Bogdan Štefane

Development of New Cathepsin B Inhibitors: Combining Bioisosteric Replacements and Structure-Based Design To Explore the Structure–Activity Relationships of Nitroxoline Derivatives

Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7, and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression.

Selective Addition of Organolithium Reagents to BF2-Chelates of β-Ketoesters

A short, mild, and highly chemoselective addition of organolithium reagents to a BF(2) complex of 3-oxopropanoates has been developed. The methodology allows straightforward preparation of various 1,3-dioxa-BF(2) complexes and subsequently leads to the formation of 1,3-diketones starting from the corresponding 3-oxopropanoates.

Advances in Catalyst Systems for the Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones

Hydrogenation of prochiral ketones using chiral transition-metal catalysts represents the cleanest way to access enantiomerically enriched secondary alcohols, which are important building blocks in fine chemicals synthesis. Despite excellent activity, selectivity and compatibility of metal complexes with variety of functional groups, no universal catalysts exist. In this article we summarize the advances in catalyst systems for the asymmetric homogenous and heterogenous hydrogenation of ketones that have been made in past decade. The development of catalysts is oriented in reaching as high as activity with low catalyst loadings, using “greener’’ conditions, and ensuring good recyclability of catalysts. Even though ruthenium complexes represent the largest part of the catalysts, other metals rapidly penetrate this field.

New cyclopentane derivatives as inhibitors of steroid metabolizing enzymes AKR1C1 and AKR1C3

A series of cyclopentane derivatives was synthesized and evaluated for inhibition of the steroid metabolizing enzymes AKR1C1 and AKR1C3. Selective inhibitors that are active in the low micromolar range were identified. These compounds represent promising starting points in the development of new anticancer agents for the treatment of hormone-dependent forms of cancer and other diseases where AKR1C1 and AKR1C3 are involved.

A new and a convenient route to enaminones and pyrazoles

A new method has been developed for the regioselective preparation of enaminones and pyrazoles from 1,3-diketonatoboron difluorides. The reactions proceed smoothly under mild reaction conditions, producing enaminones and pyrazoles in high yields.

Ceric(IV) ammonium nitrate in the selective conversion of hydrazides to esters

Abstract Hydrazides were treated with ceric(IV) ammonium nitrate (CAN) in the presence of the appropriate alcohol as a nucleophile to afford esters in good yields. Reactions took place exclusively at the hydrazino moiety even when other sensitive groups were present in either of the partners.

Enantioselective alkylative double ring-opening of epoxides derived from cyclic allylic ethers: synthesis of enantioenriched unsaturated diolsElectronic supplementary information (ESI) available: the preparation and characterisation of derivatives for ee determinations. See http://www.rsc.org/suppdata/ob/b2/b212404a/

A screen of external chiral ligands has led to enantioselective organolithium-induced alkylative double ring-opening of 3,4-epoxytetrahydrofuran 1 with n-BuLi to give 3-methyleneheptane-1,2-diol 3 in 75% yield and 55% ee in the presence of bisoxazoline 10, and in up to 60% ee in the presence of (-)-sparteine 2. Extending the alkylative double ring-opening reaction to epoxides derived from oxabicyclo[n.2.1]alkenes (n = 2.3) results in the formation of cycloalkenediols, which, when carried out in the presence of (-)-sparteine 2 affords products in up to 85% ee.

CARBOXAMIDE OXIMES AS CONVENIENT PRECURSORS FOR THE SYNTHESIS OF PYRIMIDINE N-OXIDES

A general method for the synthesis of pyrimidine N-oxides from the appropriate carboxamide oximes is described. The conversion involves a treatment of various carboxamide oximes with either 1,1,3,3-tetramethoxypropane, 2,4-pentanedione, 3-ethoxy-2-propenal, 4,4-dimethoxy-2-butanone or 4-methoxy-3-butene-2-one in the presence of trifluoroacetic acid as a catalyst. The application of an unsymmetrical dicarbonyl compound leads exclusively to one product. Our approach is a method of choice for the preparation of pyridylpyrimidine N-oxides.

Unsaturated 1,2-amino alcohols and ethers from aziridines and organolithiums

Organolithium-induced ring-opening of aziridines of 2,5-dihydrofuran (5 and 8) and 1,4-dimethoxybut-2-ene (16, 17 and 23) gives 3-substituted 2-aminobut-3-en-1-ols 9-15 and amino ethers 18-20 and 24-26.

Synthesis and X-ray crystal structures of bis(bis(μ2-2-aminoethanolato–N,O,O)–cobalt(III))–cobalt(II) hydrate, tris(biscyclohexylammonium)μ-hydroxo–bis(μ2-nitro–N,O)–hexanitro–dicobaltate(III) and biscyclohexylammonium nitrate(III)

Abstract Two new cobalt complexes: Co3(NO2)4(NH2CH2CH2O)4·H2O (1) and (NH2(C6H11)2)3[Co2(NO2)8OH]·3H2O (2) and the compound (NH2(C6H11)2)NO2 (3) were synthesised and their structures have been determined using single-crystal X-ray diffraction. Compound 1 consists of two centrosymmetrical trinuclear complexes and a water molecule of crystallization. Ligands coordinated to Co atoms are nitro and aminoethanolato groups. Structure 2 is built up of biscyclohexylammonium cations, dinuclear anions with hydroxo and nitro groups coordinated to Co atoms and water molecules. The coordination of Co atoms in both structures is roughly octahedral.