DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain

Valu, Kisione K.; Gourdie, Trudi A.; Boritzki, Theodore J.; Gravatt, G. L.; Baguley, Bruce C.; Wilson, William R.; Wakelin, Laurence P. G.; Woodgate, Paul D.; Denny, William A.

doi:10.1021/jm00173a016

Cited by 48 publications

(25 citation statements)

References 2 publications

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“…Nitrogen mustard analogues were synthesized as described previously for C3‐AA (16), C20‐AMSA and C50‐AMSA (13), and kindly donated by Prof W. A. Denny, University of Auckland, New Zealand. These were dissolved in ethanol to give 1 m m stock solutions and stored at −70 °C.…”

Section: Methodsmentioning

confidence: 99%

“…In this article, this nucleosome analysis has been extended to include four nitrogen mustard analogues, dimethyl sulphate (DMS) and three additional cisplatin analogues (Figure 1). These analogues include a series of DNA‐targeted drugs that consist of a nitrogen mustard or Pt attached to an acridine or amsacrine intercalating chromophore (12–17). A total of 14 DNA‐damaging agents have now been evaluated in this nucleosome system (9) and are summarized in this article.…”

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confidence: 99%

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The Influence of Chromatin Structure on DNA Damage Induced by Nitrogen Mustard and Cisplatin Analogues

Galea

Murray²

2010

Chem Biol Drug Des

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The interaction of anti-tumour drugs with reconstituted chromatin has been investigated using defined nucleosomal complexes. This allowed the effect of nucleosome cores on drug-induced DNA damage to be assessed for four nitrogen mustard analogues, dimethylsulphate and three cisplatin analogues. A defined nucleosomal complex was employed that contained two precisely positioned nucleosome cores. The construct was then subjected to drug treatment, and the resulting DNA damage was quantitatively analysed using a Taq DNA polymerase stop assay. At the sites of damage, densitometric comparisons between purified and reconstituted DNA were used to evaluate the influence of nucleosomal core proteins on specific drug-DNA interactions. Results were combined with previous data obtained for other DNA-damaging drugs investigated using the same nucleosomal construct. For most of the DNA-damaging agents studied, this method revealed protection at the positioned nucleosome cores and indicated that the preferred site of DNA binding for these compounds was in the linker region of the construct. Statistical analyses confirmed the significant level of damage protection conferred by the nucleosome cores and revealed differences between the examined compounds. Larger compounds generally displayed a greater tendency to target the linker region of the nucleosomal DNA and were impeded from damaging nucleosomal core DNA. In contrast, smaller molecules had greater access to nucleosomal core DNA.Key words: reconstituted nucleosome, nucleosome cores, nucleosome linker, cisplatin analogues, nitrogen mustard analogues, 5S rRNA gene

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

The Influence of Chromatin Structure on DNA Damage Induced by Nitrogen Mustard and Cisplatin Analogues

Galea

Murray²

2010

Chem Biol Drug Des

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“…Organic intercalators, including phenanthridinium [161,162], and 9-aminoacridine [163,164] have also been coupled to alkylating agents (e. g. 40 and 41, Fig.…”

Section: The Cytotoxicity Of a Variety Of Platinum And Organic Bis-mentioning

confidence: 99%

DNA Intercalators in Cancer Therapy: Organic and Inorganic Drugs and Their Spectroscopic Tools of Analysis

Wheate

Brodie²,

Collins³

et al. 2007

MRMC

206

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Since the discovery of the DNA intercalation process by Lerman in 1961 thousands of organic, inorganic octahedral (particularly ruthenium(II) and rhodium(III)) and square-planar (particularly platinum(II)) compounds have been developed as potential anticancer agents and diagnostic agents. The design and synthesis of new drugs is focused on bis-intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation with other functionalities, such as covalent binding or boron-cages (for radiation therapy). Advances in spectroscopic techniques mean that the process of DNA intercalation can be examined in far greater detail than ever before, yielding important information on structure-activity relationships. In this review we examine the history and development of DNA intercalators as anticancer agents and advances in the analysis of DNA-drug interactions.

