Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues

Laurence Hurley, Martha A. Warpehoski, J. Chong-Soon Lee, B. Patrick McGovren, Terrence A. Scahill, Robert C. Kelly, Mark A. Mitchell, Nancy A. Wicnienski, Ilse Gebhard, Paul D. Johnson, V. Susan Bradford

Research output: Contribution to journalArticle

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Abstract

(-)-CC-1065, the unnatural enantiomer of the potent and sequence-selective, DNA-reactive antibiotic, (+)-CC-1065, was prepared by synthesis and its covalent reaction with DNA was studied and compared to that of the natural product. Although (-)-CC-1065 also formed covalent adducts in which the cyclopropyl carbon was bonded to the N3 atom of adenine, and the thermal strand breakage that it produced paralleled that seen for (+)-CC-1065, it lay in the opposite direction along the minor groove and exhibited a markedly different sequence requirement for the covalently modified adenine. While (-)-CC-1065 and its full carbon framework analogue, (-)-AB'C', reacted readily at adenines near to, but generally distinct from, (+)CC-1065-reactive adenines and exhibited potent cytotoxicity, their simpler analogues did not alkylate DNA under the conditions employed and were biologically nonpotent At relatively high concentrations, the smallest such analogue, (-)-A, reacted detectably only at the same sites selected by (+)-CC-1065. An analysis of the reactivity patterns of (+)- and (-)-CC-1065 and their analogues with DNA restriction fragments supported the conclusion that the mode of sequence recognition for (-)-CC-1065 adduct formation is fundamentally different from that of (+)-CC-1065 and is primarily controlled by specific minor groove, AT-selective binding interactions, rather than by sequence requirements of the covalent step, as occurs for (+)-CC-1065 and the (+)-CPI analogues. Models are proposed comparing the interactions of the enantiomeric alkylating moieties variously oriented in the minor groove at potential reaction sites. The evolutionary significance of both the alkylating moiety and the minor groove binding segments of the natural product is discussed.

Original languageEnglish (US)
Pages (from-to)4633-4649
Number of pages17
JournalJournal of the American Chemical Society
Volume112
Issue number12
StatePublished - 1990
Externally publishedYes

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CC 1065
Enantiomers
Alkylation
DNA
Adenine
Carbon
Antibiotics
Cytotoxicity
Biological Products
Atoms

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Hurley, L., Warpehoski, M. A., Chong-Soon Lee, J., Patrick McGovren, B., Scahill, T. A., Kelly, R. C., ... Bradford, V. S. (1990). Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues. Journal of the American Chemical Society, 112(12), 4633-4649.

Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues. / Hurley, Laurence; Warpehoski, Martha A.; Chong-Soon Lee, J.; Patrick McGovren, B.; Scahill, Terrence A.; Kelly, Robert C.; Mitchell, Mark A.; Wicnienski, Nancy A.; Gebhard, Ilse; Johnson, Paul D.; Bradford, V. Susan.

In: Journal of the American Chemical Society, Vol. 112, No. 12, 1990, p. 4633-4649.

Research output: Contribution to journalArticle

Hurley, L, Warpehoski, MA, Chong-Soon Lee, J, Patrick McGovren, B, Scahill, TA, Kelly, RC, Mitchell, MA, Wicnienski, NA, Gebhard, I, Johnson, PD & Bradford, VS 1990, 'Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues', Journal of the American Chemical Society, vol. 112, no. 12, pp. 4633-4649.
Hurley L, Warpehoski MA, Chong-Soon Lee J, Patrick McGovren B, Scahill TA, Kelly RC et al. Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues. Journal of the American Chemical Society. 1990;112(12):4633-4649.
Hurley, Laurence ; Warpehoski, Martha A. ; Chong-Soon Lee, J. ; Patrick McGovren, B. ; Scahill, Terrence A. ; Kelly, Robert C. ; Mitchell, Mark A. ; Wicnienski, Nancy A. ; Gebhard, Ilse ; Johnson, Paul D. ; Bradford, V. Susan. / Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues. In: Journal of the American Chemical Society. 1990 ; Vol. 112, No. 12. pp. 4633-4649.
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abstract = "(-)-CC-1065, the unnatural enantiomer of the potent and sequence-selective, DNA-reactive antibiotic, (+)-CC-1065, was prepared by synthesis and its covalent reaction with DNA was studied and compared to that of the natural product. Although (-)-CC-1065 also formed covalent adducts in which the cyclopropyl carbon was bonded to the N3 atom of adenine, and the thermal strand breakage that it produced paralleled that seen for (+)-CC-1065, it lay in the opposite direction along the minor groove and exhibited a markedly different sequence requirement for the covalently modified adenine. While (-)-CC-1065 and its full carbon framework analogue, (-)-AB'C', reacted readily at adenines near to, but generally distinct from, (+)CC-1065-reactive adenines and exhibited potent cytotoxicity, their simpler analogues did not alkylate DNA under the conditions employed and were biologically nonpotent At relatively high concentrations, the smallest such analogue, (-)-A, reacted detectably only at the same sites selected by (+)-CC-1065. An analysis of the reactivity patterns of (+)- and (-)-CC-1065 and their analogues with DNA restriction fragments supported the conclusion that the mode of sequence recognition for (-)-CC-1065 adduct formation is fundamentally different from that of (+)-CC-1065 and is primarily controlled by specific minor groove, AT-selective binding interactions, rather than by sequence requirements of the covalent step, as occurs for (+)-CC-1065 and the (+)-CPI analogues. Models are proposed comparing the interactions of the enantiomeric alkylating moieties variously oriented in the minor groove at potential reaction sites. The evolutionary significance of both the alkylating moiety and the minor groove binding segments of the natural product is discussed.",
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AU - Hurley, Laurence

