The mode of action of cytotoxic and antitumor 1-nitroacridines. I. The 1-nitroacridines do not exert their cytotoxic effects by physicochemical binding with DNA

Pawlak, Katarzyna; Matuszkiewicz, A; Pawlak, Jan W.; Konopa, Jerzy

doi:10.1016/0009-2797(83)90092-3

Cited by 36 publications

(17 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They may intercalate if the distance between bases is somehow increased from 3.4 to 6.8 A (21), they may hydrogen bond to the bases and lie in one of the grooves of DNA or they may hydrogen bond to phosphate groups and lie outside the helix. The intercalation of 1-nitro-9-aminoacridines in DNA has been studied by Filipski and co-workers (22) and by Konopa and co-workers (23)(24)(25)(26)(27). They have shown that 1-, 2-, 3-, and 4-nitro-9-aminoacridines can bind to DNA by an intercalation mechanism; of these, however, only the 1-nitroacridines show appreciable antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Intercalation Model for DNA-Cross Linking in a 1-Nitro-9-aminoacridine Derivative, an Analog of the Antitumor Agent “Ledakrin” (Nitracrine)

Stallings

Glusker²,

Carrell³

et al. 1984

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

Ledakrin (nitracrine), C-283, is a 1-nitro-9-aminoacridine derivative that is used in Poland as an antitumor agent. In order to investigate the basis of the activity of this compound the structure of another analog, [9-(3-dimethyl-1-methylpropylimino)-1-nitro-9,10-dihydroacridin e], C-829, that has similar activity, was determined by X-ray crystallographic techniques and was compared with that of ledakrin, already reported in the literature. In both molecules the proximity of the 1-nitro to the substituted 9-aminoacridine group causes extensive distortions. These compounds are believed to act, after metabolic "activation", by cross-linking DNA. Such cross-linking does not occur in the absence of the 1-nitro group or if the nitro group is moved to the 2-, 3- or 4-position. Computer-assisted model-building has been used to test possible intercalative models. It has shown that functional groups on C-829 or C-283 are, when the acridine portion of the molecule is intercalated as in a proflavine dinucleoside phosphate complex, in positions suitable for DNA cross-linking by activated 1-nitro-9-aminoacridine derivatives.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The antitumor activity of the 1-nitro-9-aminoacridine derivatives is believed to result from the ability (after metabolic activation) to cross-link DNA in vivo (22)(23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Intercalation Model for DNA-Cross Linking in a 1-Nitro-9-aminoacridine Derivative, an Analog of the Antitumor Agent “Ledakrin” (Nitracrine)

Stallings

Glusker²,

Carrell³

et al. 1984

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

show abstract

“…In vitro studies conducted have indicated that the drug undergoes metabolic reduction of the nitro group to form a reactive species, while inhibition of this reaction by oxygen transforms the drug into an extremely potent, hypoxia selective cytotoxic agent [30]. Intercalative DNA binding does not appear to be directly responsible for cytotoxicity, but it may contribute to the high potency of the drug by serving to target reactive, reduced cellular metabolites to the DNA [31]. The position of the nitro group was an important feature, replacement of this moiety from ortho to meta position decreases the inhibitory effect.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones

et al. 2008

View full text Add to dashboard Cite

A series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a-d) and 7 (a-g) were synthesized with different substituted aromatic sulfonyl chlorides (R-SO(2)-Cl) and alkyl halides (R-X) and were characterized by (1)H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evaluated for their cell antiproliferation activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The antiproliferative effects of the synthesised compounds were tested against viable human skin fibroblast cell line and carcinoma cell lines namely HeLa cells, HT-29 cells, MCF-7 cells, HepG-2 cells by adopting positive and negative control. The importance of the nitro group on thiazolidinone moiety was confirmed and it was concluded that the fourth position of the substituted aryl ring plays a dominant role and was responsible for the antiproliferative activity. Among the synthesized compounds only 6a, 7e and 7g have potent antiproliferative activity on all the carcinoma cell lines tested.

show abstract

“…Recent work has also shown the compound to have a range of other biological activities (4,5). Efforts devoted to syntheses have been accompanied by complementary studies of the structure (6-lo), properties (1,(11)(12)(13)(14), and mechanism of the biological action (1,4,5,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) of nitracrine and other compounds. X-ray analyses re-'~u t h o r to whom correspondence may be addressed '~evision received March 24, 1993. vealed that the monohydriodide of nitracrine, in which protonation takes place at N(36), crystallizes into the imino form (I), a characteristic of which is that H (25) migrates from exocyclic to endocyclic nitrogen.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the 2-nitro isomer exists as a planar amino tautomer ( 2 ) , with coplanarity between the acridine nucleus and the nitro group (8,9). Since only nitracrine exhibits enhanced antineoplastic activity and its 2-nitro isomer does not (1,15,16), it would suggest that the imino tautomeric structure, which in the case of nitracrine could be forced by steric overcrowding, is the one responsible for its unique biological properties ( 10). The prototropic tautomerism whose consequence is the transformation between amino and imino structures is a general phenomenon characteristic of 9 -m iCan.…”

Section: Introductionmentioning

confidence: 99%

Studies on nitracrine and its nitro isomers devoted to tautomeric phenomena, structural and physicochemical features, as well as surrounding electrostatic potential

Rak¹,

Byażejowski²,

Zauhar³

1993

Can. J. Chem.

View full text Add to dashboard Cite

Relative stabilities and features of tautomers of N, N-dimethyl-N'-(l-nitro-9-acridinyl)-1,3-propanediamine (known as nitracrine by the World Health Organization (WHO) or as Ledakrin in Poland), which exhibits antitumour activity, and its three nitro isomers were examined by AM1 and, in some cases, by PM3 and ab initio (STO-3G) methods. The lowest energy form of three compounds was always an imino tautomer, while the energy of the amino tautomers was a few kcal mol-' higher and that of the aci forms (in the case of the 2-and 4-nitro isomers) was more than 25 kcal mol-' higher. Each tautomer can further exist in several structural forms (conformers or stereoisomers). In some of them internal hydrogen bonding interactions are feasible. The barriers to rotation of the -NHR group, as well as to inversion of the -NHR group (in amino tautomers of nitracrine and its 2-nitro isomer) and of the whole molecule (in the case of nonplanar imino structures), were also evaluated, as were enthalpies of formation (total energies), entropies, free energies, dipole moments, and energies of HOMO and LUMO orbitals. Molecular electrostatic potential maps reveal that only in nitracrine are both -NO2 and -NHR groups surrounded by a negative electrostatic potential, whereas in other isomers the -NHR fragment is surrounded by a positive electrostatic potential while the -NOz group remains in the region of a negative electrostatic potential. The possible influence of physicochemical features on the biological activity of the molecules is also considered. [Traduit par la rCdaction]

show abstract

The mode of action of cytotoxic and antitumor 1-nitroacridines. I. The 1-nitroacridines do not exert their cytotoxic effects by physicochemical binding with DNA

Cited by 36 publications

References 12 publications

Intercalation Model for DNA-Cross Linking in a 1-Nitro-9-aminoacridine Derivative, an Analog of the Antitumor Agent “Ledakrin” (Nitracrine)

Intercalation Model for DNA-Cross Linking in a 1-Nitro-9-aminoacridine Derivative, an Analog of the Antitumor Agent “Ledakrin” (Nitracrine)

Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones

Studies on nitracrine and its nitro isomers devoted to tautomeric phenomena, structural and physicochemical features, as well as surrounding electrostatic potential

Contact Info

Product

Resources

About