Parallel synthesis and evaluation of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins defining the contribution of the DNA-binding domain.
The solution-phase, parallel synthesis and evaluation of a library of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins containing dimeric monocyclic, bicyclic, and tricyclic heteroaromatic replacements for the DNA-binding domain are described. This systematic study revealed clear trends in the structural requirements for observation of potent cytotoxic activity and DNA alkylation efficiency, the range of which spans a magnitude of > or =10 000-fold. Combined with related studies, these results highlight that the role of the DNA-binding domain goes beyond simply providing DNA-binding selectivity and affinity (10-100-fold enhancement in properties), consistent with the proposal that it contributes significantly to catalysis of the DNA alkylation reaction accounting for as much as an additional 1000-fold enhancement in properties.
Boger
D L
DL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. boger@scripps.edu
Schmitt
H W
HW
Fink
B E
BE
Hedrick
M P
MP
D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000478:Alkylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003521:Cyclopropanes / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004279:DNA, Viral / Q000187:drug effects / Q000378:metabolism; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007933:Leucomycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013539:Simian virus 40 / Q000235:genetics; D013329:Structure-Activity Relationship
C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D000477:Alkylating Agents; D000903:Antibiotics, Antineoplastic; D003521:Cyclopropanes; D004279:DNA, Viral; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D011758:Pyrroles; D011760:Pyrrolidinones; C066098:duocarmycin SA; C018782:CC 1065; D004247:DNA; C058289:duocarmycin A