Synthesis and characterization of enantiomeric anti-2-fluorobenzo[a]pyrene-7,8-dihydrodiol-9,10-epoxides and their 2"-deoxyguanosine and oligodeoxynucleotide adducts
Library Number:
WA70055
Part Number:
WA70055
Author(s):
Cho BP;
Source:
CHEMICAL RESEARCH IN TOXICOLOGY
Content Type:
Journal Citations
Year:
2006
Volume:
19(2)
Page(s):
242-254
Benzo[a]pyrene diol epoxides (BPDEs) are the ultimate
carcinogenic species of benzo[a]pyrene, a prototype polycyclic aromatic
hydrocarbon (PAH). BPDE-modified DNA duplexes can adopt multiple
conformations depending on the nature of the modified bases, the
stereochemistry at the location of the covalent linkage, and the
sequence context surrounding the lesion site. In this paper, we
describe the preparation of enantiomeric 2-fluoro-BPDEs,
trans-(7R,8S)-dihydroxy-(9S,10R)- and
trans-(7S,8R)-(9R,-10S)-epoxy-7,8,9,10-tetrtahydro-2-fluorobenzo[a]
pyrene (22 and 23, respectively), as models for probing the
BPDE-induced conformational heterogeneity. The multistep synthesis of
the target diol epoxides described herein entails regiospecific
succinoylation of 2-fluoropyrene, followed by a ring closure, regio-and
stereospecific construction of the 7,8-dihydrodiol functionality, and a
subsequent meta-chloroperbenzoic acid-mediated epoxidation. Stereo
selectivity was achieved by using Jacobsen chiral catalysts, which
produced greater than ∼90% enantionteric excess. Absolute
configurations at the C(7,8) carbons of the FBP derivatives were
determined by comparison of the circular dichroism (CD) spectra with
those reported for the BP analogues. Analysis of the (3)J(7,8) vicinal
coupling constants, CD shape, and charge density calculations all
indicated that the prepared anti-FBPDEs preferentially adopt the
pseudo-diequatorial C(7,8) diol conformation. Hydrolysis of anti-FBPDEs
produced a 9:1 ratio of trans- to cis-opened tetraols. Reactions of
each of the anti-FBPDEs with deoxyguanosine 5''-monophosphate produced
predominantly trans-anti-N(2)-dG as the major adducts. Analogous
reactions with two 11-mer oligodeoxynucleotides (5''-CCATXGCTACC-3''
where X = dT, dC) gave FBP-modified oligodeoxynucleotides with
structures that were characterized by enzyme digest/HPLC and
electrospray ionization time-of-flight mass spectrometry data. The
oligonucleotide adducts were annealed with the appropriate sequences to
form fully complementary duplexes
[(5''-CCATXG*CTACC-3'')(5''-GGTAGCYATGG-3''), G* = FBP-N(2)-dG adduct,
X = dT, Y = dA in duplex I; X = dC, Y = dG in duplex II] for CD and UV
melting studies. The results of the present study were consistent with
those reported previously for BPDE-modified duplexes in the same
sequence contexts and support the utility of FBPDEs as useful
structural probes