Hetero-association of anticancer antibiotics in aqueous solution: NMR and molecular mechanics analysis.
In order to investigate the effect on combinations of aromatic antibiotics used in chemotherapy, the hetero-association of the antitumour antibiotics actinomycin D (AMD) with daunomycin (DAU) or novatrone (NOV) has been studied by the methods of 1D- and 2D 500 MHz 1H-NMR spectroscopy and molecular mechanics calculations. The experimental concentration and temperature dependences of the proton chemical shifts of mixtures of the aromatic drugs have been analyzed in terms of a modified statistical-thermodynamical model of hetero-association to give the equilibrium reaction constants, the thermodynamical parameters (deltaH, deltaS) of hetero-association of AMD with DAU or NOV and the limiting values of proton chemical shifts of the molecules in the hetero-complexes. The most favorable averaged structures of the 1:1 DAU-AMD and NOV-AMD hetero-association complexes have been determined using both the limiting values of proton chemical shifts of the molecules and molecular mechanics methods (X-PLOR software). The results show that intermolecular complexes between DAU-AMD and NOV-AMD are mainly stabilized by stacking interactions of the aromatic chromophores, although the DAU-AMD hetero-complex has additional stabilization, which may be explained by an intermolecular hydrogen bond between a carbonyl group of ring C of DAU and the NH group of D-Val of the pentapeptide side chain ring of AMD. The relative content of each type of molecular complex in the mixed solution has been calculated at different values of the ratio (r) of the initial concentrations of DAU and AMD. It is found that the contributions of hetero-complexes to the general equilibrium in solution are predominant at quite different values of r, viz. at r>12 for AMD with NOV and at r>2 for AMD with DAU, compared to r>0.3 for the DAU-NOV system observed previously. It is concluded that anticancer drugs have quite different affinities for formation of hetero-complexes with other aromatic antibiotics in aqueous solution, which may need to be taken into consideration for their use in combination chemotherapy.
Davies
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DB
School of Biological and Chemical Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK. davidbry@ndavies.co.uk
Evstigneev
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MP
Veselkov
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DA
Veselkov
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AN
D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods* / Q000592:standards; D008942:Mitoxantrone / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D012015:Reference Standards; D012984:Software; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D014867:Water; D008942:Mitoxantrone