Major Groove Binding and ‘DNA-Induced' Fit in the Intercalation of a Derivative of the Mixed Topoisomerase I/II Poison <i>N</i>-(2-(Dimethylamino)ethyl)acridine-4- carboxamide (DACA) into DNA:  X-ray Structure Complexed to d(CG(5-BrU)ACG)<sub>2</sub> at 1.3-Å Resolution

Todd, Alan K.; Adams, Andrew A.; Thorpe, James H.; Denny, William A.; Wakelin, Laurence P. G.; Cardin, C.J.

doi:10.1021/jm980479u

Cited by 96 publications

(96 citation statements)

References 27 publications

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“…The parallel base-stacking intercalation binding mode has been observed in a number of drugs (10,11,21,24). Although the chromophore structure of MLN944 is similar to that of the acridine carboxamides such as 9-amino-DACA, the base-stacking interactions of the two drugs with DNA base pairs is somewhat different (10,11).…”

Section: Discussionmentioning

confidence: 99%

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Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Dai

Punchihewa

Mistry³

et al. 2004

Journal of Biological Chemistry

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The new bisphenazine anticancer drug MLN944 is a novel cytotoxic agent with exceptional anti-tumor activity against a range of human and murine tumor models both in vitro and in vivo. MLN944 has recently entered Phase I clinical trials. Despite the structural similarity with its parent monophenazine carboxamide and acridine carboxamide anticancer compounds, MLN944 appears to work by a distinct mechanism of inhibiting DNA transcription rather than the expected mechanism of topoisomerase I and II inhibition. Here we present the first NMR structure of MLN944 complexed with d(ATG-CAT) 2 DNA duplex, demonstrating a novel binding mode in which the two phenazine rings bis-intercalate at the 5 -TpG site, with the carboxamide amino linker lying in the major groove of DNA. The MLN944 molecule adopts a significantly unexpected conformation and side chain orientation in the DNA complex, with the N10 on the phenazine ring protonated at pH 7. The phenazine chromophore of MLN944 is very well stacked with the flanking DNA base pairs using the parallel base-stacking intercalation binding mode. The DNA sequence specificity and the groove recognition of MLN944 binding is determined by several site-specific hydrogen bond interactions with the central G:C base pair as well as the favorable stacking interactions with the 5 -flanking thymine. The specific binding site of MLN944 is known to be recognized by a number of important transcription factors. Our electrophoretic gel mobility shift assay results demonstrated that the c-Jun DNA binding to the AP-1 site is significantly inhibited by MLN944 in a dose-dependent manner. Thus, the exceptional biological activity of MLN944 may be due to its novel DNA binding mode leading to a unique mechanism of action.The systemic therapies currently available for the treatment of various solid tumors of adult life, including those of lung, colon, breast, prostate, and ovary, remain primarily palliative, and there is an urgent need for more effective therapies. Although recently there has been a significant effort in developing molecular targeted therapies, cytotoxic agents remain the major form of therapy for the majority of cancers. Moreover, there is reason to believe that a therapeutic advantage remains to be gained from cytotoxic drugs with novel mechanisms of action, with improved safety profiles and different spectra of anti-tumor activity.The bisphenazine MLN944 (XR5944) (Fig. 1a) is a novel cytotoxic agent with exceptional anti-tumor activity against a range of human and murine tumor models both in vitro and in vivo (1). It has recently entered Phase I clinical trials. Although initial reports showed that MLN944 can bind strongly to DNA (2) and that it may interfere with the normal function of topoisomerase I and II in vitro (1), recent studies have indicated that topoisomerase I and II may not be its primary cellular target and that it works by a novel mechanism of action. The mechanistic novelty of MLN944 is suggested by the fact that in the yeast Saccharomyces cerevisiae, modulation of to...

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Section: Discussionmentioning

confidence: 99%

“…Crystal structures of 9-amino-DACA⅐DNA complexes showed that acridine rings intercalate duplex DNA at a CpG site (10,11). MLN944 has also been shown to be an efficient DNA intercalator by its induction of dose-dependent supercoiling of plasmid DNA.…”

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confidence: 99%

Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Dai

Punchihewa

Mistry³

et al. 2004

Journal of Biological Chemistry

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“…DNA is a highly charged polyelectrolyte. The negative charges of the phosphates have to be neutralized by counterions, which may be metal ions, organic amines, positively a͒ Electronic mail: knoll@mpip-mainz.mpg.de charged proteins or, in therapeutic applications, positively charged drugs [22][23][24][25][26][27][28] Therefore, ionic strength has a major influence on the DNA/DNA duplex formation, while in solution it affects PNA/DNA duplex formation less extensively. 29 PNAs have been used in a variety of methods for diagnostics and gene analysis, both in solution and immobilized on solid surfaces.…”

Section: Introductionmentioning

confidence: 99%

Effect of ionic strength on PNA-DNA hybridization on surfaces and in solution

et al. 2007

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“…13,14) Some hybrid molecules composed of a non-charged porphyrin and acridines have been synthesized as a functional BLM model. [15][16][17] Acridine is known as an intercalator, 18,19) and hence the metal complexes of the hybrids bind to DNA via the acridine moiety, and then cause strand breaks by generating reactive oxygen species in the presence of reducing or oxidizing agents. To achieve higher and more efficient chemical modification of negatively charged DNA, we have for the first time synthesized positively charged porphyrin-acridine hybrids, 1-4, which are linked with various lengths of a diamino alkyl chain.…”

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Efficient Photocleavage of DNA by Cationic Porphyrin. Acridine Hybrids with the Effective Length of Diamino Alkyl Linkage.

