Establishment of substituent effects in the DNA binding subunit of CBI analogues of the duocarmycins and CC-1065.
An extensive series of CBI analogues of the duocarmycins and CC-1065 exploring substituent effects within the first indole DNA binding subunit is detailed. In general, substitution at the indole C5 position led to cytotoxic potency enhancements that can be >/=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.
Parrish
Jay P
JP
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550North Torrey Pines Road, La Jolla, CA 92037, USA.
Kastrinsky
David B
DB
Stauffer
Frederic
F
Hedrick
Michael P
MP
Hwang
Inkyu
I
Boger
Dale L
DL
D000478:Alkylation; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D007700:Kinetics; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry
D000577:Amides; D000080890:Duocarmycins; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; D013450:Sulfones; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA; C058289:duocarmycin A