Publications by authors named "Ivan S Kondratov"

11 Publications

  • Page 1 of 1

Synthesis, biological evaluation, and modeling studies of 1,3-disubstituted cyclobutane-containing analogs of combretastatin A4.

J Mol Struct 2020 Jun 10;1210. Epub 2020 May 10.

Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine.

With the aim of circumventing the adverse /-isomerization of combretastatin A4 (CA4), a naturally occurring tumor-vascular disrupting agent, we designed novel CA4 analogs bearing 1,3-cyclobutane moiety instead of the -stilbene unit of the parent compound. The corresponding and cyclobutane-containing derivatives were prepared as pure diastereomers. The structure of the target compounds was confirmed by X-ray diffraction study. The title compounds were evaluated for their cytotoxic properties in human cancer cell lines HepG2 (hepatocarcinoma) and SK-N-DZ (neuroblastoma), and the overall activity was found in micromolar range. Molecular docking studies and molecular dynamics simulation within the colchicine binding site of tubulin were in good agreement with the obtained cytotoxicity data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molstruc.2020.128025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351177PMC
June 2020

Last of the gem-Difluorocycloalkanes: Synthesis and Characterization of 2,2-Difluorocyclobutyl-Substituted Building Blocks.

J Org Chem 2019 07 24;84(13):8487-8496. Epub 2019 Apr 24.

Enamine Ltd. , Chervonotkatska Street 78 , Kyiv 02094 , Ukraine.

An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence included deoxofluorination of O-protected 2-(hydroxylmethyl)cyclobutanone. Dissociation constants (p K) and log  P values for 2,2-difluorocyclobutaneamine and 2,2-difluorocyclobutanecarboxylic acid or their derivatives were measured and compared with the values obtained for the corresponding 3,3-difluorocyclobutane derivatives and nonfluorinated counterparts. Three-dimensional structures of 2,2- and 3,3-difluorocyclobutanamines were compared using exit vector plot analysis of X-ray crystallographic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.9b00719DOI Listing
July 2019

3-((Hetera)cyclobutyl)azetidines, "Stretched" Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery.

J Org Chem 2019 02 8;84(3):1363-1371. Epub 2019 Jan 8.

Enamine Ltd. , Chervonotkatska Street 78 , Kyiv 02094 , Ukraine.

Four 3-((hetera)cyclobutyl)azetidine-based isosteres of piperidine, piperazine, and morpholine were designed and synthesized on up to gram scale. The key step of the synthetic sequence included cyclization of N-protected 2-(azetidin-3-yl)propane-1,3-diol or the corresponding 1,3-dibromide. X-ray diffraction studies of the products obtained, followed by exit vector plot analysis of their molecular geometry, demonstrated their larger size and increased conformational flexibility as compared to the parent heterocycles and confirmed their potential utility as building blocks for lead optimization programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.8b02822DOI Listing
February 2019

Synthesis of new fluorinated proline analogues from polyfluoroalkyl β-ketoacetals and ethyl isocyanoacetate.

Chem Commun (Camb) 2018 Aug;54(69):9683-9686

Enamine Ltd, Chervonotkatska Str. 78, Kyiv, 02094, Ukraine.

The reaction of trifluoroaldol acetal and other polyfluoroalkyl β-ketoacetals with ethyl isocyanoacetate was applied for the preparation of hitherto unknown fluorinated amino acids, cis- and trans-3-CF3/C2F5-prolines as well as trans-3-CF2Br/CF2Cl/CHF2-3-hydroxyprolines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8cc05912hDOI Listing
August 2018

Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors.

Bioorg Med Chem 2018 07 9;26(12):3399-3405. Epub 2018 May 9.

Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine; National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine. Electronic address:

A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC = 1.9-7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2018.05.010DOI Listing
July 2018

Cyclobutyl-Containing Rigid Analogues of Threonine: Synthesis and Physical Chemical Properties.

J Org Chem 2017 12 2;82(23):12863-12868. Epub 2017 Nov 2.

Organisch-Chemisches Institut, Universität Münster , Corrensstraße 40, 48149 Münster, Germany.

Hitherto unknown cis- and trans-1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained compounds can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups. pK values are noticeably different for both amino acids. According to the X-ray data the cyclobutane rings in both compounds are almost planar (the corresponding torsion angles are below 7°).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.7b02259DOI Listing
December 2017

Synthesis and physical chemical properties of 2-amino-4-(trifluoromethoxy)butanoic acid - a CFO-containing analogue of natural lipophilic amino acids.