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“…The amino group of an O-tert-butyldimethylsilyl-protected amino alcohol was protected as the diphenylphosphinamide and coupled to the bromoalkylphenylindole as described (17). The aniline mustard moiety, 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline (18), was then coupled to the 2PI linker by tetra-n-butylammonium fluoride deprotection of the alcohol and reaction with p-nitrobenzyl chloroformate. The final compounds were obtained by removal of the diphenylphosphinic and methyl-methoxy ether protecting groups with 2 N HCl in MeOH at ambient temperature.…”

Section: Synthesis and Characterization Of Phenylindole-anilinementioning

confidence: 99%

Synthesis and biological activity of DNA damaging agents that form decoy binding sites for the estrogen receptor

Rink

Yarema

Solomon

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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It is a goal of cancer chemotherapy to achieve the selective killing of tumor cells while minimizing toxicity to normal tissues. We describe the design of selective toxins forming DNA adducts that attract the estrogen receptor (ER), a transcription factor that is overexpressed in many human breast and ovarian tumors. The compounds consist of 4-(3-aminopropyl)-N,N-(2-chloroethyl)-aniline linked to 2-(4-hydroxyphenyl)-3-methyl-5-hydroxy-indole. The former moiety is a DNA damaging nitrogen mustard and the latter is a ligand for the ER. The connection between these groups was refined to permit DNA adducts formed by the mustard portion of the molecule to present the ligand domain so that it was able to interact efficiently with the ER. By using 16-mers containing specific DNA adducts, it was determined that monoadducts and putative intrastrand crosslinks were preferred targets for the ER over interstrand crosslinks. A series of structurally related 2-phenylindole mustards was prepared, some of which were selectively toxic to the ER-positive breast cancer cell line MCF-7, as compared with the ER(؊) negative line MDA-MB231. The ability both to bind to DNA and to interact significantly with the ER were essential to achieve selective lethality toward ER(؉) cells. Compounds forming DNA adducts without the ability to bind receptor showed similar toxicities in the two cell lines. Several models could explain the selective toxicity of the mustard-phenylindole compounds toward ER(؉) cells. The favored model suggests that a mustard-DNA adduct is shielded by the ER from DNA repair enzymes and hence cells possessing an abundance of the ER selectively retain the adduct and are killed.DNA repair proteins recognize genetic damage by chemicals and radiation (1). The protein-DNA lesion-recognition event is the prelude to enzymatic reaction(s) restoring the structural and informational integrity of the genome. It recently came as a surprise when proteins not involved in DNA repair were discovered that bind to specific DNA lesions formed by some chemical carcinogens (2) and anticancer drugs (3-7). The discovery that most of these lesion-binding proteins are transcription factors suggests some similarity between the structure of DNA in the vicinity of certain types of DNA damage and the architectural features of DNA recognized by the proteins that affect gene expression. The binding of transcription factors to DNA lesions can be tight (K d values in the picomolar range have been observed), suggesting that these protein-adduct interactions might negatively affect cellular welfare. For example, the binding may be so tight that DNA repair proteins are unable to access the lesion (Fig. 1B), resulting in lesion persistence and accompanying toxicity (5,8). It is also possible that the adducts may disrupt gene expression by titrating or ''hijacking'' transcription factors from normal sites of action (9). If the transcription factor is necessary for cellular survival or growth, its diminished concentration could result in death or retar...

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DNA-directed alkylating agents. 3. Structure-activity relationships for acridine-linked aniline mustards: consequences of varying the length of the linker chain

Cited by 48 publications

References 2 publications

The Influence of Chromatin Structure on DNA Damage Induced by Nitrogen Mustard and Cisplatin Analogues

The Influence of Chromatin Structure on DNA Damage Induced by Nitrogen Mustard and Cisplatin Analogues

DNA Intercalators in Cancer Therapy: Organic and Inorganic Drugs and Their Spectroscopic Tools of Analysis

Synthesis and biological activity of DNA damaging agents that form decoy binding sites for the estrogen receptor

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