AU - Warpehoski, Martha A.

AU - Chong-Soon Lee, J.

AU - Patrick McGovren, B.

AU - Scahill, Terrence A.

AU - Kelly, Robert C.

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AU - Wicnienski, Nancy A.

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AU - Johnson, Paul D.

AU - Bradford, V. Susan

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N2 - (-)-CC-1065, the unnatural enantiomer of the potent and sequence-selective, DNA-reactive antibiotic, (+)-CC-1065, was prepared by synthesis and its covalent reaction with DNA was studied and compared to that of the natural product. Although (-)-CC-1065 also formed covalent adducts in which the cyclopropyl carbon was bonded to the N3 atom of adenine, and the thermal strand breakage that it produced paralleled that seen for (+)-CC-1065, it lay in the opposite direction along the minor groove and exhibited a markedly different sequence requirement for the covalently modified adenine. While (-)-CC-1065 and its full carbon framework analogue, (-)-AB'C', reacted readily at adenines near to, but generally distinct from, (+)CC-1065-reactive adenines and exhibited potent cytotoxicity, their simpler analogues did not alkylate DNA under the conditions employed and were biologically nonpotent At relatively high concentrations, the smallest such analogue, (-)-A, reacted detectably only at the same sites selected by (+)-CC-1065. An analysis of the reactivity patterns of (+)- and (-)-CC-1065 and their analogues with DNA restriction fragments supported the conclusion that the mode of sequence recognition for (-)-CC-1065 adduct formation is fundamentally different from that of (+)-CC-1065 and is primarily controlled by specific minor groove, AT-selective binding interactions, rather than by sequence requirements of the covalent step, as occurs for (+)-CC-1065 and the (+)-CPI analogues. Models are proposed comparing the interactions of the enantiomeric alkylating moieties variously oriented in the minor groove at potential reaction sites. The evolutionary significance of both the alkylating moiety and the minor groove binding segments of the natural product is discussed.

AB - (-)-CC-1065, the unnatural enantiomer of the potent and sequence-selective, DNA-reactive antibiotic, (+)-CC-1065, was prepared by synthesis and its covalent reaction with DNA was studied and compared to that of the natural product. Although (-)-CC-1065 also formed covalent adducts in which the cyclopropyl carbon was bonded to the N3 atom of adenine, and the thermal strand breakage that it produced paralleled that seen for (+)-CC-1065, it lay in the opposite direction along the minor groove and exhibited a markedly different sequence requirement for the covalently modified adenine. While (-)-CC-1065 and its full carbon framework analogue, (-)-AB'C', reacted readily at adenines near to, but generally distinct from, (+)CC-1065-reactive adenines and exhibited potent cytotoxicity, their simpler analogues did not alkylate DNA under the conditions employed and were biologically nonpotent At relatively high concentrations, the smallest such analogue, (-)-A, reacted detectably only at the same sites selected by (+)-CC-1065. An analysis of the reactivity patterns of (+)- and (-)-CC-1065 and their analogues with DNA restriction fragments supported the conclusion that the mode of sequence recognition for (-)-CC-1065 adduct formation is fundamentally different from that of (+)-CC-1065 and is primarily controlled by specific minor groove, AT-selective binding interactions, rather than by sequence requirements of the covalent step, as occurs for (+)-CC-1065 and the (+)-CPI analogues. Models are proposed comparing the interactions of the enantiomeric alkylating moieties variously oriented in the minor groove at potential reaction sites. The evolutionary significance of both the alkylating moiety and the minor groove binding segments of the natural product is discussed.

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