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

Article abstract of DOI:10.1021/acscombsci.7b00163

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.

Full text of DOI:10.1021/acscombsci.7b00163

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Article
An old story in the parallel synthesis world: an approach to hydantoin libraries
Andrey Bogolubsky, Yurii S. Moroz, Olena Savych, Sergey Pipko, Angelika Konovets, Maxim
O. Platonov, Oleksandr V. Vasylchenko, Vasyl V. Hurmach, and Oleksandr O. Grygorenko
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00163 • Publication Date (Web): 11 Dec 2017
Downloaded from http://pubs.acs.org on December 13, 2017
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An old story in the parallel synthesis world: an
approach to hydantoin libraries
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Andrey V. Bogolubsky,†,* Yurii S. Moroz,†,‡,* Olena Savych,†,‡,* Sergey Pipko,†,‡
Angelika Konovets,†,‡ Maxim O. Platonov,† Oleksandr V. Vasylchenko,† Vasyl V. Hurmach,†,‡
Oleksandr O. Grygorenko†,‡
†Enamine Ltd., 78 Chervonotkatska Street, Kyiv 02094, Ukraine, www.enamine.net
‡National Taras Shevchenko University of Kyiv, 60 Volodymyrska Street, Kyiv 01601, Ukraine
*These authors contributed equally
Corresponding author. Eꢀmail: gregor@univ.kiev.ua.
Keywords: condensation, nitrogen heterocycles, 2,2,2ꢀtrifluoroethylcarbamates, amino esters,
kinase inhibitors
Abstract. An approach to the parallel synthesis of hydantoin libraries by reaction of in situ
generated 2,2,2ꢀtrifluoroethylcarbamates and αꢀamino esters was developed. To demonstrate
utility of the method, a library of 1158 hydantoins designed according to the leadꢀlikeness criteria
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(MW 200…350, cLogP –1…3) was prepared. The success rate of the method was analyzed as a
function of physicoꢀchemical parameters of the products, and it was found that the method can be
considered as a tool for leadꢀoriented synthesis. A hydantoinꢀbearing 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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Introduction.
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Development of synthetic methods which are compatible with the requirements of
combinatorial chemistry has always been a tremendous task, and with more and more increased
pressure on the library quality, synthesis of even wellꢀknown compound types becomes a
problem to solve.1–6 For example, hydantoins (1) have been known for more than 150 years,7–9
and even a (good) beginning organic chemist can name at least one or two methods for their
preparation. These methods include:
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• the classical Bucherer–Bergs reaction (i. e. reaction of carbonyl compounds with cyanide
and ammonia carbonate) and a number of its variations (Figure 1, pathway A);10
• (in situ) cyclization of hydantoinic acids or their esters (2). In turn, the latter are prepared
by the reaction between αꢀamino esters 3 and isocyanates,11,12 carbamoyl chlorides,13 or
silylated Nꢀcarboxyanhydrides of αꢀaminoacids (Figure 1, pathway B).14 Alternatively,
αꢀamino esters 3 react with phosgene, triphosgene or CDI and then –primary amine
(pathway C).15,16 In some cases, formation of 2 is followed by hydrolysis prior the
cyclization;17–22
• other methods such as the Ugi reaction (Figure 1, pathway D),23,24 cyclization of
activated carbamates 4 (pathway E),25,26 reaction between amides of amino acids and
triphosgene (pathway F),27 condensation of 1,2ꢀdicarbonyl compounds with ureas
(pathway G),28 or domino condensation of α,βꢀunsaturated acid esters with
carbodiimides (pathway H).29
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Figure 1. Synthetic routes to form a hydantoin core.
Since the hydantoin moiety is present is several marketed and investigational drugs, i. e. an
antiꢀconvulsant medications phenytoin (5) and etotoin (6), a nonsteroidal antiandrogen
nilutamide (7), a postsynaptic muscle relaxant dantrolene (8), or an aldose reductase inhibitor
sorbinil 9) (Figure 2),30 an efficient and robust approach to the hydantoin libraries would be of
high interest to early medicinal chemistry programs. Most of the approaches shown in Figure 1,
however, are inconvenient for the parallel synthesis conditions due to the use of toxic, gaseous or
scarcely available reagents; some of these methods also do not allow for variation at all the
possible substitution points of the hydantoin core. Nevertheless, examples of hydantoin libraries
synthesis were described in the literature previously. Many of them relied on the use of
isocyanates (Figure 1, pathway B and other transformations);31–39 some allowed for the
preparation of the libraries with specific substitution patterns36–46 or were multistep.32,47–50 But
isocyanates are toxic, have limited shelf stability and commercial availability (as compared to
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other common building blocks), which hampers wide application of the synthetic procedures
cited above in the parallel conditions.
