Solid-phase synthesis of bleomycin group antibiotics. Construction of a 108-member deglycobleomycin library.
The bleomycins (BLMs) are structurally related glycopeptide antibiotics isolated from Streptomyces verticillus that mediate the sequence-selective oxidative damage of DNA and RNA. Deglycobleomycin, which lacks the carbohydrate moiety, cleaves DNA analogously to bleomycin itself, albeit less potently, and has been used successfully for analyzing the functional domains of bleomycin. Although structural modifications to bleomycin and deglycobleomycin have been reported, no bleomycin or deglycobleomycin analogue having enhanced DNA cleavage activity has yet been described. The successful synthesis of a deglycobleomycin on a solid support has permitted the facile solid-phase synthesis of 108 unique deglycobleomycin analogues through parallel solid-phase synthesis. Each of the deglycobleomycin analogues was synthesized efficiently; the purity of each crude product was greater than 60%, as determined by HPLC integration. The solid-phase synthesis of the deglycobleomycin library provided near-milligram to milligram quantities of each deglycobleomycin, thereby permitting characterization by (1)H NMR and high-resolution mass spectrometry. Each analogue demonstrated supercoiled plasmid DNA relaxation above background cleavage; the library included two analogues that mediated plasmid relaxation to a greater extent than the parent deglycobleomycin molecule.
Leitheiser
Christopher J
CJ
Departments of Chemistry and Biology, University of Virginia, Charlottesville, VA 22904, USA.
Smith
Kenneth L
KL
Rishel
Michael J
MJ
Hashimoto
Shigeki
S
Konishi
Kazuhide
K
Thomas
Craig J
CJ
Li
Chunhong
C
McCormick
Michael M
MM
Hecht
Sidney M
SM
D000596:Amino Acids / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D005449:Fluorenes / Q000737:chemistry; D008715:Methionine / Q000031:analogs & derivatives; D019906:Nuclear Magnetic Resonance, Biomolecular; D021241:Spectrometry, Mass, Electrospray Ionization
D000596:Amino Acids; D000903:Antibiotics, Antineoplastic; D004278:DNA, Superhelical; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D001761:Bleomycin; C033284:deglycobleomycin; D008715:Methionine