Design, synthesis and sequence selective DNA cleavage of functional models of bleomycin--II. 1,2-trans-disubstituted cyclopropane units as novel linkers.
The design and syntheses of functional models for bleomycin in which AMPHIS, a simplified model of the metal-chelating subunit of bleomycin is connected to distamycin analogs with a series of linkers, are described. Kinetic studies and DNA cleavage assay show that 1,2-trans-disubstituted cyclopropane units are the best linkers within this series. Study of selective DNA cleavage on high resolution polyacrylamide sequencing gels indicates that the linker modified hybrids generally cleave selectively at the 5' end of poly T sites and at the 3' end of poly A sites. Cleavage activity is enhanced for most of the compounds related to those with shorter linkers, previously reported, (Huang, L.; Quada, Jr J. C.; Lown, J. W. Bioconjugate Chem. 1995, 6, 21, Ref. 1) probably as a result of the linker allowing the active complex to approach the target deoxyribose more closely and efficiently. Certain of the compounds, ones containing a (S)-methyl in the linker and the (S,S)-cyclopropyl linker, exhibit unique cleavage sites, indicating that these linkers allow the hybrids to locate novel, individual DNA binding sites.
Huang
L
L
Department of Chemistry, University of Alberta, Edmonton, Canada.
Quada
J C
JC
Lown
J W
JW
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001761:Bleomycin / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry*; D004247:DNA / Q000187:drug effects*; D004214:Distamycins / Q000737:chemistry; D015195:Drug Design; D006639:Histidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D003521:Cyclopropanes; D004214:Distamycins; D011758:Pyrroles; D001761:Bleomycin; D006639:Histidine; C030000:stallimycin; C093042:methyl 2-(((2-aminoethyl)amino)methyl)-6-carboxylpyridinehistidinate; D004247:DNA; C030797:cyclopropane; C096654:N-methylpyrrole