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Figure 2. Hydantoins – marketed and investigational drugs.
A few years ago, we had introduced parallel methods of assembling two different amino
components to obtain unsymmetrical ureas51,52 with 2,2,2ꢀtrifluoroethylchlorocarbonate (10a) or
bis(2,2,2ꢀtrifluoroethyl)carbonate (10b) (Scheme 1). The intermediate 2,2,2ꢀtrifluoroethyluretane
11 can be preꢀsynthesized, or generated in situ from amines and reagents 10. By replacing one of
the amino components with the αꢀamino acid ester 3, this method could be extrapolated to the
hydantoin synthesis since hydantoinic acid ester 2 is formed, which would undergo cyclisation
under basic conditions (Scheme 2). This strategy follows pathway C of Figure 1; however, since
less toxic and easily handled reagents 10a or 10b are used instead of phosgene, triphosgene or
CDI, and the only byꢀproduct formed in the cyclization step is volatile 2,2,2ꢀtrifluoroethanol, this
procedure should be amendable for parallel synthesis conditions.
Scheme 1.
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Scheme 2.
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In this work, utility of the approach depicted in the Scheme 2 to the preparation of hydantoin
libraries has been shown. In addition, the developed method has been applied in discovery of
Aurora kinase A inhibitors with a combination of rational design, parallel synthesis, in silico and
in vitro screenings, which resulted in submicromolar primary hits.
Results and discussion.
Method development. Depending on the substrate, one of the following synthetic procedures
was used (Scheme 3):
• Method A – in situ generation of carbamate 11 from the aromatic or heteroaromatic
amine 12 and reagent 10a, followed by reaction with amino acid ester 3;
• Method B – in situ generation of carbamate 11 from the aliphatic amine 12 and reagent
10b, followed by reaction with 3.
The choice of the procedure was restricted by reactivity of the nucleophile at the first step
(formation of 11). For the aromatic and heteroaromatic substrates, the choice of the method was
defined by their lowered reactivity, so that more reactive 10a should be applied. With reactive
aliphatic amines 12, symmetric 10b could be used. Whereas the Method B followed the reaction
conditions published by us previously for the urea synthesis,52 in the Method A, we had slightly
modified the synthetic procedure51 for our purposes, as, for example, replacing DBU with DIPEA
and using dioxane as a solvent.
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Scheme 3. Synthesis of the hydantoin library 1 and selected examples of the products
To validate the process, we have randomly selected 20 amino esters 3(1–20) and 20 primary
amines 12(1–20) with varied chemical reactivity and hydrophilicity as the starting compounds
(Figures S1 and S2 in the Supporting information). Both methods A and B gave satisfactory
results in these preliminary experiments: the 20 corresponding hydantoins were obtained with
moderate to good yields (25–84%), which are acceptable for parallel synthesis. Moderate yields
observed in some cases could be explained as a result of parallel workꢀup procedures, in which
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compounds were not fully extracted from the aqueous solution. Indeed, LCꢀMS and/or H NMR
analysis of the crude reaction mixtures of the validation set showed that hydantoin formation had
proceeded with high yields (>80% of the desired product).
To demonstrate utility of the method for the leadꢀoriented synthesis, we have designed a
library of 1461 leadꢀlike hydantoins 1 starting from 185 amino esters 3(1–185) and 629 primary
amines 12(1–629) (Figures S1 and S2 in the Supporting information). The physicoꢀchemical
parameters of the library were adjusted according to the definition of leadꢀlikeness by Churcher
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and coꢀworkers (MW 200…350, cLogP –1…3, except 11 compounds prepared in the validation
step).4, 53 Further prioritization of the compounds for including into the final library was
performed using REAL methodology,54 Tanimoto indexꢀbased diversity selection using ECFP4
fingerprints,55 and visual inspection. Parallel synthesis of the library 1 resulted in successful
isolation of 1158 library members (79% success rate), with 42% average yield (Figure 3).
