Effect of Chemically Transformed Macrocyclic Polyene Antibiotics on Tumor Cells.

Comparative analysis of the effects of chemically transformed polyene antibiotics pimaricin, nystatin, lucensomycin, amphotericin B, and levorin on biological objects in vivo and in vitro revealed the greatest biological activity of original amphotericin B and levorin with its derivatives. The study also examined the effects of alkyl derivatives of amphotericin B and levorin modified in certain parts of the lactone ring on the lipid and biological membranes. It is established that methylated levorin possesses larger biological activity than the original antibiotic. Examination of the effects of alkyl derivatives of levorin and amphotericin B on cell cultures C6 (rat glioma) and HeLa (human cervical carcinoma) in vitro revealed the antitumor action of methylated levorin and original amphotericin B.

[Action of the alkyl derivatives of amphotericin B on the conductivity of bilayer lipid membranes]. / Deistvie alkil'nykh proizvodnykh amfoteritsina B na provodimost' bisloinykh lipidnykh membran.

Amphotericin B alkyl derivatives increased conductivity of bilayer membranes by formation of channels in them. The properties of such channels were studied. A new method for determination of the polyene antibiotic toxicity is described. The method is based on measurement of the constant of the relaxation time on the antibiotic removal from the membrane solution. It was shown that the amphotericin B alkyl derivatives had very low toxicity for the mammalian cells and were highly toxic for the fungal cells. These antibiotics may be used as new effective antifungal compounds.

How do ionic channel properties depend on the structure of polyene antibiotic molecules?

A study has been made of the properties of ionic channels formed in phospholipid-cholesterol bilayers by polyene antibiotics of various molecular structures. Properties of channels created by natural antibiotics with different structures of the lactone ring (amphotericin B-nystatin-mycoheptin) as well as by some derivatives of amphotericin B modified with respect to the amino and carboxyl groups are compared. Neutralization of one or both charges of the amphotericin B molecule (both by chemical modification and by pH shift) increases the probability of the channel to be in a nonconducting state. An increase of cholesterol concentration in the membrane produces an opposite effect. It is assumed that the electrostatic interaction of the amino group of an antibiotic molecule with the carboxyl group of an adjacent one stabilized the channel. Conductance and selectivity of an open channel are not influenced by changes in the charged groups. These properties strongly depend on the structure of the polar chain of the lactone ring. For example, the appearance of one more carbonyl group in the mycoheptin molecule results in a sharply decreasing anion permeability of channels. An antibiotic concentration which is necessary to observe single channels depends on the polyene chain structure: this is about 10(-7) M for tetraene nystatin and 2.10(-8) M for heptaene amphotericin B an mycoheptin.

[Penetration of polyene antibiotics into human embryonic kidney tissue cell cultures]. / O proniknovenii polienovykh antibiotikov v kletki kul'tury tkani pochek émbriona cheloveka.

Penetration of 14C-amphotericin AM-2 into the cells of the tissue culture of the human embryon kidneys was studied by means of light autoradiography after incubation with the antibiotic. Microscopic examination of the autographs of the cell slices revealed the presence of the radioactive label in the cytoplasm and nucleoplasm of the cells. The revealed intracellular localization of the label was evident of the antibiotic penetration into the cells.

[Nystatin and amphotericin B sorption complexes with polyvinyl-pyrrolidone in nonaqueous solvent systems]. / Sorbtsionnye kompleksy nistatina i amfoteritsina B s polivinilpirrolidonom v nevodnykh sistemakh rastvoritelei

Complexes of polyenic antibiotics with polyvinylpyrrolidone (PVP) can be used for preparing effective pharmaceutical forms soluble in water and consisting of fine dispersions. Studies were carried out; they are of great importance for revealing the mechanism of polyen interaction with neutral polymers, as well as for development of the technological processes for production of the pharmaceutical forms. The sorption isoterms of PVP with the molecular weight of 10 000 and 35 000 on nystatin and amphotericin B were obtained in the process of precipitation in the system of dimethylformamide-ethylacetate. The constants of the strength of the antibiotic binding with the polymer in a complex were calculated. It was shown that the complex strength increased with a rise in the relative amount of the precipitant in the system. The temperature dependence of the binding strength constant was studied. The process of the complex forming was shown to be exothermic, the activation energy of the complex being 26-30 kcal per a mole of the antibiotic. No significant differences in the binding strength of nystatin and amphotericin B were observed. On the basis of the experimental data, a scheme of the complex structure explaining the binding process by formation of a number of hydrogen bonds between the antibiotic hydroxyl groups and the PVP tertiaryamide groups is proposed.

[Study of the association of nystatin and amphotericin B in nonaqueous solvent systems]. / Issledovanie assotsiatsii nistatina i amfoteritsina B v mevodnykh sistemakh rastvoritelei

Association of nystatin and amphotericin B in non-aqueous systems was studied with the method of equilibria dialysis. A specially treated celophane membrane arresting colloid associats and macromolecules with a molecular weight of more than 30000 in the systems of dimethylformamide-ethylacetate was used for the dialysis. Relation between the dialysis rate and the difference of the concentrations at every side of the membrane was used for estimation of the antibiotic colloid association level. It was found that nystatin formed stable associates of the colloid type in the system of dimethylformamide-ethylacetate, close by the composition to the critical one or that providing precipitation of the antibiotic. Unlike nystatin, amphotericin B formed not colloid but larger conglomerates which precipitated. Neither of the antibiotics formed colloid associates in dimethylformamide. The level of the nystatin colloid association increased with a rise in the solution concentration and reached 80%. On the basis of the results obtained the following supposition concerning the mechanism of formation of the antibiotic complexes with polyvinylpyrrolidone (PVP) in non-aqueous systems is possible: sorption of PVP on the colloids formed or larger associates of the polyenic antibiotics must take place during coprecipitation which is accompanied by formation of a precipitate of the sorption complex.