Structure-activity relation for synthetic phenoxazone drugs: evidence for a direct correlation between DNA and pro-apoptotic activity.

The structure-activity relations of a series of synthetic phenoxazone drugs with aminoalkyl side chains of variable length and different terminal groups were investigated by examining their biological activity and DNA complexation affinity. Biological activity was determined from their ability to induce apoptosis and cell cycle perturbations (activation of cell cycle checkpoints) using the human malignant MOLT-3 cell line. The thermodynamic parameters of drug-DNA complexation were determined by differential scanning calorimetry.

[Dependence of mode of DNA binding to benzo crown derivatives of actinocin on the size and distance from the chromophore of crown fragments].

Complexes of DNA with benzocrown derivatives of actinocin were studied by viscometry and dynamic birefringence. Changes in the macromolecular structure of DNA caused by complex formation were determined. Models of DNA binding to the studied compounds were suggested on the basis of data obtained.

[Effect of a substituent origin in actinocin amides on their binding to DNA].

The results of studies on the structure of complexes of DNA with compounds based on the actinocin chromophore, a center of binding of the antitumor antibiotic actinomycin D to DNA, were analyzed. In positions 1 and 9 of the chromophore of these compounds, pentapeptide lact ones of actinomycin D are replaced by groups of various origin. By using spectral, optical, and hydrodynamic methods a model of binding to DNA for each compound was constructed, and some regularities of complex formation depending on the structure of actinocin substituents and the amount of ligands in the complex were revealed.

[Interactions of DNA with ampholytes based on actinocin].

The interaction of DNA with actinocin monoamides containing a substitute with the cationoide center in one of the amide groups were studied by spectrophotometry, induced circular dichroism, viscometry and flow birefringence methods. At pH values of solution exceeding their isoelectric point, these substances, which are in nature ampholytes, occur as zwitterions. At lover pH values they occur in the cationoid form.

Role of crown-like side chains in the biological activity of substituted-phenoxazone drugs.

The antitumour activity of a number of synthetic crown-ether analogues of actinomycin D (AMD) was investigated in order to test the role of side chains that can complex metal cations. The AMD analogues consisted of two series of phenoxazone derivatives substituted with either benzo-15-crown-5 or benzo-18-crown-6 and with different lengths of spacers between the crown groups and the phenoxazone chromophore. The biological activities of the synthetic compounds were investigated by examination of drug-induced apoptosis and cell cycle perturbations in a human leukemia MOLT-3 cell line by flow cytometry.

[Interaction of DNA with benzocrown derivatives of actinocin].

Complexes of DNA with actinocin derivatives containing benzocrown groups at the 1 and/or 9 positions of the chromophore were studied by spectrophotometric titration and circular dichroism. The actinocin chromophore and the crown fragments are the binding sites of the ligands with DNA. The mode of ligand-DNA binding is shown to depend on the size of the crown group, its distance to the actinocin chromophore, and the ionic strength of the medium.

[DNA interaction with low molecular weight ligands of different structure. III. DNA complexes with distactins].

The DNA complexes with distactins have been investigated by means of spectrophotometry, viscosimetry and flow birefringence methods. The distactins are actinocin's derivatives containing in the 1,9 positions of the phenoxazone moiety oligopyrrolcarboxamide groups (like those of distamycin A), which have from one to three fragments of 1-methyl-4-amino-2-pyrrolic acid. The mode of DNA-distactins binding in water solution depends on the quantity of the methylpyrrole rings in the oligopeptide groups.

[DNA interaction with low molecular ligands of different structure. II. Complexes of DNA with actinomine and its analogs].

DNA-complexes with actinomine and its analogues containing omega-dialkylaminoalkyl groups at 1,9 positions of the phenoxazone moiety were studied by technique of spectrophotometry, viscometry and flow birefringence. In the process of spectrophotometry titration two groups of spectra corresponding to different DNA--ligand ratio in a complex were observed. According to the experimental data the investigated compounds are bounded to DNA by means of intercalation and external binding.

[Interactinos of DNA with low molecular weight ligands of various structures. I. Complexes of DNA with actinomycin and its simple analogs].

The DNA complexes with actinomycin D and its simple analogues have been investigated by means of spectrophotometry, viscometry and flow birefringence methods. The number of binding sites per base pair of ligand on DNA depends on the nature of substitute in 1.9 position of the phenoxasone chromophore.