Sequence Specificity, Reactivity, and Antitumor Activity of DNA-Alkylating Pyrrole-Imidazole Diamides

Bando, Toshikazu; Iida, Hirokazu; Tao, Zhi Fu; Narita, Akihiko; Fukuda, Noboru; Yamori, Takao; Sugiyama, Hiroshi

doi:10.1016/s1074-5521(03)00160-1

Cited by 49 publications

(40 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…30) containing a trans-alkene linker and n-propyl end group bind DNA in AT rich regions with slightly different sequence selectivity to CC-1065 and with additional alkylation of guanine [74]. Similar compounds such as 53 have been prepared [75][76][77]. Hybrid 53 was shown to alkylate double stranded DNA predominantly at the purines of sequence 5'-PyG(A/T)CPu-3' of both strands (sites 1-3) by co-operative homodimer formation, indicating a potential application for duocarmycin hybrids in the development of novel sequence specific DNA-crosslinking agents [75].…”

Section: Bifunctional Alkylating Agentsmentioning

confidence: 99%

“…Hybrid 53 was shown to alkylate double stranded DNA predominantly at the purines of sequence 5'-PyG(A/T)CPu-3' of both strands (sites 1-3) by co-operative homodimer formation, indicating a potential application for duocarmycin hybrids in the development of novel sequence specific DNA-crosslinking agents [75]. Comparison with similar agents where the polyamide is directly bonded to the CPI unit showed that the vinyl linker in 53 increased DNA alkylation efficiency and biological activity (average IC 50 = 5.62 nM in the Cancer Chemotherapy Centre of Japan's 39 human cancer cell line panel) [77].…”

Section: Bifunctional Alkylating Agentsmentioning

confidence: 99%

“…41) were prepared by incorporating a neutral sugar moiety (76), a phosphoryl group (77) and a N-methylpiperazine (78) at the free hydroxyl group. Although these derivatives did not alkylate DNA in vitro, they exhibited potent in vitro cytotoxicity and in vivo activity, suggesting that the prodrugs 41 were activated by enzymatic mechanisms.…”

Section: Figure (37) Activity Against L1210 Cellsmentioning

confidence: 99%

See 2 more Smart Citations

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

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

View full text Add to dashboard Cite

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

show abstract

Section: Bifunctional Alkylating Agentsmentioning

confidence: 99%

Section: Bifunctional Alkylating Agentsmentioning

confidence: 99%

Section: Figure (37) Activity Against L1210 Cellsmentioning

confidence: 99%

See 1 more Smart Citation

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

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

View full text Add to dashboard Cite

show abstract

“…46) We synthesized a series of alkylating diamides, ImPyDu, ImPyDu86, and ImPyLDu86, and evaluated their cytotoxicity using a panel of 39 human cancer cell lines. 47) The log IC 50 values of ImPyDu, ImPyDu86, and ImPyLDu86 were Ϫ4.59, Ϫ5.95, and Ϫ8.25, respectively. Array-based chip 472 Vol.…”

Section: )mentioning

confidence: 96%

Biology of N-Methylpyrrole-N-methylimidazole Hairpin Polyamide

Murty

Sugiyama

2004

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

“…We examined in detail comparative studies of DNA sequence-specific alkylation and the antitumor activity of the alkylating ImPy conjugates using high-resolution denaturing gel electrophoresis and the panel of 39 human cancer cell lines. 29 Recently, we found that alkylating Py-Im polyamides 9 and 10, which differ only in that the C-H atoms is substituted by an N atom in the second ring, showed significantly different cytotoxicity in the 39 human cancer cell line panel (Fig. 12).…”

Section: Recognition Of Dna Sequencesmentioning

confidence: 97%

Chemical Biology that Controls DNA Structure and Function: Lessons in Organic Chemistry from Nature

Sugiyama¹

2007

Bulletin of the Chemical Society of Japan

Self Cite

View full text Add to dashboard Cite

Fifty years after the discovery of the double-helical structure of DNA, the complete sequence of the human genome has been determined. All genetic information, which is necessary for life, is written in 30 billion base pairs of DNA. Many diseases, including cancer, and hereditary and viral diseases, can now be understood at the DNA sequence level. Local DNA conformations are also thought to play an important role in biological processes, such as gene expression. Therefore, DNA sequences and local DNA conformations are the targets of novel drugs that would precisely switch certain genes on or off. Modified bases that perform various functions can also be incorporated into defined DNA sequences. DNA can now be synthesized by the phosphoramidite method and amplified by PCR, and by using organisms such as Escherichia coli, DNA becomes a promising unit for nanotechnology applications. In this review, I focus on our efforts in understanding the DNA reactivity, structure, and function of DNA. The prospective uses of the chemical biology of DNA will also be discussed.Chemistry has greatly contributed to the understanding of cellular processes by allowing the identification of metabolic pathways, enzymatic processes, and signal transduction mechanisms. Understanding of the chemistry of nucleic acids has played a key role in the progressive development of molecular biology and life science through the development of many epoch-making techniques, such as the DNA sequencing, the synthesis of oligonucleotides, and PCR amplification. During my Ph.D. course, I started research on photochemistry between DNA and proteins as a model of photoinduced DNA-protein crosslinking for examining the ternary structure of the nucleosome and understanding the mechanisms of photodamage of DNA. We found that the "-amino group of the lysine residues of histone crosslinked with thymine residues in DNA.1 Interestingly, the crosslink site was cleaved upon heating to regenerate the thymine ring on the "-amino group of the lysine residues in the protein by Michael addition (Figure 1). At that time, not so many researchers were interested in chemical modification in a nucleosome.Because we applied this photoreaction for T specific cleavage of DNA, 1d I was attracted to the molecular mechanisms of DNA modification at an atomic level. I had the chance to study the mechanism of action of the antitumor antibiotic bleomycin at Sidney Hecht's group at the University of Virginia from 1984 to 1986. We investigated how these glycopeptides recognize specific DNA sequences and efficiently oxidize C4 0 deoxyribose to induce DNA strand cleavage using synthetic oligonucleotides with defined sequences. 2 We identified the formation of C4 0 hydroxy abasic sites in addition to the known oxidative direct-strand scission via a Criegee type rearrangement of the C4 0 hydroperoxy intermediate. 3 We found that the C4 0 hydroxy abasic site generated by Fe-bleomycin underwent aldol condensation and subsequent elimination and rearrangement to produce cyclic hydroxy pentenon...

show abstract

Sequence Specificity, Reactivity, and Antitumor Activity of DNA-Alkylating Pyrrole-Imidazole Diamides

Cited by 49 publications

References 35 publications

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

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

Biology of N-Methylpyrrole-N-methylimidazole Hairpin Polyamide

Chemical Biology that Controls DNA Structure and Function: Lessons in Organic Chemistry from Nature

Contact Info

Product

Resources

About