Interaction of a macrocyclic bisacridine with DNA

Abstract

The binding of the macrocycle SDM to DNA was investigated by visible spectroscopy, stopped-flow kinetics, and NMR spectroscopy. SDM is composed of two 9-aminoacridines linked via the amino groups by a spermine side chain and via the 4-positions by a N,N'-[(methylthio)ethyl]succinamide side chain [Zimmerman, S. C., Lamberson, C. R., Cory, M., & Fairley, T. A. (1989) J. Am. Chem. Soc. 111, 6805-6809]. The visible spectrum of SDM bound to poly[d(A-T)]2 or poly[d(G-C)]2 is red-shifted relative to the spectrum of SDM alone and displays considerable hypochromicity. Results from titrations of SDM with polymer indicate a binding site size of three base pairs per macrocycle. The dissociation constant for SDM bound to either poly[d(A-T)]2 or poly[d(G-C)]2 is an order of magnitude lower than that for a similar bisacridine linked only by a spermine side chain. In addition, the dependence of the dissociation constant on ionic strength is significantly reduced. NMR studies of SDM complexes with poly[d(A-T)]2 or a tetramer, d(CGCG)2, show that intercalation is the mode of binding. The magnitudes of the chemical shift differences for SDM aromatic protons in the free and bound states support intercalation with the acridine ring systems essentially parallel to the long axis of the base pairs. Cross peaks from NOESY spectra of the SDM complex with d(CGCG)2 further support this mode of binding and provide information on the structure of the complex. The results are analyzed for consistency with each of three binding models: (i) bisintercalation with the two side chains in the same groove; (ii) bisintercalation according to the neighbor-exclusion principle with the two side chains in opposite grooves; and (iii) bisintercalation with two side chains in opposite grooves but with violation of the neighbor-exclusion principle. Model i is found to be unlikely on the basis of all evidence obtained, including preliminary modeling studies. Both models ii and iii can be reconciled with the experimental evidence and from a modeling standpoint are energetically feasible.

Using Molecular Modelling to Study Interactions Between Molecules with Biological Activity

“…Using these DNA models, our studies on the mono and bisintercalation of benzo[g]phthalazine derivatives strongly suggest the possibility of bisintercalation and the important role played by an Nmethyl group in stabilising the DNA complex of one of the compounds, throwing some light over the experimental results obtained [Rodríguez-Ciria et al, 2003]. The possibility of bisintercalation for a 1,4-disubstituted piperazine has been studied on duplexes of five and six base pairs, obtaining much better results in the case of five base pairs, in accordance with the theoretical calculations of binding mode not conforming to the neighbouring exclusion principle proposed by different authors [Veal et al, 1990].…”

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

“…A variety of nonclassical intercalators are known to stack on opposite sides of the same base pair in violation of this principle. 34,35 Alternatively, these ions may be the result of electrostatic interactions between the positively charged amine of daunomycin and the phosphate backbone of DNA. That higher numbers of bound drug were not observed for nogalamycin is perhaps not surprising given that the binding will be more restricted than daunomycin owing to the dumbbell shape of nogalamycin requiring the DNA helix to 'breathe' to allow intercalation.…”

A Role of the 9-Aminoacridines and their Conjugates in a Life Science

“…The theoretical conformation analysis of DNA bound bis-9-aminoacridine macrocycle was performed by distance geometry method [140]. The frozen DNA coordinates were taken from the crystal structure of ditercalinium-d(CGCG) 2 complex.…”