DNA binding studies of antitumor antibiotics and antitumor anthracene derivatives: Computer simulations and spectrophotometric titrations.

Abstract

Quinocarcin binds to d(ATGCAT)₂ with a preferred direction of 3' and the R configuration at C4 of the drug. A mode of action involving ring opening of the oxazolidine ring to form an iminium ion which can then alkylate the N2 of guanine has been reinforced by the current computer modeling study. The absolute configuration for quinocarcin should be reversed based on the fact that the optical isomer of the structure arbitrarily assigned in the literature forms a much better binding complex to DNA. Anthramycin binds to the 2-amino group of guanine but its mechanism of action proceeds through a neutral imine. The 3' direction is again favored but for this molecule, the preferred configuration is S. This computer modeling study provided a basis for a 2D NMR study which confirmed that anthramycin forms a 3'S adduct when it binds to d(ATGCAT)₂. Bisantrene and R9 are synthetic anthracene derivatives with antitumor activity. Use of UV spectroscopy provided insight into the ability of these compounds to intercalate between the base pairs of double helical DNA. Standard Scatchard plot analysis proved useless in determining the binding parameters. A McGhee-von Hippel equation was able to describe a portion of the data but a smoothing spline function was able to describe the data completely. Naphthyridinomycin studies indicate that it too prefers a covalent adduct in which the direction is 3' and the configuration is R at C7. When the noncovalent drug binds to d(ATGCAT)₂ it may bind with either the C3a face or the C7 face closest to N2 of guanine. Iminium ion mechanisms have been proposed for the binding of naphthyridinomycin to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms. Saframycin A binds much better to d(GATGCATC)₂ as a hydroquinone species but the quinone can still bind in the same site. The 3' direction is clearly preferred with the R configuration at C7. The hydrogen bonding network of the hydroquinone is conserved in the noncovalent, iminium ion, and covalent 3'R models after 32 ps of dynamics. Iminium ion mechanisms have been proposed for the binding of saframycin A to N2 of guanine in the minor groove of DNA and the computer modeling presents evidence to support such mechanisms.