Sequence‐Selective Intercalation of Antitumour Bis‐Naphthalimides into DNA

Bailly, Christian; Braña, Miguel F.; Waring, Michael J.

doi:10.1111/j.1432-1033.1996.0195h.x

Cited by 79 publications

(78 citation statements)

References 53 publications

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“…It is important to mention that the footprinting patterns determined here with R-3 are strongly reminiscent of those obtained previously with nogalamycin (Fox and Waring, 1986) and certain bisnaphthalimide derivatives (Bailly et al, 1996a). Nogalamycin is an intercalative antibiotic containing a planar anthracycline chromophore substituted with two bulky carbohydrate groups that come to lie simultaneously in the minor and major grooves of the double helix at DNA sequences containing GpT and/or TpG steps (Smith et al, 1995).…”

Section: Discussionmentioning

confidence: 91%

“…Nogalamycin is an intercalative antibiotic containing a planar anthracycline chromophore substituted with two bulky carbohydrate groups that come to lie simultaneously in the minor and major grooves of the double helix at DNA sequences containing GpT and/or TpG steps (Smith et al, 1995). Recently, we not only reported that a series of tumor active bisnaphthalimide derivatives exhibit a sharp selectivity for TG/GT-containing sequences but also presented strong evidence that these bisintercalating drugs recognize DNA sequences via major groove contacts (Bailly et al, 1996a). Our present footprinting studies show that R-3 shares with nogalamycin and the bisnaphthalimides the rare property of interacting selectively with TpG-and GpT-containing sequences.…”

Section: Discussionmentioning

confidence: 99%

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Recognition of Specific Sequences in DNA by a Topoisomerase I Inhibitor Derived from the Antitumor Drug Rebeccamycin

et al. 1998

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We investigated the interaction with DNA of two synthetic derivatives of the antitumor antibiotic rebeccamycin: R-3, which is a potent topoisomerase I inhibitor and contains a methoxyglucose moiety appended to the indolocarbazole chromophore, and its aglycone, R-4. Spectroscopic measurements indicate that R-3 intercalates into DNA and that its carbohydrate domain contributes significantly to reinforce the affinity for DNA. Two complementary ligation assays concur that R-3, but not its aglycone counterpart, exerts a significant effect on the curvature and/or the flexibility of DNA. The sugar moiety may be responsible for preferential binding of R-3 to circular (or bent) DNA molecules as opposed to linear DNA fragments. The sequence selectivity of binding to DNA has been studied thoroughly by footprinting with DNase I and two other nucleases. The glycosylated compound is highly selective for nucleotide sequences containing GpT (ApC) and TpG (CpA) steps. The derivative lacking the sugar moiety on the indolocarbazole chromophore binds at essentially identical sites but with considerably lower affinity, so it seems that the chromophore rather than the carbohydrate is responsible for the preferential binding to sequences surrounding GpT and TpG steps. The influence of the exocyclic substituents present on the bases at the recognition sites (i.e., the 2-amino group of guanine and the 5-methyl group of thymine) was evaluated using two series of modified DNA molecules prepared by polymerase chain reaction containing inosine and/or 2,6-diaminopurine and uridine and/or 5-methylcytosine residues. The introduction of the amino group onto purine residues or the addition of a methyl group to pyrimidine residues suffices to create new drug binding sites. Therefore, unlike most DNA-binding small molecules, the rebeccamycin analogue seems to be highly sensitive to any modification of the exocyclic substituents on the bases in both the major and minor grooves of the double helix. The footprinting profiles with the different DNA fragments bear a remarkable resemblance to those determined for nogalamycin and bisnaphthalimide compounds known to recognize their preferred GpT and TpG sites via intercalation from the major groove. The unique DNA binding characteristics of the rebeccamycin analogue correlate well with its inhibitory effects on topoisomerase I .The camptothecin derivatives irinotecan (CPT-11) and topotecan recently introduced in cancer chemotherapy are arguably the best characterized topoisomerase I poisons (Pommier and Tanizawa, 1993). These drugs interfere with the breakage-rejoining reaction by stabilizing a covalent topoisomerase I/DNA intermediate (usually referred to as cleavable complex), which can be detected by the appearance of DNA strand breaks on denaturation of the protein with a detergent. So far, relatively few other drugs have been shown to promote topoisomerase I-mediated DNA cleavage. Intoplicine, saintopins, and related naphthacene-dione antibiotics as well as alkaloids such as bulgarein and cor...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Recognition of Specific Sequences in DNA by a Topoisomerase I Inhibitor Derived from the Antitumor Drug Rebeccamycin

et al. 1998

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“…The CH 2 Cl 2 solution was washed with water, dried over Na 2 SO 4 and the solvent evaporated to give pure tert-butyl N-(6-aminohexyl) 23 (m, 2 H), 1.32 (m, 8 H), 1.43 (s, 9 H), 2.67 (t, J ϭ 6.7 Hz, 2 H), 3.10 (q, J ϭ 6.5 Hz, 2 H), 4.55 (t unresolved, 1 H). 13 H 11.18, N 12.95, O 14.79; found C 61.01, H 11.02, N 12.73, O 15.02.…”

