Design of NDA Intercalators To Overcome Topoisomerase II-Mediated Multidurg Resistance

Bc, Baguley; Km, Holdaway; Lm, Fray

doi:10.1093/jnci/82.5.398

Cited by 58 publications

(24 citation statements)

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“…Anilinoacridines have successfully been used to target isozymes of mammalian DNA topoisomerase II (3,14), and various analogs are clinically effective against some forms of cancer (11,12). Therefore, we tested a wide variety of substituted 9-anilinoacridines for their activities against Trypanosoma lewisi (9) and, on the assumption that protozoal DNA topoisomerases would be closely related, the subset of compounds most active against T. lewisi and additional derivatives were screened against L. major.…”

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confidence: 99%

9-Anilinoacridines as potential antileishmanial agents

Mauël

Denny

Gamage

et al. 1993

Antimicrob Agents Chemother

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A number of 1'-substituted 9-anilinoacridines were evaluated for their activities against promastigote and amastigote forms of Leishmania major and for their toxicities to human Jurkat leukemia cells. Several compounds possessing l'-NH-alkyl substituents produced more than 80% growth inhibition of macrophageinfected L. major amastigotes at or below a concentration of 1 ,uM. l'-Hexylamino-9-anilinoacridine (compound 14) was the least toxic compound to human Jurkat cells, while it retained strong antileishmanial activity. There was a general trend for the more lipophilic compounds to show the greatest antileishmanial activity, whereas 3,6-di-NH2 substitution of the acridine nucleus reduced or eliminated activity. Some structure-activity relationships of the various compounds are discussed.The widespread occurrence of leishmaniasis (2) and the limited repertoire of drugs currently capable of treating leishmanial infections without undesirable side effects (18) are spurring efforts to find more effective cures for the disease. There is evidence that some drugs active against bacterial and mammalian DNA topoisomerases II have limited activity against Leishmania donovani (7) and Leishmania mexicana (20) and that two other potent antileishmanial drugs, sodium stibogluconate and ureastilbamine, inhibit DNA topoisomerase I of L. donovani (6). Also, it was recently reported that a number of aminoacridines have in vitro activity against Leishmania promastigotes (21). These observations suggested that a more systematic study of DNA topoisomerase inhibitors for their potential activities against trypanosomes, and in particular Leishmania species, would be worthwhile.Anilinoacridines have successfully been used to target isozymes of mammalian DNA topoisomerase II (3,14), and various analogs are clinically effective against some forms of cancer (11,12). Therefore, we tested a wide variety of substituted 9-anilinoacridines for their activities against Trypanosoma lewisi (9) and, on the assumption that protozoal DNA topoisomerases would be closely related, the subset of compounds most active against T. lewisi and additional derivatives were screened against L. major. In the present study we identified a small group of compounds that show in vitro activity against macrophage-infected L. major in the concentration range of <0.1 to 1 ,uM. The structures and properties of the range of compounds tested together with data on their activities against L. major and their toxicities to human Jurkat cells are described. The results confirm that it is possible to modify existing anticancer drugs targeted at DNA topoisomerase II and improve their activities and specificities against other organisms, such as trypanosomes, that cause leishmaniasis. Better knowledge of the structure-activity relationships that increase the potencies of drugs against parasite DNA topoisomerases and that decrease their activities against human cells is now being sought to aid in the design of new drugs that are effective against these and other pathogenic parasi...

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confidence: 99%

9-Anilinoacridines as potential antileishmanial agents

Mauël

Denny

Gamage

et al. 1993

Antimicrob Agents Chemother

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“…Amsacrine and its analogs contain a DNA-binding domain (acridine moiety) and a topoisomerase II-binding domain (aniline moiety). Amsacrine itself, distinct from anthracyclines, is not affected by transport-mediated MDR; in addition, its topoisomerase II-binding domain can be modified to overcome the observed atypical MDR (10). Thus, structural modifications of amsacrine analogs may provide effective second-line therapeutics for tumors that have developed resistance to doxorubicin and etoposide.…”

