Publications by authors named "Oleksandr O Grygorenko"

43 Publications

One-pot parallel synthesis of 1,3,5-trisubstituted 1,2,4-triazoles.

Mol Divers 2021 Apr 2. Epub 2021 Apr 2.

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

An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible ("REAL") compounds may be generated based on the proposed methodology. Analysis of physicochemical parameters shows that the library contains significant fractions of both drug-like and "beyond-rule-of-five" members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.
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http://dx.doi.org/10.1007/s11030-021-10218-2DOI Listing
April 2021

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds.

iScience 2020 Nov 15;23(11):101681. Epub 2020 Oct 15.

Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.

An approach to the generation of ultra-large chemical libraries of readily accessible ("REAL") compounds is described. The strategy is based on the use of two- or three-step three-component reaction sequences and available starting materials with pre-validated chemical reactivity. After the preliminary parallel experiments, the methods with at least ∼80% synthesis success rate (such as acylation - deprotection - acylation of monoprotected diamines or amide formation - click reaction with functionalized azides) can be selected and used to generate the target chemical space. It is shown that by using only on the two aforementioned reaction sequences, a nearly 29-billion compound library is easily obtained. According to the predicted physico-chemical descriptor values, the generated chemical space contains large fractions of both drug-like and "beyond rule-of-five" members, whereas the strictest lead-likeness criteria (the so-called Churcher's rules) are met by the lesser part, which still exceeds 22 million.
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http://dx.doi.org/10.1016/j.isci.2020.101681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593547PMC
November 2020

Fluoroalkyl-Substituted Cyclopropane Derivatives: Synthesis and Physicochemical Properties.

J Org Chem 2020 10 11;85(19):12692-12702. Epub 2020 Sep 11.

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

A series of all 12 - and -cyclopropanecarboxylic acids and cyclopropylamines bearing CHF, CHF, and CF substituents were synthesized by different methods on a multigram scale. Dissociation constants (p) and log  values were measured for the obtained compounds or their derivatives to evaluate the influence of the type and relative position of fluoroalkyl substituents on the acidity and lipophilicity of monofunctionalized cyclopropanes. An analysis of the selected products by X-ray crystallography was carried out to obtain a better insight into the observed differences in physicochemical properties.
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http://dx.doi.org/10.1021/acs.joc.0c01848DOI Listing
October 2020

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

Formyl MIDA Boronate: C Building Block Enables Straightforward Access to α-Functionalized Organoboron Derivatives.

Angew Chem Int Ed Engl 2020 10 13;59(41):18016-18022. Epub 2020 Aug 13.

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

Formyl MIDA boronate has been known to be an elusive type of acylboronate that has not been obtained to date. In this work, an approach to the one-pot preparation and chemical transformations of formyl MIDA boronate were developed to provide new types of α-functionalized organoboron compounds. Among them are acylboronate reagents which present boron-substituted analogues of ynones and β-dicarbonyl compounds. The developed synthetic procedures, utilizing formyl MIDA boronate, are tolerant to diverse functional groups, making this reagent an advantageous C building block for extending the scope of organoboron chemistry.
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http://dx.doi.org/10.1002/anie.202007651DOI Listing
October 2020

Photochemical [2 + 2] Cycloaddition of Alkenyl Boronic Derivatives: An Entry into 3-Azabicyclo[3.2.0]heptane Scaffold.

J Org Chem 2020 May 13;85(9):5927-5940. Epub 2020 Apr 13.

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

The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi- and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C-C coupling or oxidative deborylation reactions.
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http://dx.doi.org/10.1021/acs.joc.0c00265DOI Listing
May 2020

Twisting and Turning the Sulfonamide Bond: A Synthetic, Quantum Chemical, and Crystallographic Study.

J Org Chem 2020 04 24;85(8):5288-5299. Epub 2020 Mar 24.

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

Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S-N bond. Thus, going from the sp-hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette's sultam resulted in an increase in S-N bond length by ca. 0.06 Å. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.
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http://dx.doi.org/10.1021/acs.joc.9b03394DOI Listing
April 2020

Building the Housane: Diastereoselective Synthesis and Characterization of Bicyclo[2.1.0]pentane Carboxylic Acids.

J Org Chem 2020 02 6;85(4):2321-2337. Epub 2020 Jan 6.

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

An approach to 1,3-disubstitued bicyclo[2.1.0]pentane (housane) derivatives was developed. The method relied on lithium bis(trimethylsilyl)amide-mediated intramolecular cyclization of trisubstitued cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed for the preparation of both - and -1,3-disubstituted housane-1-carboxylic acids in diastereoselective manner on up to 80 g scale. In particular, bicyclic γ-amino acids-γ-aminobutyric acid analogues-were synthesized. It was shown that the bicyclo[2.1.0]pentane did not significantly affect p of the corresponding derivatives and slightly increased their hydrophilicity (by 0.07-0.25 Log units) as compared to cyclopentane. X-ray diffraction studies showed that - and -1,3-disubstituted housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with fixed envelope conformation of the five-membered ring.
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http://dx.doi.org/10.1021/acs.joc.9b03044DOI Listing
February 2020

Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles.

