ATOMIC RESOLUTION STUDIES OF THE BINDING OF ANTITUMOUR ACRIDINES TO DNA DUPLEXES
Alan K. Todd1, Adrienne Adams2, James H. Thorpe1, William A. Denny3, and Christine J. Cardin1
1Chemistry Department, University of
Reading, Whiteknights, Reading, RG6 6AD, U.K.,
2Biochemistry Department, Trinity
College, Dublin 2, Ireland.
cFaculty of Medicine and Health
Sciences, University of Auckland, NZ
Keywords : DNA, cancer, drugs, MAD, acridine
DACA is an antitumour agent currently undergoing clinical trials in the UK, which is known to inhibit both topoisomerases I and II. It is known to be an intercalator but up till now the orientation of the crucial sidechain has been the subject of controversy.
1 = DACA X=H, Y=H, Z=X
2 = 6Br,9NH2 X=H, Y=Br, Z=NH2
3 = 5Br,9NH2 X=Br, Y=H, Z=NH2,
4 = 9NH2 X=H, Y=H, Z = NH2
We have carried out, to atomic and near-atomic resolution, the
first structural studies on the binding of members of the DACA
family of drugs to DNA duplexes. Using the DNA duplex sequence
d(CG(5-BrU)ACG)2 and 9-amino-5-bromo-DACA (3)
we have solved the structure using MAD methodology and refined it
to 1.2 . We have shown that the 4-carboxamide sidechain is
located in the major groove in all cases so far. The precise
hydrogen bonding pattern has so far been slightly different for
each drug examined (2-4), and depends on the pKa
of the acridine N10 as well as the steric bulk of the
substituents. The structures were solved in P31, a
highly diffracting form which seems only to be obtained due to an
interduplex hydrogen bond formed by the 9-NH2 group.
Results obtained to date with DACA itself (1) will also be
reported at the meeting. Topoisomerases I and II are both enzymes
for which structural information is now available, and it may be
possible to draw some conclusions useful in drug design.
Submission information
Group session intended for
Biological
Contact details for author responsible for the submission:
Name>>Christine Cardin
Address>>Chemistry Dept., University of Reading, Whiteknights, Reading, RG6 6AD
Telephone>>0118-9318215
Fax>>0118-9316632
email>>c.j.cardin@reading.ac.uk