Molecular Cloning, Heterologous Expression, Purification, and Evaluation of Protein-Ligand Interactions of CYP51 of Azole-Resistant Fungal Strain.

Due to the increasing prevalence of fungal diseases caused by fungi of the genus and the development of pathogen resistance to available drugs, the need to find new effective antifungal agents has increased. Azole antifungals, which are inhibitors of sterol-14α-demethylase or CYP51, have been widely used in the treatment of fungal infections over the past two decades. Of special interest is the study of CYP51, since this fungus exhibit resistance not only to azoles, but also to other antifungal drugs and there is no available information about the ligand-binding properties of CYP51 of this pathogen.

Novel O-acylated (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-one oximes targeting HSP90-HER2 axis in breast cancer cells.

Novel O-acylated (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-one oximes were designed as potential HSP90 inhibitors. A series of the compounds was synthesized by oximation of (E)-3-aryl-6,7-dihydrobenzisoxazol-4(5H)-ones followed by O-acylation with acylamidobenzoic acids. The obtained compounds showed an antiproliferative effect on three breast cancer cell lines (MCF7, MDA-MB-231 and HCC1954).

Fluorine-containing lupane triterpenoid acid derivatives: Design, synthesis and biological evaluation as potential anti-inflammatory agents.

A series of novel fluorine-containing lupane triterpenoid acid derivatives with fluoroaromatic amide moieties at the C-28 position (1-8) or with 2-(fluoroacyl)cyclopentane-1,3-dione fragments at the C-3 position (9-18) of lupane skeleton was synthesized. A simple synthesis of novel lupane triterpenoid hybrids with 2-(fluoroacyl)-2-cyclopenten-1-one moieties was developed. An interaction of 2-acyl-3-chlorocyclopent-2-en-1-ones, obtained from corresponding cyclic β-triketones, with methyl 3-amino-3-deoxybetulinate gave 3β-isomers (9-13) and 3α-isomers (14-18) of target hybrids, which were isolated as individual compounds.

Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage.

An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have been synthesized via an acylation of corresponding 6,7-dihydro-1H-indazol-4(5H)-one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH resulted in a formation of betulinic acid-indazolone hybrids in excellent yields.

Solvolysis of 14,17-etheno-bridged 16α-nitroestratrienyl acetate and lactam formation pathways studied by LC-NMR and LC-MS. Structures of minor products.

The ethanol solvolysis of 3-methoxy-14,17-etheno-16α-nitroestra-1,3,5(10)-trien-17β-yl acetate in the presence of NaHCO3 was studied by means of real-time NMR experiments, LC-SPE-NMR, and LC-MS. The pathway to form 3-methoxy-2'-oxopyrrolidino-[4',5':14β,15β]-estra-1,3,5(10)-trien-17-one was disclosed. The intermediacy of nitrile oxide and alkoxynitrone was postulated based on the analysis of the reaction products.

Azide phosphoramidite in direct synthesis of azide-modified oligonucleotides.

Azide and phosphoramidite functions were found to be compatible within one molecule and stable for months in solution kept frozen at -20 °C. An azide-carrying phosphoramidite was used for direct introduction of multiple azide modifications into synthetic oligonucleotides. A series of azide-containing oligonucleotides were modified further using click reactions with alkynes.

Human steroid and oxysterol 7α-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants.

Oxysterols and neurosteroids are important signaling molecules produced by monooxygenases of the cytochrome P450 family that realize their effect through nuclear receptors. CYP7B1 catalyzes the 6- or 7-hydroxylation of both steroids and oxysterols and thus is involved in the metabolism of neurosteroids and bile acid synthesis, respectively. The dual physiological role of CYP7B1 is evidenced from different diseases, liver failure and progressive neuropathy, caused by enzyme malfunction.

Diels-Alder reaction of androsta-14,16-dien-17-yl acetates with nitroethylene: product distribution and selected adduct transformations.

The Diels-Alder cycloaddition of nitroethylene to some androsta-14,16-dien-17-yl acetates has been studied. The addition occurs stereoselectively, giving predominantly head-to-head-adduct. 14β-Cyanomethyl steroids were obtained via the reductive cleavage reaction of bridged nitro compounds.

Synthesis and molecular structure of 14,15-pyrrolidino-and 14,16-ethano derivatives of estrone.

Hydrolysis of 3-methoxy-16alpha-nitro-14,17-ethenoestra-1,3,5(10)-trien-17beta-yl acetate under weakly basic conditions leads to formation of 3-methoxy-2'-oxopyrrolidino-[4',5':14beta,15beta]-estra-1,3,5 (10)-trien-17-one, the structure of which has been confirmed by X-ray analysis and some chemical transformations. The reactivity of 3-methoxy-16alpha-nitro-14,17-ethanoestra-1,3,5(10)-trien-17beta-yl acetate under various conditions of basic hydrolysis has been investigated. The derived compounds have been identified by means of NMR spectroscopy and X-ray analysis.

Oxidative modification of quercetin by hemeproteins.

The ability of a number of hemeproteins to oxidize the flavonoid quercetin has been shown. It was found that quercetin undergoes chemical modification in the presence of cytochrome c, myoglobin, and hemoglobin but not cytochrome b(5). In the range of investigated proteins the most effective oxidant appears to be cytochrome c.