Section: Discussionmentioning

confidence: 99%

“…9-Anilinoacridines have displayed an advantage over other topoisomerase II inhibitors in that they were not affected by transport-mediated multidrug resistance (MDR). In addition, atypical MDR can be overcome by structure modification at its topoisomerase II-binding domain (10). In an attempt to develop improved chemotherapeutic agents, 9-anilinoacridine has been subjected to various structural modifications on the acridine backbone as well as on the aniline ring.…”

Section: Introductionmentioning

confidence: 99%

CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

Sun

Chen

Kwon

et al. 2015

Molecular Medicine Reports

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Abstract. 3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl} (3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino) ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF-7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G 2 /M-phase arrest with a decreased S-and G 0 /G 1 -phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK04 02 aga inst est rogen receptor-negative a nd HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

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“…It would probably be better to attach the groove binding entity directly to the acridine ring, in a way similar to that used for oligonucleotide-acridine conjugates (12, and references cited therein). However, it may also be beneficial in terms of biological activity to Downloaded by [Rutgers University] at 21: 24 11 April 2015 retain the anilino-aminoacridine structure because the anilino group is believed to represent the topoisomerase IT-binding domain (69). The bulky substituent on the acridine ring is probably essential for the topoisomerase 11-mediated antitumour activity of amsacrine.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Two Peptide-Acridine Conjugates Containing the SPKK Peptide Motif with DNA and Chromatin

Flock

Bailly

et al. 1994

Journal of Biomolecular Structure and Dynamics

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The interaction between DNA and two peptide-acridine conjugates containing one (1) or two (2) moieties of the Ser-Pro-Lys-Lys (SPKK) minor groove-binding peptide motif has been studied by a combination of hydrodynamic, biochemical and spectroscopic methods including diffusion-enhanced luminescence energy transfer (DELET) measurements with a Tb(III) lanthanide chelate as donor. Viscometric titrations do not reveal any significant difference between the two hybrid molecules which both unwind (by about 15 degrees) and extend the DNA similarly. DELET measurements show that the acridinyl chromophore of compounds 1 and 2 is much more accessible than that of a simple monointercalating drug such as acridine orange or ethidium. The accessibility factor increases proportionally with the peptide length, reflecting the extent of perturbation imposed upon the intercalating chromophore by the binding to DNA of the peptide moiety of the hybrids. Experiments with the osmium tetroxide-bispyridine reagent indicate that the two hybrid compounds both affect the local conformation of DNA rendering certain thymine residues conspicuously accessible to the probe. The drug-induced sites of hyperreactivity towards OsO4 in DNA are very similar with the exception of a short run of three T residues which is attacked more strongly in the presence of tetrapeptide-acridine conjugate 1 than with the octapeptide-acridine conjugate 2. These results are fully in agreement with previous footprinting studies and support the view that a minimum of two SPKK motifs is required to mimic the AT-specific minor groove binding antibiotic netropsin. On the basis of the DNA-binding properties of these two peptide-acridine hybrids, we present DNA-binding models in which the acridinyl moiety of compound 1 protrudes slightly outside the double helix but remains more or less parallel to the plane of the base-pairs. In contrast, with compound 2, where the octapeptide SPKKSPKK is bound to the minor groove, we postulate that the chromophore lies only partially overlapped with the base pairs in the intercalation site and, in addition, the heterocyclic chromophore is significantly tilted with respect to the double helix axis. Electric linear dichroism and DELET measurements with chromatin reveal that the presence of histone proteins affects the intercalative binding of compound 2 while it has practically no effect on the binding of compound 1.

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Design of NDA Intercalators To Overcome Topoisomerase II-Mediated Multidurg Resistance

Cited by 58 publications

References 0 publications

9-Anilinoacridines as potential antileishmanial agents

9-Anilinoacridines as potential antileishmanial agents

CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

Interaction of Two Peptide-Acridine Conjugates Containing the SPKK Peptide Motif with DNA and Chromatin

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