Substituent effects within the DNA binding subunit of CBI analogues of the duocarmycins and CC-1065.
A series of CBI analogues of the duocarmycins and CC-1065 exploring substituent effects within the first indole DNA binding subunit are detailed. Substitution at the indole C5 position led to cytotoxic potency enhancements that are > or =1000-fold, providing simplified analogues containing a single DNA binding subunit that are more potent (IC(50)=2-3 pM) than CBI-TMI, duocarmycin SA, or CC-1065.
Boger
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DL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. boger@scripps.edu
Stauffer
F
F
Hedrick
M P
MP
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites / Q000502:physiology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007933:Leucomycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; C055641:CC-1065-(N(3)-adenine)-DNA; D018736:DNA Adducts; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011758:Pyrroles; D011760:Pyrrolidinones; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA; D000225:Adenine; C058289:duocarmycin A