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Figure 3. Yields of the hydantoin library members 1{3(1–185),12(1–629)}
Figure 4 shows that calculated physicoꢀchemical parameters of the library 1{3(1–185),12(1–
629)} comply well with the leadꢀlikeness criteria. The average values are: molecular weight
(MW) – 309; calculated logarithm of the partitioning coefficient (cLogP) – 1.23, Hꢀbond
acceptor and donor counts (HAcc and HDon) – 3.5 and 0.3, respectively; rotatable bond count
(RotB) – 3.2; Fsp3 – 0.52. It was found that the yield weight of the product was not affected
strongly by the aboveꢀmentioned parameters (except HDon, which led to significant drop in
average method efficiency upon its increasing). In particular, no “LogP drift” effect4 was
observed. It is also interesting to note that the highest average yields were observed for the
compounds with Fsp3 = 0.4–0.8. These facts demonstrate suitability of the methods developed
for leadꢀoriented synthesis.
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Figure 4. Calculated physicoꢀchemical parameters of the library members 1{3(1–185),12(1–
629)} and their correlation with yields of the products
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In general, reactivity of the substrates 12(1–629) followed trends described in our previous
works on urea synthesis,51, 52 and it correlated positively with nucleophilicity of these primary
amines. Nevertheless, the products could be obtained even in the case of lowꢀnucleophilic
amines (e. g. 12(39), 12(57), 12(60), 12(72), 12(83), or 12(409), Figure 5), although these
substrates showed low success rate. It should be noted that steric factors affecting nucleophilicity
of 12 appeared to be of lesser importance for the reaction outcome as compared to the electronic
ones. The presence of additional basic centers in the molecules of 12 also diminished both yields
of the products 1 and the success rate, which might be related to the isolation issues.
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Figure 5. Examples of lowꢀnucleophilic amines 12 – substrates for the hydantoin synthesis
Similar tendencies were observed for the reactivity of the amino esters 3(1–185). In particular,
steric hindrance seem not to be very important factor since αꢀsubstituted and α,αꢀdisubstituted
amino esters gave comparable average yields of the products. Primary amino esters were less
effective substrates for the hydantoin synthesis than secondary ones; the presence of additional
basic centers also diminished average yields of the products. Both these facts can be addressed to
more problematic isolation of the target compounds. Interestingly, primary amino esters with a
single (het)aryl or COOEt substituent at the α position showed low success rate (28%), hence the
method showed poor effectiveness for the preparation of hydantoins with the (het)aryl substituent
at the Cꢀ5 position. The reason behind this fact is not clear but it might be again related to the
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isolation issues since formation of the corresponding hydantoins with moderate to good yields
was observed in the crude reaction mixtures by LCMS.
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Design and synthesis of the potential Aurora kinase A inhibitor library. To
demonstrate utility of the hydantoin libraries for medicinal chemistry projects, we have applied
them to discovery of Aurora kinase A inhibitors. Kinases of Aurora family play crucial role in
cell proliferation.56 Aurora kinase A, particularly, takes part in the mitotic spindle formation and
therefore segregation of chromosomes. Overexpression of this kinase is tightly connected with
tumor formation,57–59 and its inhibition is an important issue in cancer therapy. Various Aurora
inhibitors have been reported60 and are now at clinical trials stage,61 but still a lot of relevant
chemical space remains unexplored.
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Our choice of this target relied on our preliminary results which included in silico search
within our medicinal chemistry dataset of already synthesized compounds and analysis of the
reported ligands. This allowed us to suggest main pharmacophore features for the ligand (Figure
6). It consisted of a hingeꢀbinding group with Hꢀbond acceptor and a steric group attached to it,
an anchor – aromatic fragment with Hꢀbond acceptor, and a linker –flexible chain between hingeꢀ
binding group and anchor. Among the set, several fragments represented hingeꢀbinding motif
repeatedly, and a hydantoin core was found quite often. Preliminary in vitro screening at 10 ꢀM
revealed over 50% inhibition of the target for some of these virtual hits. Encouraged by these
positive results, we decided to create a library of hydantoins 13 that met the presented
pharmacophore scheme.
