Influence of molecular
structure on the biological properties of aromatic hydrocarbons
There has been
a proposal that non-planarity of polycyclic aromatic hydrocarbons may
influence their DNA adduct
forming abilities and the net biological effect of the DNA adducts.
Therefore, our group has been interested in the synthesis of
PAHs as well as their metabolic profiles and biological activities.
In this context we have synthesized 1,4-dimethylbenzo[c]phenanthrene
(1,4-DMBcPh) and its metabolites. This PAH is 35 degrees out
of plane (Figure 4) compared to the unsubstituted benzo[c]phenanthrene
(BcPh, which is 25 degrees out of plane).
have shown that 1,4-DMBcPh and its putative
metabolites exhibit helical properties and the isomers undergo slow
helical interconversion (Figure 5). In addition, 1,4-DMBcPh is less readily
oxidized to its terminal diol epoxide metabolites by cytochrome P450
1B1 and metabolic activation in the final epoxidation step is
substantially influenced by the distortion in the molecule.
synthesis of new nucleoside paradigms
unnatural nucleosides hold promise as novel pharmacophores in addition
to their use in probing biofunction. For example, nucleoside
analogs are used
as anti-cancer and anti-viral agents, some are modulators of adenosine
receptors and many are products of xenobiotic metabolism and DNA
binding. For these reasons, development of novel methods for
nucleoside modification is of considerable importance. Our
research currently focuses on the use of palladium catalyzed methods
for accomplishing C-N and C-C bond formation of nucleoside substrates.
Two C-6 halo nucleoside substrates have been used to synthesize N6
aryl 2'-deoxyadenosine analogs and C-6 aryl purine nucleosides (Scheme
1). The C-2 bromo nucleoside has been used to prepare C-2 aryl
We have also demonstrated that C-6
arylsulfonate derivatives of 2'-deoxyguanosine undergo metal insertion
readily. Therefore, these arylsulfonates can be used to prepare
N6 aryl 2,6-diaminopurine nucleoside analogs or C-6 aryl 2-aminopurine
derivatives (Scheme 2). However, our studies show that as with
the C-6 bromo nucleoside shown in Scheme 1, substantially different
catalytic systems are required for C-N and C-C bond formation.
Using our fundamental research in this field, we
have synthesized xenobiotic metabolism products (examples shown in
Figure 6) that can be used for site-specific DNA modification. We
anticipate continued studies of other metal catalyzed processes for
nucleoside and DNA modification.