas 83 worms were recovered from the control, thus corroborating the results obtained by means of oograms and coproscopy. These results confirm the efficacy of 9-acridanone-hydrazones previously tested against the LE strain of S. mansoni. The low curative dose and apparent absence of toxicity render these drugs an important therapeutic reserve, taking into consideration the reports on the resistance of S. mansoni to the modern drugs oxamniquine and praziquantel.

Activity of 9-acridanone-hydrazone drugs detected at the pre-postural phase, in the experimental schistosomiasis mansoni.

The compound Ro-15.5458/000, derivative in the class of 9-acridanone-hydrazones, was found to be effective against Schistosoma mansoni in mice, killing almost all the skin schistosomules (24 hr after infection), when administered at the dose of 100 mg/kg. In experiments carried out with Cebus monkeys, the drug was shown to be fully effective at 25 mg/kg, 7 days after infection. These data, associated with the good results obtained earlier at the post-postural phase of schistosomiasis, allow the inference that this promising compound may be important in the set of antischistosomal drugs, depending on further toxicological and clinical tests.

Schistosoma mansoni: preclinical studies with 9-Acridanone-hydrazones in Cebus monkeys experimentally infected.

Derivatives of acridine (9-Acridanone-hydrazones) were tested in Cebus monkeys experimentally infected with Schistosoma mansoni, at the dosages of 50, 25, and 12.5 mg/kg (p.o., single dose). At least, four compounds seemed to be very promising, promoting alterations in the oogram and reducing the worm burden drastically, even at the lowest dose (12.5 mg/kg). No side effects could be detected after drug administration.

[Correlation between non-empirical electronic parameters and the therapeutic action of aminoacridine]. / Correlação de parâmetros eletrônicos não-empíricos com a atividade quimioterápica de aminoacridinas

By using the omega technique of molecular orbital calculations, certain non-empirical electronic parameters (charge density, HOMO and LEMO) in acridine, five monoaminoacridines, and five diaminoacridines were determined. High correlations were found between: a) pKalpha and electron density at the ring nitrogen; b) pKalpha and LEMO; c) electron density at the ring nigrogen and bacteriostatic index; d) LEMO and bacteriostatic index. However, no good correlation was seen between HOMO and both pKalpha and bacteriostatic index. It was also found that LEMO values in acridines allow them to act as good electron acceptors in a charge-transfer process.