A demonstration of the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the non-covalent CC-1065/B-DNA binding.
The comparative DNA binding properties and cytotoxic activity of CDPIn methyl esters (n = 1-5) vs. PDE-In methyl esters (n = 1-3) are detailed in studies which provide experimental evidence for the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the CC-1065/B-DNA minor groove binding. High affinity minor groove binding to DNA was established through: (1) the observation of CDPI3 binding (UV) but not unwinding of supercoiled DNA (phi 174 RFI DNA) thus excluding intercalative binding; (2) the observation of CDPI3 binding to T4 phage DNA (UV, delta Tm) in which the major groove is occluded by glycosylation thus excluding major groove binding; (3) the observation of salt (Na+) concentration independent high affinity CDPI3 binding to poly(dA . poly(dT) thus excluding simple electrostatic binding to the DNA phosphate backbone; and further inferred through (4) the observation of an intense induced dichroism (ICD, poly(dA) . poly(dT) and poly(dG) . poly(dC) [phi]23(358) = 24,000 and 23,500). This high affinity minor groove binding is sufficient to produce a potent cytotoxic effect.(ABSTRACT TRUNCATED AT 400 WORDS)
Boger
D L
DL
Department of Chemistry, Purdue University, West Lafayette, IN 47907.
Invergo
B J
BJ
Coleman
R S
RS
Zarrinmayeh
H
H
Kitos
P A
PA
Thompson
S C
SC
Leong
T
T
McLaughlin
L W
LW
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001483:Base Sequence; D002219:Carbamates / Q000378:metabolism / Q000627:therapeutic use; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism*; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000627:therapeutic use; D007933:Leucomycins / Q000378:metabolism* / Q000627:therapeutic use; D046911:Macromolecular Substances; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D009690:Nucleic Acid Conformation; D011758:Pyrroles / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D002219:Carbamates; D000080890:Duocarmycins; D007211:Indoles; D007933:Leucomycins; D046911:Macromolecular Substances; D011758:Pyrroles; C018782:CC 1065; D004247:DNA