Krystian Pyta

To reduce toxicity of geldanamycin (GDM), the domino transformation of its benzoquinone core into benzoxazole has been performed. Structural studies of ester-phenol and ester-ether benzoxazole-type ansamycins indicate that the former is present as (Sp)-diastereomer, whereas the latter is present as conformation-“locked” (Rp)-diastereomer, which is more favorable at binding to Hsp90. Several of the obtained benzoxazole ansamycins revealed high anticancer potency in SKBr-3, MCF-7, SKOV-3, and PC-3 lines with improved selectivity and lower affinity to glutathione, compared to GDM. The most potent derivative 6 reveals excellent anticancer activity (IC50 < 0.6 μM) with Hsp90 as the primary target [KD6-Hsp90 = 0.3 μM], limited off-target effects (kinases), and decreased toxicity (selectivity indices = 2.75−3.48) regarding GDM. Ester-ether type derivative 22 reveals good anticancer potency in SKOV-3 (IC50 = 0.62 μM) with reduced toxicity in human dermal fibroblast and human umbilical vein endothelial cells, improved selectivity (SISKOV-3 = 2.75), apoptotic index AISKOV-3 ∼8, and high chemical and in vivo stabilities.

A ketolide derivative with (12R)-configuration was obtained via a novel ketene acetal in acidic conditions. The structure of this atypical β-keto ketene acetal intermediate within the macrocyclic system has been determined by NMR and X-ray methods. The use of basic conditions at an elevated temperature yielded new, doubly α,β-unsaturated ketone macrolide derivatives with (4E)-configuration as two conformational isomers of folded-in or folded-out conformations.

Rifamycins are a group of macrocyclic antibiotics mainly used for the treatment of various bacterial infections including tuberculosis. Spectroscopic studies of rifamycins evidence the formation of temperature- and solvent-dependent equilibria between A-, B-, C-type conformers in solutions. The B- and C-type conformers of rifamycin antibiotics are exclusively formed in the presence of water molecules. A- and B-type conformers exhibit hydrophilic and “open” ansa-bridge nature whereas the C-type conformer is more lipophilic due to the presence of a “closed” ansa-bridge structure. Involvement of the lactam moiety of the ansa-bridge in intramolecular H-bonds within rifapentine and rifampicin implicates formation of a more hydrophilic A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin and rifaximin "free" lactam group enhances conformational flexibility of the ansa-bridge, thereby enabling interconversion between A- and C-type conformers. In turn, an equilibrium between A- and C-type conformers for rifamycins improves their adaptation to changing nature of bacteria cell membranes, especially those of Gram-negative strains and/or to efflux pump systems.

Amidobenzylidene ruthenium chelates – latent catalysts of olefin metathesis can be easily activated by the addition of Brønsted or Lewis acids. Their activation in the presence of hydrogen chloride involves the formation of catalytically active trans-dichloro carbamatobenzylidene ruthenium chelates.

Huisgen cycloaddition allowed obtaining of novel triazole-bridged antibiotics (6–16) with the reconstructed C(5) arm of spiramycin. ¹H–¹H NOESY couplings indicated the structure of novel derivatives in solution and demonstrated that the rebuilt C(5) arm is slightly differently oriented relative to the aglycone part if compared to that of spiramycin (1). Combined analysis of biological data together with experimentally determined lipophilicity (clogP) and solubility show the importance of the chemical nature of the newly introduced triazole C(5) arm in the presence of attractive antibacterial and anticancer potency. The most cytotoxic active triazole conjugates having a hydrophobic and bulky C(5) arm showed higher selectivity toward cancer cell lines (HeLa, KB, MCF-7, Hep-G2, and U87) relative to HDF normal cells than that of the parent spiramycin. Our studies have demonstrated that the aldehyde group is not crucial for the presence of interesting antibacterial [MIC_{(S. pneumoniae)} ∼ 1.2 μM] and anticancer [IC_50(HepG2) ∼ 6 μM] properties of 16-membered lactone macrolides based on spiramycin’s aglycone.