Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans ® all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

Herein, the stereostructure of the aromatic heptaene macrolide (AHM) antifungal antibiotic candicidin A3 (syn. ascosin A3, levorin A3) has been established upon the 2D NMR studies, consisting of DQF-COSY, TOCSY, ROESY, HSQC & HMBC experiments, as well as upon extensive molecular dynamics simulations. The geometry of the heptaenic chromophore was defined as: (22E, 24E, 26Z, 28Z, 30E, 32E, 34E). The previously unreported absolute configuration of the chiral centres of candicidin A3 was established as: (3R,

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents previously synthesized by our group. Our recent studies have demonstrated their high antitumor potential against multiple cancer cell lines and human tumor xenografts in nude mice. At the cellular level, these compounds affected 3D cancer spheroid growth and their cellular uptake was selectively modulated by quantum dots. UAs were shown to undergo metabolic transformations in vitro and in tumor cells. However, the physicochemical properties of UAs, which could possibly affect their interactions with molecular targets, remain unknown. Therefore, we selected four highly active UAs for the assessment of physicochemical parameters under various pH conditions. We determined the compounds’ pKa dissociation constants as well as their potential to self-associate. Both parameters were determined by detailed and complex chemometric analysis of UV-Vis spectra supported by nuclear magnetic resonance (NMR) spectroscopy. The obtained results indicate that general molecular properties of UAs in aqueous media, including their protonation state, self-association ratio, and solubility, are strongly pH-dependent, particularly in the physiological pH range of 6 to 8. In conclusion, we describe the detailed physicochemical characteristics of UAs, which might contribute to their selectivity towards tumour cells as opposed to their effect on normal cells.

Aromatic heptaene macrolides (AHMs) belong to the group of polyene macrolide antifungal antibiotics. Members of this group were the first to be used in the treatment of systemic fungal infections. Amphotericin B (AmB), a non-aromatic representative of heptaene macrolides, is of significant clinical importance in the treatment of internal mycoses. It includes the all-trans heptaene chromophore, whereas the native AHMs contain two cis-type (Z) double bonds within the chromophore system. Lately we have proven that it is possible to obtain AHMs’ stable derivatives in the form of all-trans (AmB-type) isomers by photochemical isomerization. Our further studies have shown that such alteration leads to the improvement of their selective toxicity in vitro. Computational experiments carried out so far were only an initial contribution in the investigation of the molecular basis of the mechanism of action of AHMs and did not provide explanation to observed differences in biological activity between the native (cis-trans) and isomeric (all-trans) AHMs. Herein, we presented the results of two-dimensional metadynamics studies upon AmB and its aromatic analogues (AHMs), regarding preferable binary antibiotic/sterol complexes orientation, as well as more detailed research on the behaviour of AHMs’ alkyl-aromatic side chain in cholesterol- or ergosterol-enriched lipid bilayers.

Aromatic heptaene macrolides (AHMs) belong to the group of polyene macrolide antifungal antibiotics. Members of this group were the first to be used in the treatment of systemic fungal infections. Amphotericin B (AmB), a non-aromatic representative of heptaene macrolides, is of significant clinical importance in the treatment of internal mycoses. It includes the all-trans heptaene chromophore, whereas the native AHMs contain two cis-type (Z) double bonds within the chromophore system. Lately we have proven that it is possible to obtain AHMs’ stable derivatives in the form of all-trans (AmB-type) isomers by photochemical isomerization. Our further studies have shown that such alteration leads to the improvement of their selective toxicity in vitro. Computational experiments carried out so far were only an initial contribution in the investigation of the molecular basis of the mechanism of action of AHMs and did not provide explanation to observed differences in biological activity between the native (cis-trans) and isomeric (all-trans) AHMs. Herein, we presented the results of two-dimensional metadynamics studies upon aromatic AmB analogues regarding preferable binary antibiotic/sterol complexes orientation, as well as more detailed research on the behavior of their alkyl-aromatic side chain in cholesterol- or ergosterol-enriched lipid bilayers.