J Org Chem 2019 12 8;84(23):15212-15225. Epub 2019 Nov 8.

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

A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
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http://dx.doi.org/10.1021/acs.joc.9b02258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310498PMC
December 2019

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes.

J Org Chem 2019 12 30;84(24):15877-15899. Epub 2019 Oct 30.

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

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.
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http://dx.doi.org/10.1021/acs.joc.9b02264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341682PMC
December 2019

Far Away from Flatland. Synthesis and Molecular Structure of Dihetera[3.3.]propellanes and Trihetera[3.3.]propellanes: Advanced Analogues of Morpholine/Piperazine.

J Org Chem 2019 11 26;84(21):13908-13921. Epub 2019 Sep 26.

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

An approach to di- and trihetera[3.3.]propellanes ( = 2-4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3 + 2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3-5 steps on a multigram scale with 10-72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat-chair, twist chair-chair, and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).
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http://dx.doi.org/10.1021/acs.joc.9b02067DOI Listing
November 2019

Scalable Synthesis of Biologically Relevant Spirocyclic Pyrrolidines.

ACS Omega 2019 Apr 24;4(4):7498-7515. Epub 2019 Apr 24.

Taras Shevchenko National University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine.

Synthetic approaches toward multigram preparation of spirocyclic α,α-disubstituted pyrrolidines from readily available starting materials are discussed. It was shown that although a number of synthetic methodologies have been known to date, many of the title compounds remain hardly accessible. The most appropriate literature method (which relied on reaction of imines and allyl magnesium halide, followed by bromocyclization) was identified and optimized. It was found that the method is most fruitful for simple non-functionalized substrates. Two novel approaches based on the Sakurai or Petasis reactions of cyclic ketones, followed by hydroboration-oxidation at the allyl moiety thus introduced, were elaborated. The latter method had the largest scope and was beneficial for the substrates containing organosulfur or protected amino functions. For the synthesis of 4-azaspiro[2.4]heptane, an alternative synthetic scheme commencing from -butyl cyclopropanecarboxylate (instead of the corresponding ketone) was developed. It was shown that the whole set of the methodologies developed can be used for the synthesis of various spirocyclic α,α-disubstituted pyrrolidines-advanced building blocks of potential importance to medicinal and agrochemistry-at up to a 100 g scale.
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http://dx.doi.org/10.1021/acsomega.9b00896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648774PMC
April 2019

SAR by Space: Enriching Hit Sets from the Chemical Space.

Molecules 2019 Aug 26;24(17). Epub 2019 Aug 26.

Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Kyiv, Ukraine.

We introduce SAR-by-Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolecular hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand- and structure-based approaches in hit generation and lead optimization stages.
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http://dx.doi.org/10.3390/molecules24173096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749418PMC
August 2019

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles.

ACS Comb Sci 2019 09 29;21(9):635-642. Epub 2019 Aug 29.

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

Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.
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http://dx.doi.org/10.1021/acscombsci.9b00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297054PMC
September 2019

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry.

Chemistry 2020 Jan 30;26(6):1196-1237. Epub 2019 Oct 30.

Awridian Ltd., Stevenage Bioscience Catalyst, Gunnelswood Road, Stevenage, Herts, SG1 2FX, UK.

All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increasingly complex targets. This Review article sets out to give a concise appraisal of this symbiotic relationship between organic chemistry and drug discovery, along with a discussion of the design concepts and highlighting key milestones along the journey. In particular, criteria for a high-quality compound library design enabling efficient virtual navigation of chemical space, as well as rise and fall of concepts for its synthetic exploration (such as combinatorial chemistry; diversity-, biology-, lead-, or fragment-oriented syntheses; and DNA-encoded libraries) are critically surveyed.
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http://dx.doi.org/10.1002/chem.201903232DOI Listing
January 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.
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http://dx.doi.org/10.1021/acs.joc.9b00719DOI Listing
July 2019

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space.

Chemistry 2019 May 1;25(28):6928-6940. Epub 2019 Apr 1.

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

Two novel solid reagents-1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives-for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pK , Log P, microsomal stability, and reactivity towards typical electrophiles). Similar to other organosulfur(VI) derivatives with S=N bonds, these compounds can be considered as promising bioisosteres of amides, ureas, or sulfonamides.
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http://dx.doi.org/10.1002/chem.201900440DOI Listing
May 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.
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http://dx.doi.org/10.1021/acs.joc.8b02822DOI Listing
February 2019

(Chlorosulfonyl)benzenesulfonyl Fluorides-Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library.

ACS Comb Sci 2018 11 1;20(11):672-680. Epub 2018 Nov 1.

National Taras Shevchenko University of Kyiv, Volodymyrska Street 60 , Kyiv 01601 , Ukraine.

Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.
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http://dx.doi.org/10.1021/acscombsci.8b00130DOI Listing
November 2018

Regioselective synthesis of isoxazole and 1,2,4-oxadiazole-derived phosphonates via [3 + 2] cycloaddition.