Ishikawa

Yamashita

Uno

2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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The development of compounds which modify nucleic acid structure is a current research area and can make a significant contribution to anti-tumor and -viral chemotherapy.1,2) For example, drugs like bleomycin (BLM) [3][4][5] capable of binding to and cleaving nucleic acids are expected to suppress the proliferation of malignant cells by blocking the flow of genetic information. From this point of view, cationic meso-tetrakis(4-N-methylpyridiniumyl)porphine (TMPyP) has been carefully studied and noted for its bifunctionality: i) the tight interaction with DNA through the three types of binding mode including intercalation, outside binding in the groove, and outside binding with self-stacking along the DNA surface, 6,7) and ii) the marked photochemical nuclease activity.8-10) Such a positively charged photosensitizer 11,12) would also be useful in the photodynamic therapy of cancer. 13,14) Some hybrid molecules composed of a non-charged porphyrin and acridines have been synthesized as a functional BLM model. [15][16][17] Acridine is known as an intercalator, 18,19) and hence the metal complexes of the hybrids bind to DNA via the acridine moiety, and then cause strand breaks by generating reactive oxygen species in the presence of reducing or oxidizing agents. To achieve higher and more efficient chemical modification of negatively charged DNA, we have for the first time synthesized positively charged porphyrin-acridine hybrids, 1-4, which are linked with various lengths of a diamino alkyl chain. In this paper we report their photo-nuclease activity and interaction with DNA. Our data show that they exhibit more enhanced photo-induced nuclease activity than TMPyP, and suggest that acridine and porphyrin moiety in the hybrids interact with DNA by the intercalative and outside groove binding, respectively. Results and DiscussionSynthesis of the Cationic Porphyrin-Acridine HybridsThe synthetic procedures for the positively charged porphyrin-acridine hybrids 1-4 are illustrated in Chart 1. One equivalent of terephthalaldehydic acid methyl ester, 3 eq of pyridine-4-aldehyde, and 4 eq of pyrrole were reacted in propionic acid for 1.5 h. The resultant mixture including six porphyrin isomers was separated on silica gel. The fifth eluted isomer, 5-(4-methoxycarbonylphenyl)-10,15,20-tris(4-pyridyl)-porphine, 9, obtained in 5.9% yield was then hydrolyzed with lithium hydroxide to give 5-(4-carboxyphenyl)-10,15,20-tris(4-pyridyl)porphine, 10, almost quantitatively. Condensation of 1 eq of 10 with 5-7 eq of acridine-diaminoalkane derivatives, 20) 5-8, using 5-7 eq of carbonyldiimidazole (CDI) in an absolute 50/50 (v/v) DMF-DMSO solution afforded corresponding porphyrin-acridine hybrids, 11-14, in 22-46% yield. The products were then methylated with excess methyl iodide in DMF for 3 h to give the final products, 1-4, quantitatively. Characterization of the compounds was accomplished using 1 H-NMR spectroscopy, matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and elemental analysis.Photo...

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Major Groove Binding and ‘DNA-Induced' Fit in the Intercalation of a Derivative of the Mixed Topoisomerase I/II Poison N-(2-(Dimethylamino)ethyl)acridine-4- carboxamide (DACA) into DNA: X-ray Structure Complexed to d(CG(5-BrU)ACG)₂ at 1.3-Å Resolution

Cited by 96 publications

References 27 publications

Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Effect of ionic strength on PNA-DNA hybridization on surfaces and in solution

Efficient Photocleavage of DNA by Cationic Porphyrin. Acridine Hybrids with the Effective Length of Diamino Alkyl Linkage.

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Major Groove Binding and ‘DNA-Induced' Fit in the Intercalation of a Derivative of the Mixed Topoisomerase I/II Poison N-(2-(Dimethylamino)ethyl)acridine-4- carboxamide (DACA) into DNA: X-ray Structure Complexed to d(CG(5-BrU)ACG)2 at 1.3-Å Resolution

Cited by 96 publications

References 27 publications

Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Novel DNA Bis-intercalation by MLN944, a Potent Clinical Bisphenazine Anticancer Drug

Effect of ionic strength on PNA-DNA hybridization on surfaces and in solution

Efficient Photocleavage of DNA by Cationic Porphyrin. Acridine Hybrids with the Effective Length of Diamino Alkyl Linkage.

Contact Info

Product

Resources

About

Major Groove Binding and ‘DNA-Induced' Fit in the Intercalation of a Derivative of the Mixed Topoisomerase I/II Poison N-(2-(Dimethylamino)ethyl)acridine-4- carboxamide (DACA) into DNA: X-ray Structure Complexed to d(CG(5-BrU)ACG)₂ at 1.3-Å Resolution