Interactions of antitumor triazoloacridinones with DNA.
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Triazoloacridinones (TA) are a new group of potent antitumor compounds, from which the most active derivative, C-1305, has been selected for extended preclinical trials. This study investigated the mechanism of TA binding to DNA. Initially, for selected six TA derivatives differing in chemical structures as well as cytotoxicity and antitumor activity, the capability of noncovalent DNA binding was analyzed. We showed that all triazoloacridinones studied stabilized the DNA duplex at a low-concentration buffer but not at a salt concentration corresponding to that in cells. DNA viscometric studies suggested that intercalation to DNA did not play a major role in the mechanism of the cytotoxic action of TA. Studies involving cultured cells revealed that triazoloacridinone C-1305 after previous metabolic activation induced the formation of interstrand crosslinks in DNA of some tumor and fibroblast cells in a dose dependent manner. However, the detection of crosslink formation was possible only when the activity of topoisomerase II in cells was lowered. Furthermore, it was impossible to validate the relevance of the ability to crosslink DNA to biological activity of TA derivatives. (+info)
Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum.
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A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum. (+info)
Antitumour properties of acridone alkaloids on a murine lymphoma cell line.
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The aim of the present study was to investigate the anticancer properties of a set of furanoacridone alkaloids, arborinine and evoxanthine, including the inhibitory effect of P-glycoprotein (Pgp) and the apoptosis-inducing capacity. The tested alkaloids were evaluated for multidrug resistance (MDR)-reversing activity on human Pgp-transfected L5178 mouse lymphoma cells, using the rhodamine-123 (Rh-123) assay. The antiproliferative effects of natural compounds and their interactions with doxorubicin were determined in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Apoptosis-inducing activity was additionally measured by means of dual annexin V and propidium iodide staining. RT-PCR was used to test the expression of Pgp mRNA after acridone treatment. All of the acridones investigated increased the accumulation of Rh-123. Gravacridonetriol and gravacridonediol monomethyl ether increased the antiproliferative effect of doxorubicin on resistant L5178 cells. Treatment with these agents resulted in a decrease in Pgp mRNA levels. Naturally occurring acridone alkaloids exhibit a beneficial combination of anticancer effects and, accordingly, the acridone skeleton can be considered useful in the design of novel antiproliferative agents. (+info)
A new acridone alkaloid from Micromelum integerrimum.
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A new acridone alkaloid, 1,3-dihydroxy-4-methoxy-10-methylacridone (1), was isolated from leaves of the plant Micromelum integerrimum, together with two known carbazole alkaloids, glycozolinol (2) and methyl carbazole-3-carboxylate (3). Their structures were elucidated by extensive spectroscopic analysis. (+info)
Fluorescent properties of acridonyl group in DNA duplex.
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Isolation of acridone alkaloids and N-[(4-monoterpenyloxy)phenylethyl]-substituted sulfur-containing propanamide derivatives from Glycosmis parva and their anti-herpes simplex virus activity.
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Six acridone alkaloids including a new glycosparvarine (1), three limonoids, and four N-[(4-monoterpenyloxy)phenylethyl]-substituted sulfur-containing propanamide derivatives including two new species, (+)-S-deoxydihydroglyparvin (10) and (+)-S-deoxytetrahydroglyparvin (11), were isolated from the branches and the leaves of Glycosmis parva CRAIB collected in the east of Thailand. Antiviral activity evaluation of isolates against herpes simplex virus (HSV) type 1 and 2 disclosed that two acridone alkaloids, glycosparvarine (1) and glycofolinine (4), showed moderate inhibitory activities with 50% effective concentration (EC50) of 348 microM and 151 microM, respectively; as well, (+)-S-deoxydihydroglyparvin (10) exhibited anti-HSV activity at the lower concentration. (+info)
Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis.
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Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/acridone analogs, their application as anticancer drugs and methods for their preparation. (+info)
Synthesis of o-(dimethylamino)aryl ketones and acridones by the reaction of 1,1-dialkylhydrazones and arynes.
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