[Dependence of mode of DNA binding to benzo crown derivatives of actinocin on the size and distance from the chromophore of crown fragments]. / Issledovanie zavisimosti sposoba sviazyvaniia s DNK benzokraunsoderzhashchikh proizvodnykh aktinotsina ot razmera i udalennosti ot khromofora kraun-gruppirovok.

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. The intercalation of actinocin chromophore of benzocrown derivatives of actinocin was shown to occur only when benzocrown groups were bound to the chromophore via glycine fragment. A change in the distance between the crown group and the chromophore prevents ligand intercalation. Increase in medium ionic strength results in appearance of new nonintercalational binding mode for crown-containing compounds with DNA caused by interaction of the crown groups with DNA.

[Effect of a substituent origin in actinocin amides on their binding to DNA]. / Vliianie prirody zamestitelei amidov aktinotsina na sposob ikh sviazyvaniia s DNK.

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]. / Vzaimodeistvie DNK s amfolitami na osnove aktinosina.

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. The constants of binding of these compounds to DNA were determined, and changes in DNA macromolecular structure caused by complexation were revealed. Models for the binding of these compounds to DNA were advanced. It was shown that compounds in the zwitterion form do not intercalate into the DNA double helix. The mode of binding of compounds to DNA in the cationoid form depends on the position of the cationoid center within the chromophore actinocin. Circular dichroism spectra of actinocyn-based ampholytes that bind to DNA in a different manner were obtained.

[Interaction of DNA with benzocrown derivatives of actinocin]. / Vzaimodeistvie DNK s benzokraun-proizvodnymi aktinotsina.

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. Selective toward Na+ ion benzocrown fragments combine with DNA phosphate groups. The simultaneous interaction of the actinocin chromophore with the DNA bases is possible only at optimal distance between both the binding sites of ligand molecule.

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. A compound with dimethylaminopropyl side chains on the phenoxazone chromophore was used as a control; this molecule was shown to intercalate into DNA by UV-visible spectroscopy and was found to have considerable cytotoxic activity in the 1-9 microM concentration range. Compounds with five-membered crown-ether side chains showed biological activity comparable with the control drug, whereas increasing the length of the spacers between the crown groups and the phenoxazone chromophore reduced the cytotoxic effect of the drugs. Compounds with six-membered crown-ether side chains reduced stabilization of the DNA double helical structure and abolished biological activity. Cell cycle alterations were observed only in drug systems which demonstrated cytotoxic activity. Cell cycle regulation was found to be sensitive to minor modifications (elongation of the spacer by one methylene group) in the side chains of the benzo-15-crown-5 derivatives, indicating that such series of synthetic drugs may serve as useful probes for investigation of cell cycle regulation processes.

[DNA interaction with low molecular weight ligands of different structure. III. DNA complexes with distactins]. / Vzaimodeistvie DNK s nizkomolekuliarnymi ligandami razlichnoi struktury. III. Kompleksy DNK s distaktsinami.

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. The ligand with oligopeptide groups containing three methylpyrrole rings joins the DNA double helix only from outside by means of oligopeptide groups. The compounds with one and two methylpyrrole rings form two kinds of complexes with DNA: external binding and intercalation. In the latter case both chromophore and methylpyrrole fragments, interact with DNA.

[DNA interaction with low molecular ligands of different structure. II. Complexes of DNA with actinomine and its analogs]. / Vzaimnodeistvie DNK s nizkomolekuliarnymi ligandami razlichnoi struktury. II. Kompleksy DNK s aktinominom i ego analogami.

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. There within a region of low degrees of binding the intercalation type of the ligand--DNA interaction prevails. In virtue of the spectrophotometry data the intercalation binding share was calculated. The intrinsic viscosity of a complex increases in the case of ligand intercalation and does not change as it joins to the DNA double-helix from outside. Optical anisotropy of DNA molecule increases linearly irrespective of the way of ligand binding. Data on the flow birefringence permits to conclude that under external binding the angle between the normal to the ligand chromophore plane and the axis of DNA double-helix is about zero. During ligand intercalation the equilibrium rigidity of DNA molecules increases.

[Interactinos of DNA with low molecular weight ligands of various structures. I. Complexes of DNA with actinomycin and its simple analogs]. / Izuchenie vzaimodeistviia DNK s nizomolekuliarnymi ligandami razlichnoi struktury. I. Kompleksy DNK s aktinomitsinom i ego prostymi analogami.

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. It has been shown that phenoxasone derivatives without aminogroup in 2 position complex with DNA as in the case of simple actinomycin analogues. The intrinsic viscosity and optical anisotropy of DNA-analogues complexes increase linerly with increasing quantity of bound ligand. This testifies that the binding of the compounds under investigation to DNA molecule is of intercalation type. The character of variation of hydrodynamical and optical parameters of DNA molecule by its binding with actinomycin differs qualitatively from that observed by the binding with analogues. The experimental data obtained for DNA-actinomycin complexes can be interpreted only by suggesting a specific secondary structure alteration of the DNA molecule. It has been shown that the simple actinomycin analogues can not be used as an appropriate model for investigation of DNA-actinomycin complexes structure.