Figure 6. General features of the potential Aurora kinase A ligands proposed
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To simplify enumeration and further synthesis of the library 13, we have not separated the
steric fragment from the hingeꢀbinding motif and considered this fragment as a hydantoin with
(di)alkyl or spiro substitution at Cꢀ5 position; also, we circumscribed set of hydantoins steric
fragment to those containing 2–9 carbon atoms. As the linkers, we have selected nonꢀbranched
ωꢀchlorocarboxylic acids of 2–4 carbon atoms due to simplicity of attachment to the hingeꢀ
binding group and further modification of the carboxylic group with an anchorꢀintroducing
reagent. As the latter, we have chosen aromatic frameworks of 1–3 rings, with a heteroaromatic
moiety (for biꢀ and tricyclic systems) or an amide bond for the monocyclic system. The linker
attachment functionality was either aliphatic amino group (to form an amide bond) or aliphatic
halogen (to form an ester bond with carboxylic part of the linker).
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Enumeration of the library 13 involved 24 αꢀamino esters 3 with only saturated and mostly
conformationally restricted moieties to form the hydantoin core, three linkers introduced by ωꢀ
chloro esters 14(1–3), and two groups of the anchorꢀintroducing building blocks, i. e. ester
(alkylation agents 16(1–1500)) and amide (amines 17(1–1000)) bondꢀforming. These building
blocks were selected to be capable of introducing an aromatic fragment and Hꢀbond acceptor into
the anchor.
The resulting database of 108,000 compounds was subjected to in silico screening against
Aurora A kinase. The binding site model was created on the basis of entry 2C6E in Protein Data
Bank.62 Filtering was based on such criteria as the builtꢀin QXP scoring function,63 the number of
hydrogen bonds, the proteinꢀligand contact surface area and the distance from ligand to key
points of the corresponding pharmacophore model. The main interactions for a selected series of
compounds were the formation of two hydrogen bonds with Ala 212, the hydrogen bond with
Lys 161, and placing the hydrophobic heterocycle in a subꢀpocket remote from the kinase binding
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site (Figure 7). The substituents R1 and R2 additionally stabilized the position of hydantoin in the
binding site model. According to the proposed interaction model, the optimal length of the linker
between the two parts of the molecule was optimal at 4–5 atoms.
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Figure 7. Schematic interaction between Aurora kinase A and ligand 13{3(189),14(1),16(5)}
(left), and 3D structure with a pharmacophore model (right). The constraints are shown in: red –
hydrogen bond acceptor, blue – hydrogen bond donor, orange – aromatic part of the molecule.
The selection procedure, followed by visual inspection gave 367 compounds with high
predicted binding affinity. Synthesis of these library members was performed according to the
Scheme 4. To allow for the linker variation, the synthesis commenced from 1,3ꢀunsubstituted
hydantoins 1{3(10–191),12(630)} modifiable at the Nꢀ1 position, which were in turn prepared
from ammonium chloride (12(630)), bis(2,2,2ꢀtrifluoroethyl)carbonate (10b), and amino esters 3.
To introduce the linkers, alkylation of these hydantoins with ωꢀchloro esters 14(1–3) were used.
After deprotection, carboxylic acids 15{3(10–191),14(1–3)} were obtained. It should be noted
that these three steps were performed as a single parallel reaction sequence, so that carboxylic
acids 15{3(10–191),14(1–3)} were obtained directly from the amino esters 3. The crude products
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15 were used in the ester/amide formation step, which gave 302 of 367 compounds 13{3(10–
191),14(1–3),16(1–174)} or 13{3(10–191),14(1–3),17(1–63)} in 9–34% overall yield (82%
success rate) (Figure S3).
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O
1.
R5 Cl
16
Cl
Ot-Bu
n
X = O:
14(1), n = 1
14
O
DIPEA, DMF,
100 oC, 6 12 h
R5 NH2
17
CMPI, i-Pr2NEt,
MeCN, 100 oC, 6 h
O
O
(2), n = 2
2HN
R1
R2
O
n
1HN
R
R
O
n
NH
14(3), n = 3
N
R5
N
R1
R2
X
DIPEA, DMF,
100 oC, 6 12 h
2. CF3COOH,
CH2Cl2, rt, 12 h
X = NH:
N
OH
O
H
O
O
6
1{3,12(630)}
15
13
, X = O, NR
Scheme 4. Synthesis of the hydantoin library 13 (CMPI – 2ꢀchloroꢀ1ꢀmethylpyridinium iodide)
In vitro evaluation of the library. In vitro testing of the 302 hydantoins 13 was performed at
10 µМ concentration of the ligand (Figure S3). For the compounds which showed at least 50%
inhibition at this concentration, IC50 was determined. Five compounds inhibited Aurora kinase A
in a (sub)micromolar range, with IC50 of the most active one (13{3(189),14(1),16(5)}) being
equal to 0.97 µМ (Table 1).