Org Biomol Chem 2017 Jan;15(3):672-679

Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, Münster 48149, Germany. and Cells-in-Motion Cluster of Excellence, Universität Münster, Waldeyerstraße 15, 48149 Münster, Germany.

2-Amino-2-(trifluoromethoxy)butanoic acid (O-trifluoromethyl homoserine) was synthesized as a racemate and in both enantiomeric forms. The measured pK and log D values establish the compound as a promising analogue of natural aliphatic amino acids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6ob02436jDOI Listing
January 2017

Radical Reactions of Alkyl 2-Bromo-2,2-difluoroacetates with Vinyl Ethers: "Omitted" Examples and Application for the Synthesis of 3,3-Difluoro-GABA.

J Org Chem 2015 Dec 25;80(24):12258-64. Epub 2015 Nov 25.

Organisch-Chemisches Institut, Universität Münster , Corrensstraße 40, 48149 Münster, Germany.

Addition reactions of perfluoroalkyl radicals to ordinary or polyfluorinated alkenes have been frequently used to synthesize perfluoroalkylated organic compounds. Here ethyl/methyl 2-bromo-2,2-difluoroacetate, diethyl (bromodifluoromethyl)phosphonate, [(bromodifluoromethyl)sulfonyl]benzene, and ethyl 2-bromo-2-fluoroacetate were involved in Na2S2O4-mediated radical additions to vinyl ethers in the presence of alcohols to give difluoro or monofluoroacetyl-substituted acetals or corresponding difluoromethylphosphonate- and (difluoromethylphenyl)sulfonyl-substituted alkyl acetals. This methodology has also been applied as a key step in the synthesis of hitherto unknown 3,3-difluoro-GABA, completing the series of isomeric difluoro GABAs. Comparison of the pKa values of 3-fluoro- and 3,3-difluoro-GABA with that of the fluorine free parent compound showed that introduction of each fluorine lead to acidification of both the amino and the carboxyl functions by approximately one unit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.5b02171DOI Listing
December 2015

Synthesis of diverse pyrazole-4-sulfonyl chlorides starting from 2-(benzylthio)malonaldehyde.

Mol Divers 2016 Feb 12;20(1):1-7. Epub 2015 Sep 12.

Kyiv National Taras Shevchenko University, 64 Volodymirska st., Kyiv, 33, 01033, Ukraine.

A series of pyrazole-4-sulfonyl chlorides was obtained by a convenient 2-step method starting from synthetically available 2-(benzylthio)malonaldehyde. The method can be applied for the effective multi-gram synthesis of diverse pyrazole-containing sulfonyl chlorides which are mostly not available by other methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11030-015-9633-zDOI Listing
February 2016

Reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and its use for the synthesis of new polyfluoroalkyl pyrroles and pyrrolidines.

Org Biomol Chem 2012 Nov;10(44):8778-85

Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Sciences, Murmanska 1, Kiev-94, 02660, Ukraine.

The hitherto unreported reactions of β-alkoxyvinyl polyfluoroalkyl ketones with ethyl isocyanoacetate and equimolar amounts of potassium-tert-butoxide proceeded mainly in the β-position of the α,β-unsaturated ketones in cases of α-nonsubstituted 1a–e and α-methyl substituted ketones 1g–j. Other α- or β-substituted ketones 1f,k–o gave mainly products 4 of initial attack at the carbonyl carbon. Depending on the solvent, the major products of β-attack do exist in different tautomeric forms. Generally the openchain enol tautomers 5 predominate in the polar DMSO-d(6), while the cyclic γ-hemiaminals 8 are the major tautomers in the less polar CDCl(3). Acid treatment of the latter compounds 8 led to the hitherto unknown ethyl 5-polyfluoroalkyl-pyrrole-2-carboxylates 11 by elimination of formic acid. Catalytic hydrogenation of pyrrole 11a was used for the synthesis of earlier unknown 5-trifluoromethyl proline 16.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c2ob26176fDOI Listing
November 2012

"Reported, but still unknown." A closer look into 3,4-bis- and 3,4,5-tris(trifluoromethyl)pyrazoles.

J Org Chem 2012 Jan 21;77(1):47-56. Epub 2011 Dec 21.

Enamine Ltd., Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine.

Straightforward practical synthetic approaches to 3,4-bis- and 3,4,5-tris(trifluoromethyl)pyrazoles have been developed. The key step of the both syntheses is a transformation of the carboxylic group in a pyrazole core into the trifluoromethyl group by sulfur tetrafluoride. The elaborated synthetic protocols allow gram-scale preparation of the target products. The obtained compounds are comprehensively characterized by means of crystallographic analysis, determination of pK(a) values and fluorescence measurements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo202305cDOI Listing
January 2012