Org Biomol Chem 2018 12;16(47):9152-9164

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

The results of the study on reactions of halogenoximes bearing (protected) functional groups or fluorinated substituents with various phosphorus-containing dipolarophiles are described. To control the regioselectivity of the reaction, vinylphosphonates bearing a leaving group (i.e. bromine or dialkylamino group) in the α or β position were used; 3,5- and 3,4-disubstituted isoxazoles were obtained in 47-80% and 63-75% yields, respectively. The reaction was also effective for the parent vinyl phosphonate and cyanophosphonate; in this case, the corresponding isoxazoline- and 1,2,4-oxadiazole-derived phosphonates were isolated in 55-69% and 34-73% yields, respectively. The utility of the products obtained was demonstrated by the preparation of direct conformationally restricted analogues of phosphohistidine.
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http://dx.doi.org/10.1039/c8ob02257gDOI Listing
December 2018

A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold.

Amino Acids 2019 Feb 4;51(2):255-261. Epub 2018 Oct 4.

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

An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid-a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.
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http://dx.doi.org/10.1007/s00726-018-2660-1DOI Listing
February 2019

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

[2+2]-Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-Azabicyclo[3.2.0]heptanes.

J Org Chem 2018 06 12;83(12):6275-6289. Epub 2018 Mar 12.

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

A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2]-photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated. The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery.
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http://dx.doi.org/10.1021/acs.joc.8b00077DOI Listing
June 2018

An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries.

ACS Comb Sci 2018 01 27;20(1):35-43. Epub 2017 Dec 27.

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

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.
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http://dx.doi.org/10.1021/acscombsci.7b00163DOI Listing
January 2018

Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery.

J Org Chem 2017 09 25;82(18):9627-9636. Epub 2017 Aug 25.

Department of Chemistry, National Taras Shevchenko University of Kyiv , Volodymyrska 64, Kyiv 01033, Ukraine.

We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectular [2+2]-photochemical cyclization.
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http://dx.doi.org/10.1021/acs.joc.7b01678DOI Listing
September 2017

Beyond the Five and Six: Evaluation of Seven-Membered Cyclic Anhydrides in the Castagnoli-Cushman Reaction.

Org Lett 2017 01 21;19(1):130-133. Epub 2016 Dec 21.

National Taras Shevchenko University of Kyiv , Volodymyrska Street 64, Kyiv 01601, Ukraine.

The Castagnoli-Cushman reaction with benzo[d]oxepine-2,4(1H,5H)-dione as an anhydride component allowed for preparation of 2,3-disubstituted 4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acids in 21-75% yields and with good trans diastereoselectivity. The method worked with imines generated from aromatic or α-branched aliphatic aldehydes and is amenable for both parallel synthesis and scale-up. The procedure for epimerization of the resulting trans-disubstituted tetrahydrobenzo[d]azepines to their cis isomers was also developed.
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http://dx.doi.org/10.1021/acs.orglett.6b03426DOI Listing
January 2017

Synthesis and structural analysis of angular monoprotected diamines based on spiro[3.3]heptane scaffold.

J Org Chem 2015 Apr 25;80(8):3974-81. Epub 2015 Mar 25.

‡Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine.

The synthesis of all stereoisomers of spiro[3.3]heptane-1,6-diamines suitably protected for use as building blocks in drug discovery is reported. Structural analysis revealed the similarity between the spiro[3.3]heptane and cyclohexane scaffolds. Comparison of the distance between functional groups and their spatial orientation proved that (1S,4r,6R)- and (1R,4r,6S)-1,6-disubstituted spiro[3.3]heptanes can be considered as restricted surrogates of cis-1,4-disubstituted cyclohexane derivatives. Similarly, (1S,4s,6R)- and (1R,4s,6S)-1,6-disubstituted spiro[3.3]heptanes are the restricted surrogates of trans-1,3-disubstituted cyclohexanes. Such replacement can be recommended for use in optimization of ADME parameters of lead compounds in drug discovery.
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http://dx.doi.org/10.1021/acs.joc.5b00323DOI Listing
April 2015

Toward lead-oriented synthesis: one-pot version of Castagnoli condensation with nonactivated alicyclic anhydrides.

ACS Comb Sci 2014 Mar 6;16(3):146-53. Epub 2014 Feb 6.

The Institute of High Technologies, Taras Shevchenko National University of Kyiv , Glushkov Street 4, Kyiv 03187, Ukraine.

One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues. Utility of the method to multigram preparation of building blocks and synthetic intermediates was also demonstrated. The final products are obtained in high yields and diastereoselectivity. The method fits well in the concept of lead-oriented synthesis; in particular, it can be used for the design of lead-like compound libraries, even if the strictest cut-offs are applied to the physicochemical properties of their members.
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http://dx.doi.org/10.1021/co4001277DOI Listing
March 2014

The catalytic asymmetric α-benzylation of aldehydes.

Angew Chem Int Ed Engl 2014 Jan 24;53(1):282-5. Epub 2013 Nov 24.

Max-Planck-Institut für Kohlenforschung, Kaiser Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany).

The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.
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http://dx.doi.org/10.1002/anie.201306037DOI Listing
January 2014