Table 1. Results of in vitro testing of the hyd1antoins 13 against Aurora kinase A
Inhibition %
(at 10 ꢀM)
IC50
(ꢀM)
Overall
yield (%)
Entry No.
1
Compound
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97
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0.97
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Conclusions.
Synthesis of hydantoins by reaction of in situ generated 2,2,2ꢀtrifluoroethylcarbamates and αꢀ
amino esters is an efficient method for the preparation of combinatorial libraries. The procedures
developed are amenable for wide range of substrates including aliphatic, aromatic and
heteroaromatic amines, as well as compounds with additional functional groups (e. g. hydroxyl,
amide, or additional basic center). A library of 1158 hydantoins which fully comply with leadꢀ
likeness criteria was prepared with 79% success rate and 42% average yield. It was shown that
the average yield of the products only slightly increased upon increase of the product molecular
weight (MW), and no “LogP drift” was observed; thus the method is compatible with criteria of
leadꢀoriented synthesis. Analysis of other factors showed that while Hꢀbond acceptor count (Hꢀ
Acc) did not influence the yield of the products significantly, increasing the number of Hꢀdonors
(HꢀDon) resulted in significant drop in average method efficiency. The method was more
effective for the products with higher rotatable bond count (RotB), and the highest average yields
were observed for the compounds with Fsp3 = 0.4–0.8. Finally, the utility of the approach was
demonstrated by discovery of submicromolar Aurora kinase A inhibitor bearing the hydantoin
moiety.
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Experimental part.
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General. All chemicals and solvents were obtained from Enamine Ltd. and used without
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further purification. H and C NMR spectra were acquired on Bruker Advance DRX 400 and
Bruker Avance DRX 500 spectrometers using DMSOꢀd6 as a solvent and tetramethylsilane as
internal standerd. Melting points were determined on a Buchi melting point apparatus. LCMS
data were recorded on Agilent 1100 HPLC equipped with diodeꢀmatrix and massꢀselective
detector Agilent LC/MSD SL, column: Zorbax SBꢀC18, 4.6 mm × 15 mm; eluent, A, acetonitrile
− water with 0.1% of TFA (95:5), B, water with 0.1% of TFA; flow rate: 1.8 mL/min. Elemental
analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Kyiv
National Taras Shevchenko University.
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Syntheses of the libraries 3 and 13 were performed in 8 mL vials (Figure S1, Supporting
Information); loading of the reagents, as well as workꢀup of the reaction mixtures was performed
manually in a parallel fashion. Reactions were performed in ultrasonic baths or laboratory ovens
with a shaker (Figure S2, Supporting Information); up to 1,000 vials could be used
simultaneously (the whole library 3 was synthesized in three runs). The shaking of the reaction
vials and extraction were done in an ultrasonic bath; the phases were separated manually with
Pasteur pipettes. Centrifugal evaporators were used to remove the solvents from the vials in a
parallel fashion.
The target library members were typically obtained with >90% purity. If necessary, they were
purified by the following method: the crude product (obtained from 1 mmol of the starting
compound) was dissolved in MeOH (1 mL), and C18ꢀmodified silica gel (100 mg) was added.
The suspension was stirred for 2 h, filtered, and the filtrate was evaporated in vacuo. If the
product still was not pure enough, it was subjected to preparative flash chromatography
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(Combiflash Companion chromarograph, 12 g RediSep columns, gradient Hexanes – iꢀPrOH as
eluent).
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Parallel synthesis of hydantoins 1 from amino esters 3 and (hetero)aromatic amines 12
(Method A). To a solution of amine 12 (1 mmol) in dioxane (1 mL), iꢀPr2NEt (2.5 mmol;
additional 1 mmol for the amine/amino ester hydrochlorides) and 2,2,2ꢀtrifluoroethyl
cloroformate (10a) (1 mmol) were added successively. This mixture was shaken at rt for 1.5 h
and then amino ester 3 (1 mmol) was added, and the mixture was heated at 100 °C for 12 h. After
cooling, 10% aq AcOH (6 mL) was added, and the mixture was extracted with CHCl3 (3 mL).
The extract was washed twice with H2O (6 mL), and the organic phase was evaporated in vacuo
to give the target product 1.
