Modulation of Sequence Specificity of Duocarmycin-Dependent DNA Alkylation by Pyrrole−Imidazole Triamides

Fujiwara, Tsuyoshi; Tao, Zhi‐Fu; Ozeki, Yohei; Saito, Isao; Wang, H.-J.; Lee, Moses; Sugiyama, Hiroshi

doi:10.1021/ja991331i

Cited by 23 publications

(13 citation statements)

References 16 publications

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“…As a first step toward this goal, we are interested in finding out how AR‐1‐144 modulates the alkylating sequence of duocarmycin A and CC‐1065 [25]. Those studies are underway, and some of those results from this will be presented elsewhere [40].…”

Section: Discussionmentioning

confidence: 99%

Binding of AR‐1‐144, a tri‐imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy

Yang

Kaenzig

Lee

et al. 1999

European Journal of Biochemistry

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The interactions of N‐[2‐(dimethylamino)ethyl]‐1‐methyl‐4‐[1‐methyl‐4‐[4‐formamido‐1‐methylimidazole‐2‐carboxamido]imidazole‐2‐carboxamido]imidazole‐2‐carboxamide (AR‐1‐144), a tri‐imidazole polyamide minor groove binder, with DNA have been investigated by NMR and CD spectroscopy. A series of DNA oligonucleotides with a C/G‐containing four‐bp core, i.e. CCGG, CGCG, GGCC, and GCGC, have been titrated with AR‐1‐144 at different ratios. AR‐1‐144 favors the CCGG sequence. The flanking sequence of the CCGG core also influences the binding preference, with a C or T being favored on the 3′‐side of the CCGG core. The three‐dimensional structure of the symmetric 2 : 1 side‐by‐side complex of AR‐1‐144 and GAACCGGTTC, determined by NOE‐constrained NMR refinement, reveals that each AR‐1‐144 binds to four base pairs, i.e. at C5‐G6‐G7‐T8, with every amide‐imidazole unit forming two potential hydrogen bonds with DNA. The same DNA binding preference of AR‐1‐144 was also confirmed by circular dichroism spectroscopy, indicating that the DNA binding preference of AR‐1‐144 is independent of concentration. The cooperative binding of an AR‐1‐144 homodimer to the (purine)CCGG(pyrimidine) core sequence appears to be weaker than that of the distamycin A homodimer to A/T sequences, most likely due to the diminished hydrophobic interactions between AR‐1‐144 and DNA. Our results are consistent with previous footprinting data and explain the binding pattern found in the crystal structure of a di‐imidazole drug bound to CATGGCCATG.

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Section: Discussionmentioning

confidence: 99%

Binding of AR‐1‐144, a tri‐imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy

Yang

Kaenzig

Lee

et al. 1999

European Journal of Biochemistry

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“…34) [91]. It was shown that the addition of distamycin causes duocarmycins to switch their site of DNA alkylation to N3 of guanine [92], and further that a synthetic pyrrole/imidazole polyamide can be substituted for distamycin to direct the site of DNA alkylation [93]. Hybrids 61 were unreactive with DNA in the absence of distamycin; in its presence they readily alkylated guanine of a nucleotide sequence designed to match the specific hybrid.…”

Section: Bifunctional Alkylating Agentsmentioning

confidence: 99%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

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“…(330) On the basis of this sequence-selective strategy, Sugiyama and colleagues developed a series of sequence-specific DNA-alkylating agents by conjugation to Py/Im polyamides. (331–334) They also synthesized dimers as DNA interstrand cross-linking agents with potential application of inhibition of both DNA replication and gene expression. (335, 336)…”

Section: Small Molecules Targeting Nucleic Acid Sequencementioning

confidence: 99%

Using Genome Sequence to Enable the Design of Medicines and Chemical Probes

et al. 2018

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Rapid progress in genome sequencing technology has put us firmly into a postgenomic era. A key challenge in biomedical research is harnessing genome sequence to fulfill the promise of personalized medicine. This Review describes how genome sequencing has enabled the identification of disease-causing biomolecules and how these data have been converted into chemical probes of function, preclinical lead modalities, and ultimately U.S. Food and Drug Administration (FDA)-approved drugs. In particular, we focus on the use of oligonucleotide-based modalities to target disease-causing RNAs; small molecules that target DNA, RNA, or protein; the rational repurposing of known therapeutic modalities; and the advantages of pharmacogenetics. Lastly, we discuss the remaining challenges and opportunities in the direct utilization of genome sequence to enable design of medicines.

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Modulation of Sequence Specificity of Duocarmycin-Dependent DNA Alkylation by Pyrrole−Imidazole Triamides

Cited by 23 publications

References 16 publications

Binding of AR‐1‐144, a tri‐imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy

Binding of AR‐1‐144, a tri‐imidazole DNA minor groove binder, to CCGG sequence analyzed by NMR spectroscopy

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Using Genome Sequence to Enable the Design of Medicines and Chemical Probes

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