Solid-phase synthesis of deglycobleomycins: a C-terminal tetraamine linker that permits direct evaluation of resin-bound bleomycins.
Deglycobleomycin analogues having different length polyamine side chains at the C-terminus were synthesized using a novel solid-phase synthesis strategy that produces fully deprotected deglycobleomycin congeners attached to the resin. Detailed studies of DNA cleavage by these compounds and their resin-bound counterparts using supercoiled plasmid DNAs and DNA restriction fragments as substrates revealed that (i) the length of the polyamine side chain of free deglycoBLM had limited effect on its DNA cleavage potency or sequence selectivity, and (ii) the nature of the linker moiety between the resin and attached deglycobleomycin had a more substantial effect on the potency of DNA cleavage, but no effect on sequence selectivity of resin-bound deglycoBLMs. Resin-bound 4 exhibited efficient DNA cleavage, indicating that its tetraamine linker moiety could be used for the elaboration and direct evaluation of bleomycin congeners attached to resins.
Tao
Zhi-Fu
ZF
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Leitheiser
Christopher J
CJ
Smith
Kenneth L
KL
Hashimoto
Shigeki
S
Hecht
Sidney M
SM
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D008024:Ligands; D008856:Microscopy, Fluorescence; D012116:Resins, Plant / Q000737:chemistry / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D001952:Bridged-Ring Compounds; D008024:Ligands; D012116:Resins, Plant; D001761:Bleomycin; C033284:deglycobleomycin; D004247:DNA; C010349:tetramethylenedisulfotetramine