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Parallel synthesis of hydantoins 1 from amino esters 3 and aliphatic amines 12 (Method
B). A mixture of amine 12 (1.2 mmol; for the hydrochloride, iꢀPr2NEt (1.3 mmol) was also
added) and bisꢀ2,2,2ꢀtrifluoroethylcarbonate (10b) (1.5 mmol) in acetonitrile (2 mL) was heated
at 75 °C in a sealed vial for 2 h. After cooling, xylene (0.3 mL) was added, and the volatile
liquids were removed in vacuo. Then MeCN (2 mL), amino ester 3 (1 mmol), and DBU (1.5
mmol; 2.6 mmol for the hydrochloride) were added to the residue, and the resulting mixture was
heated at 100 °C for 4 h. After cooling, 10% aq AcOH (6 mL) was added, and the mixture was
extracted with CHCl3 (3 mL). Extract was washed twice with H2O (6 mL), and CHCl3 was
evaporated in vacuo to give the target product 1.
One-pot parallel synthesis of carboxylic acids 15. Hydantoin 1{3(10–191),12(630)} was
prepared by method A starting from amino ester 3 (1 mmol) and NH4Cl (1.2 mmol). The crude
product was dissolved in DMF (2 mL), iꢀPr2NEt (1.2 mmol) was added, and the mixture was
stirred at rt for 0.5 h. Then tertꢀbutyl ester 14 (1 mmol) was added, the mixture was stirred at rt
for 1 h and at 100 °C for 6 h (14(1)), 9 h (14(2)) or 12 h (14(3)), and then cooled to rt. H2O (6
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mL) was added, and the mixture was extracted with CHCl3 (3 mL). The organic phase was
evaporated in vacuo, CH2Cl2 (1 mL) and CF3COOH (1 mL) were added, and the mixture was
stirred at rt for 12 h. The volatiles were removed in vacuo to give the crude product 15 which
was used in the next step without characterization.
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Parallel synthesis of esters 13{3(10–191),14(1–3),16(1–174)}. Carboxylic acid 15 (0.1 mmol)
was dissolved in DMF (0.5 mL), iꢀPr2NEt (0.12 mmol) was added, and the mixture was stirred at
rt for 0.5 h. Then alkyl halide 16 (0.1 mmol) was added, the mixture was stirred at rt for 1 h and
at 100 °C for 6 h, and then cooled to rt. H2O (6 mL) was added, and the mixture was extracted
with CHCl3 (3 mL). The organic phase was evaporated in vacuo to give the target product 13.
Parallel synthesis of amides 13{3(10–191),14(1–3),17(1–63)}. Carboxylic acid 15 (0.1 mmol)
was dissolved in MeCN, and DIPEA (0.12 mmol) was added. The mixture was stirred at rt for
0.5 h, 2ꢀchloroꢀ1ꢀmethylpyridinium iodide (CMPI) (0.1 mmol) was added, and the mixture was
stirred at rt for additional 0.5 h and then at 100 °C for 6 h. H2O (6 mL) was added, and the
mixture was extracted with CHCl3 (3 mL). The organic phase was evaporated in vacuo to give
the target product 13.
Virtual screening. Molecular docking was performed using a flexible ligand and a fixed
receptor model. We used an algorithm of systematic docking (SDOCK+) implemented in QXP
docking software, which had shown high reproducing ability of ligand conformation with
minimum RMSD as compared to the crystallographic data.64 The maximum number of SDOCK+
routine steps was set to 100, and the 10 best structures (based on builtꢀin QXP scoring function63)
were retained for each compound. In accordance with the defined pharmacophore models, the
resulting proteinꢀligand complex structures had been filtered by intrinsic Flo+ filters and
multiRMSD software package.65
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Prior to the docking routine, water molecules were removed from the PDB structures. All Arg
and Lys residues were protonated in order to be capable of forming a large number of hydrogen
bonds. A set of 108′000 small molecule structures was docked into the model binding sites. All
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possible stereoisomers were generated (maximum 8) resulting in about 486′000 threeꢀ
dimensional structures, subsequently docked into the binding sites using QXP/Flo software with
100 steps of SDOCK+ routine. The 10 lowest energy complex structures were selected for each
small molecule, resulting in a total of about 4′860′000 of proteinꢀligand complexes, which were
then filtered by the internal Flo+ filters and the geometryꢀbased filters. Filtering criteria for the
internal scoring functions were as following: pI > 3, Cntc < –59, Pslv > 8. These criteria
eliminated frankly unsuccessful proteinꢀligand complexes.
