PubMed · 1389917
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C E Myers. 1992. Anthracyclines.. https://pubmed.ncbi.nlm.nih.gov/1389917/
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Absorbance spectroscopy is used to examine the thermodynamic properties associated with the interaction of the experimental antitumor agents N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide (AAC) and N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) with nucleic acids. Placement of the amino substituent at the C9 position on the acridine ring results in marked changes to the acridine chromophore's electronic properties, with the overall charge of AAC increasing to +2 in comparison to DACA's charge of +1 at neutral pH. In comparative DNA binding studies, we examine the influence that the electrostatic properties of these ligands have on the binding energies as well as their effects on enthalpy and entropy contributions. These studies show that placement of the amino moiety at C9 results in 6 times greater DNA binding affinity as compared the deamino analog (DACA). Comparisons of ionic strength dependence for these two analogs reveal a difference in the binding energies of the compounds which can be attributed to electrostatic effects. Further dissection of the enthalpy and entropy components of the binding energy reveals the enhanced electrostatic effects are related to an increased entropy contribution upon formation of the AAC-DNA complex. Groove selectivity of these acridine analogs was probed by examining the binding profiles to native and groove-modified DNAs which included glycosylated T4 DNA and the distamycin-DNA complex. These studies are indicative of minor groove interactions for both compounds with DNA.
A series of bifunctional ligands has been developed as prototype DNA-binding combilexins using a DNA template-directed approach. These novel agents contain a 1,3-diaryltriazene linker moiety, present in the established DNA minor groove-binder berenil [1,3-bis(4'-amidinophenyl)-triazene], which is attached to an intercalating acridine chromophore by a functionalized thiazole residue. This 9-arylacridine is predicted to confer rotational freedom to the hybrid molecule and thus facilitate bifunctional interaction with double-stranded DNA through a combination of 'classical' intercalation and minor groove-binding processes. The noncovalent DNA-binding properties of these acridine-triazene combilexins, together with the component molecular fragments, have been examined by fluorescence quenching and thermal denaturation studies with calf thymus DNA and two oligonucleotides, [poly(dA-dT)]2 and [poly(dG-dC)]2. In addition, the binding behaviors of these acridine compounds are compared to those of proflavine (3,6-diaminoacridine) and its 9-phenyl derivative. The results indicate that the hybrid agents (i) are more DNA-affinic than either molecular component, (ii) retain the AT-preferential binding properties of the parent difunctionalized 1,3-diaryltriazene residues, despite weak GC-preferential behavior associated with the acridine chromophore, and (iii) have a reduced binding affinity at pH 7 that reflects the protonation status of the acridine. In contrast, the more basic proflavines show much greater binding affinity and a marked preference for GC-rich DNA sequences. In vitro cytotoxicity data with L1210 mouse leukemia and A2780 human colon cancer cell lines show that the conjugate molecules are approximately 10-40-fold more potent than the acridine or triazene subunits and have activities that compare favorably with those of other reported synthetic combilexins. Intercalative binding modes with a model d(GATACGATAC).d(GTATCGTATC) target duplex have been investigated using molecular modeling techniques. These studies provide a rational basis for the binding properties and suggest that the prototype combilexins can bind in a bimodal manner that induces little distortion of the host DNA duplex. Energy-minimized models for the possible dual interactions are discussed.
The effects of rutin on liver microsomes, peritoneal macrophages, and blood neutrophils isolated from iron-overloading (IOL) and normal rats were studied. The formation of 2-thiobarbituric acid-reactive products and the level of lucigenin-amplified chemiluminescence (CL) were determined in liver microsomes. Oxygen radical production by phagocytes was measured by luminol- and lucigenin-amplified CL and superoxide dismutase-sensitive cytochrome c reduction. These ex vivo findings were compared with the in vitro effects of rutin on cellular free processes. It was found that rutin administration sharply suppressed free radical production in liver microsomes and by phagocytes of IOL animals and only slightly affected these processes in normal rats. The selective inhibitory effect of rutin under pathologic conditions induced by iron overload is thought to be due to the formation of inactive iron-rutin complexes which are unable to catalyse the conversion of superoxide ion into reactive hydroxyl radicals, a process responsible for the free radical-mediated toxic effects of iron overload. These findings may account for the favourable effects of the treatment of pathologies associated with iron overload with rutin.