Tautomerism and steric effects in 1-nitro-9-(alkylamino)acridines (ledakrin or nitracrine analogs): probing structure-activity relationships at the molecular level

Stezowski, John J.; Kollat, P.; Bogucka-Ledóchowska, M.; Glusker, Jenny P.

doi:10.1021/ja00293a042

Cited by 35 publications

(10 citation statements)

References 2 publications

(3 reference statements)

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“…The cytotoxicity of nitracrine is clearly ascribable to covalent binding to DNA [Gniazdowski and Szmigiero, 1995;Bartoszek et al, 1997a]. Whether crosslinking of DNA is a major contributor to toxicity remains debatable [Pawlak et al, 1984;Stezowski et al, 1985;Wilson et al, 1989;Ferguson and Denny, 1991;Gniazdowski and Szmigiero, 1995;Bartoszek et al, 1997b;Gorlewska et al, 2001].…”

Section: Discussionmentioning

confidence: 99%

“…Nitracrine, also called ledakrin, is a cancer chemotherapy drug that has received extensive study related to antitumor activity, toxicity, and interactions with DNA [Stezowski et al, 1985;Ferguson and Denny, 1991;Gniazdowski and Szmigiero, 1995]. It has been used in Poland to treat ovarian, colon, lung, and mammary carcinomas, but its toxicity and clinical side effects have limited its use [Gniazdowski and Szmigiero, 1995].…”

Section: Introductionmentioning

confidence: 99%

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Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

Hoffmann

Yin

Terry

et al. 2006

Environ. Mol. Mutagen.

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Acridines are well-known as compounds that intercalate noncovalently between DNA base pairs and induce +/-1 frameshift mutations at sites of monotonous repeats of a single base. Reactive derivatives of acridines, including acridine mustards and nitroacridines, form covalent adducts in DNA and exhibit mutagenic properties different from the simple intercalators. We compared the frameshift mutagenicity of the cancer chemotherapy drug nitracrine (1-nitro-9-(3'-dimethylaminopropylamino)-acridine), its des-nitro counterpart 9-(3'-dimethylaminopropylamino)-acridine (DAPA), and its 2-, 3-, and 4-nitro isomers (2-, 3-, and 4-nitro-DAPA) in the lacZ reversion assay in Escherichia coli. DAPA is a simple intercalator, much like the widely studied 9-aminoacridine. It most strongly induced +/-1 frameshift mutations in runs of guanine residues and more weakly induced -1 frameshifts in a run of adenine residues. A nitro group in the 1, 3, or 4 position of DAPA reduced the yield of +/-1 frameshift mutations. DAPA weakly induced -2 frameshifts in an alternating CG sequence. In contrast, nitracrine and its 3-nitro isomer resembled the 3-nitroacridine Entozon in effectively inducing -2 frameshift mutations. The 2- and 4-nitro isomers were less effective than the 1- and 3-nitro compounds in -2 frameshift mutagenesis. The results are interpreted with respect to intercalation, steric interactions, effects of base strength on DNA binding, enzymatic processing, and a slipped mispairing model of frameshift mutagenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

Hoffmann

Yin

Terry

et al. 2006

Environ. Mol. Mutagen.

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“…dine nucleus folding, and hydrogen (25), in the imino forms, appropriate Z matrices for the C-283 (irnino form) and C-264 lies on the line connecting C (9) and N(10).…”

Section: Geometry Of Isolated Moleculesmentioning

confidence: 99%

“…60" to atoms in the acridine ring (1,6,7). 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).…”

Section: Introductionmentioning

confidence: 99%

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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.

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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]

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Synthese und cytostatische Wirkung des 9‐Nitronoracronycins

Reisch

Probst

1989

Archiv der Pharmazie

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Tautomerism and steric effects in 1-nitro-9-(alkylamino)acridines (ledakrin or nitracrine analogs): probing structure-activity relationships at the molecular level

Cited by 35 publications

References 2 publications

Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

Frameshift mutations induced by four isomeric nitroacridines and their des-nitro counterpart in thelacZ reversion assay inEscherichia coli

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

Synthese und cytostatische Wirkung des 9‐Nitronoracronycins

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