At the next step of filtering, conditions that we deemed necessary for the binding of the
substance in the active site model were given. For the filtering, the following modules were used:
Nearest atom filter, Hydrogen bonds filter. The created model of interaction included five
parameters: minimum three hydrogen bonds, Ala 212.A O – 2.25 Å – H, Ala 212.A NH – 2.25 Å
– O, Lys 161.A NZH 2.65 Å – any acceptor and Gln 184.A CG – 5.5 Å – any atom. All
complexes retained after filtering were the subject for visual inspections.
Supporting Information Available: Figures S1–S5, Table S1, compound characterization
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data, and copies of H and C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgments. The authors thank Mr. Vitaliy V. Polovinko for NMR measurements.
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References and footnotes.
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(1)
Abet, V.; Mariani, A.; Truscott, F. R.; Britton, S.; Rodriguez, R. Biased and Unbiased
Strategies to Identify Biologically Active Small Molecules. Bioorg. Med. Chem. 2014, 22,
4474–4489.
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54
55
56
57
58
59
60
(2)
(3)
(4)
(5)
Liu, R.; Li, X.; Lam, K. S. Combinatorial Chemistry in Drug Discovery. Curr. Opin.
Chem. Biol. 2017, 38, 117–126.
Doveston, R.; Marsden, S.; Nelson, A. Towards the Realisation of LeadꢀOriented
Synthesis. Drug Discov. Today 2014, 19, 813–819.
Nadin, A.; Hattotuwagama, C.; Churcher, I. LeadꢀOriented Synthesis: A New Opportunity
for Synthetic Chemistry. Angew. Chem. Int. Ed. 2012, 51, 1114–1122.
Dandapani, S.; Rosse, G.; Southall, N.; Salvino, J. M.; Thomas, C. J. Selecting, Acquiring,
and Using Small Molecule Libraries for HighꢀThroughput Screening. Curr. Protoc. Chem.
Biol. 2012, 4, 177–191.
(6)
GarciaꢀCastro, M.; Zimmermann, S.; Sankar, M. G.; Kumar, K. Scaffold Diversity
Synthesis and Its Application in Probe and Drug Discovery. Angew. Chem. Int. Ed. 2016,
55 (27), 7586–7605.
(7)
(8)
Ware, E. The Chemistry of the Hydantoins. Chem. Rev. 1950, 46, 403–470.
Meusel, M.; Gütschow, M. Recent Developments in Hydantoin Chemistry. A Review.
Org. Prep. Proced. Int. 2004, 36, 391–443.
(9)
Avendaño, C.; Menendez, J. C. Hydantoin and Its Derivatives. In Kirk-Othmer
Encyclopedia of Chemical Technology; John Wiley & Sons, Inc., 2000.
(10) Li, J. J. BuchererꢀBergs Reaction. In Name Reactions: A Collection of Detailed Reaction
Mechanisms; Springer Berlin Heidelberg: Berlin, Heidelberg, 2006; pp 92–93.
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(11) Scozzafava, A.; Supuran, C. T. Protease Inhibitors: Synthesis of Potent Bacterial
5
6
Collagenase and Matrix
Metalloproteinase Inhibitors Incorporating Nꢀ4ꢀ
7
8
9
Nitrobenzylsulfonylglycine Hydroxamate Moieties. J. Med. Chem. 2000, 43, 1858–1865.
(12) Von Geldern, T. W.; Kester, J. A.; Bal, R.; WuꢀWong, J. R.; Chiou, W.; Dixon, D. B.;
Opgenorth, T. J. Azole Endothelin Antagonists. 2. StructureꢀActivity Studies. J. Med.
Chem. 1996, 39, 968–981.
10
11
12
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23
24
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(13) Plechanovová, A.; Byun, Y.; Alquicer, G.; Škultétyová, L.; Mlčochová, P.; Němcová, A.;
Kim, H. J.; Navrátil, M.; Mease, R.; Lubkowski, J.; Pomper, M.; Konvalinka, J.; Rulíšek,
L.; Bařinka, C. Novel SubstrateꢀBased Inhibitors of Human Glutamate Carboxypeptidase
II with Enhanced Lipophilicity. J. Med. Chem. 2011, 54, 7535–7546.