Section: Dna Solutionsmentioning

confidence: 92%

“…13 C NMR (50 MHz, CD 3 OD): δ ϭ 27.1 (CH 2 ), 27.7 (CH 2 ), 28.5 (CH 2 ), 30.1 (CH 2 ), 40.6 (CH 2 ), 40. N-(tert-butoxycarbonyl) H 7.16, N 11.71; found C 67.81, H 7.38, N 11.37.…”

Section: N-[n-(tert-butoxycarbonyl)-6-aminohexyl]-9-acridinecarboxamidementioning

confidence: 99%

Bis‐ and Tris‐DNA Intercalating Porphyrins Designed to Target the Major Groove: Synthesis of Acridylbis‐arginyl‐porphyrins, Molecular Modelling of Their DNA Complexes, and Experimental Tests

et al. 2004

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In order to increase the DNA binding affinity of a bis‐arginyl‐porphyrin which has been previously shown to bind preferentially in the major groove of the d(GGCGCC)2 sequence (Mohammadi et al., Biochemistry 1998, 37, 9165), we have synthesized bis‐ and tris‐intercalating derivatives in which one or both arginyl arms are connected through a flexible chain to an acridine ring. We report here the synthesis of these two molecules along with the molecular modelling of their complexes with a GC‐rich oligonucleotide encompassing the central d(GGCGCC)2 hexamer. The modelling computations showed that when the porphyrin was intercalated into the central d(CpG)2 site with both arginyl side‐chains bonded to the guanines flanking the intercalation site, the acridine ring(s) could intercalate immediately upstream from the central hexamer, but at the cost of substantial DNA conformational energy. A significant preference for major‐groove binding over minor‐groove binding was found. The results of circular dichroism studies and topoisomerase I‐unwinding experiments supported the bis‐ and tris‐intercalation of these derivatives. The bis‐acridyl derivative provided, as expected, greater stabilization against thermal denaturation than the mono‐acridyl and the parent bis‐arginyl‐porphyrin compounds. Based on the modelling results, the structures of derivatives can be tailored to facilitate tris‐intercalation in rigid GC‐rich sequences, and thereby enhance the selective targeting of GC base pairs by the arginyl side‐chains, by lengthening the porphyrin‐acridine connectors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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“…-Naphthalimide (= 1H-benz [de]isoquinoline-1,3(2H)-dione) belongs to a group of promising DNA-targeting anticancer agents [1]. Bisnaphthal-A C H T U N G T R E N N U N G imides Elinafide (1) [2] and Bisnafide (2) [3] [4] consisting of two naphthalimide residues connected by an aminoalkyl linker have been reported to inhibit topoisomerase II [5] by acting as bisintercalators in the major groove of DNA [6] [7]. These symmetrical compounds are currently undergoing clinical trials [8 -10].…”

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confidence: 99%

Intercalating Nucleic Acids Containing Insertions of Naphthalimide

Wamberg¹,

Walczak²,

Andersen³

et al. 2006

HCA

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In a study of linker-length dependence, we evaluated naphthalimide (= 1H-benzo [de]isoquinoline-1,3(2H)-dione) and 4-bromonaphthalimide as intercalating nucleic acids. We used a vicinal dihydroxy system when incorporating the six different naphthalimide monomers into DNA, and found the minimum linker-length to be five C-atoms. With this length of the linker, naphthalimide was discriminating between DNA and RNA -stabilizing DNA, while destabilizing RNA. Furthermore, naphthalimide showed universal base character by hybridizing to the four natural bases with a range as narrow as 1.48. When compared to pyrene, naphthalimide with the same linker-length gave significantly higher thermal meltings when hybridized to DNA.

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Sequence‐Selective Intercalation of Antitumour Bis‐Naphthalimides into DNA

Cited by 79 publications

References 53 publications

Recognition of Specific Sequences in DNA by a Topoisomerase I Inhibitor Derived from the Antitumor Drug Rebeccamycin

Recognition of Specific Sequences in DNA by a Topoisomerase I Inhibitor Derived from the Antitumor Drug Rebeccamycin

Bis‐ and Tris‐DNA Intercalating Porphyrins Designed to Target the Major Groove: Synthesis of Acridylbis‐arginyl‐porphyrins, Molecular Modelling of Their DNA Complexes, and Experimental Tests

Intercalating Nucleic Acids Containing Insertions of Naphthalimide

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