Conformationally constrained analogues of bleomycin A5

Michael J. Rishel, Craig J. Thomas, Zhi Fu Tao, Corine Vialas, Christopher J. Leitheiser, Sidney Hecht

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The bleomycin (BLM) group antitumor antibiotics are glycopeptide-derived natural products shown to cause sequence selective lesions in DNA. Prior studies have indicated that the linker region, composed of the methylvalerate and threonine residues, may be responsible for a conformational bend in the agent required for efficient DNA cleavage. We have synthesized a number of conformationally constrained methylvalerate analogues and incorporated them into deglycobleomycin A5 congeners using our recently reported procedure for the solid phase construction of (deglyco)bleomycin and its analogues. These analogues were designed to probe the effects of conformational constraint of the native valerate moiety. Initial experiments indicated that the constrained molecules, none of which mimic the conformation proposed for the natural valerate linker, possessed DNA cleavage activity, albeit with potencies less than that of (deglyco)BLM and lacking sequence selectivity. Further experiments demonstrated that these analogues failed to produce alkali-labile lesions in DNA or sequence selective oxidative damage in RNA. However, two of the conformationally constrained deglycoBLM analogues were shown to mediate RNA cleavage in the absence of added Fe2+. The ability of the analogues to mediate the oxygenation of small molecules was also assayed, and it was shown that they were as competent in the transfer of oxygen to low molecular weight substrates as the parent compound.

Original languageEnglish (US)
Pages (from-to)10194-10205
Number of pages12
JournalJournal of the American Chemical Society
Volume125
Issue number34
DOIs
StatePublished - Aug 27 2003
Externally publishedYes

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Valerates
DNA Cleavage
DNA
RNA
RNA Cleavage
Glycopeptides
Bleomycin
Alkalies
Threonine
Biological Products
Molecules
Oxygenation
Antibiotics
Molecular Weight
Oxygen
Anti-Bacterial Agents
Conformations
Experiments
Molecular weight
deglycobleomycin

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Rishel, M. J., Thomas, C. J., Tao, Z. F., Vialas, C., Leitheiser, C. J., & Hecht, S. (2003). Conformationally constrained analogues of bleomycin A5 Journal of the American Chemical Society, 125(34), 10194-10205. https://doi.org/10.1021/ja030057w

Conformationally constrained analogues of bleomycin A5 . / Rishel, Michael J.; Thomas, Craig J.; Tao, Zhi Fu; Vialas, Corine; Leitheiser, Christopher J.; Hecht, Sidney.

In: Journal of the American Chemical Society, Vol. 125, No. 34, 27.08.2003, p. 10194-10205.

Research output: Contribution to journalArticle

Rishel, MJ, Thomas, CJ, Tao, ZF, Vialas, C, Leitheiser, CJ & Hecht, S 2003, 'Conformationally constrained analogues of bleomycin A5 ', Journal of the American Chemical Society, vol. 125, no. 34, pp. 10194-10205. https://doi.org/10.1021/ja030057w
Rishel, Michael J. ; Thomas, Craig J. ; Tao, Zhi Fu ; Vialas, Corine ; Leitheiser, Christopher J. ; Hecht, Sidney. / Conformationally constrained analogues of bleomycin A5 In: Journal of the American Chemical Society. 2003 ; Vol. 125, No. 34. pp. 10194-10205.
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