(14) MateosꢀCaro, J.; Robin, Y.; Levacher, V.; Marsais, F. Controlled Ring Opening of Nꢀ
Sulfinylꢀ and NꢀSilylꢀNꢀCarboxyanhydrides (NCA): OneꢀPot Synthesis of Dipeptides and
Unsymmetrical Peptidyl Ureas from Unprotected NCA. Synlett 2009, 279–283.
(15) Triballeau, N.; Peixoto, C.; Lefranc, J.; Alvey, L.; Manioc, M.; Housseman, C.; Klaassen,
H.; Beeck, K. Van; Namour, F.; Minet, D.; Aar, E. Van Der; Feyen, J.; Fletcher, S.;
Blanque, R.; RobinꢀJagerschmidt, C.; Deprez, P. Identification of a 4ꢀ (Hydroxymethyl)ꢀ
diarylhydantoin as a Selective Androgen Receptor Modulator. J. Med. Chem. 2012, 55,
8236–8247.
(16) Schulze, W. Zur Synthese von NꢀChlorcarbonylꢀNꢀArylꢀAlaninmethylestern Und Deren
Reaktion Rnit Aminen. Z. Chem. 1989, 29, 285–286.
(17) Nakane, M.; Reid, J. A.; Han, W.; Das, J.; Truc, V. C.; Hadanger, M. F.; Garber, D.;
Harris, D. N.; Hedberg, A.; Ogletree, M. L.; Hall, S. E. 7ꢀOxabicyclo[2.2.1]heptyl
Carboxylic Acids as Thromboxane A2 Antagonists: Aza OꢀChain Analogues. 1990, No. 9,
2465–2476.
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(18) Hartwig, S.; Schwarz, J.; Hecht, S. From Peptides to Their Alternating EsterꢀUrea
Analogues: Synthesis and Influence of Hydrogen Bonding Motif and Stereochemistry on
Aggregation. J. Org. Chem. 2010, 75, 772–782.
9
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(19) Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; Fouquet, A.; Maillet,
M.; Nicolai, E.; Dorgeret, L.; Chevallier, F.; Besse, D.; Dufort, M.; Caussade, F.; Ahmad,
S. Z.; Stetsko, D. K.; Skala, S.; Davis, P. M.; Balimane, P.; Patel, K.; Yang, Z.; Marathe,
P.; Postelneck, J.; Townsend, R. M.; Dhar, T. G. M. Discovery and Development of 5ꢀ
[(5S,9R)ꢀ9ꢀ(4ꢀCyanophenyl)ꢀ3ꢀ(3,5ꢀDichlorophenyl)ꢀ1ꢀMethylꢀ2,4ꢀDioxoꢀ1,3,7ꢀ
triazaspiro[4.4]nonꢀ7ꢀYlꢀMethyl]ꢀ3ꢀThiophenecarboxylic Acid (BMSꢀ587101). A Small
Molecule Antagonist of Leukocyte Function Associated Antigenꢀ1. J. Med. Chem. 2006,
49, 6946–6949.
(20) Turner, E. M.; Blazer, L. L.; Neubig, R. R.; Husbands, S. M. Small Molecule Inhibitors of
Regulator of G Protein Signalling (RGS) Proteins. ACS Med. Chem. Lett. 2012, 3, 146–
150.
(21) Xie, Z.; Chai, K.; Piao, H.; Kwak, K.; Quan, Z. Synthesis and Anticonvulsant Activity of
of 7ꢀAlkoxylꢀ4,5ꢀdihydroꢀ[1,2,4]triazolo[4,3ꢀa]quinolines. Bioorg. Med. Chem. Lett.
2005, 15, 4803–4805.
(22) Park, K. H.; Kurth, M. J. Diastereoselective Synthesis of Hydantoinꢀ and Isoxazolineꢀ
Substituted Dispirocyclobutanoids. J. Org. Chem. 2000, 65, 3520–3524.
(23) Ignacio, J. M.; Macho, S.; Marcaccini, S.; Pepino, R.; Torroba, T. A Facile Synthesis of
1,3,5ꢀTrisubstituted Hydantoins via Ugi FourꢀComponent Condensation. Synlett 2005,
3051–3054.
(24) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S. Y.; Cherrier, M. P.; Choi, S.;
Salvino, J.; Labaudiniere, R. Novel Applications of Carbon dioxide/MeOH for the
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5
6
Synthesis of Hydantoins and Cyclic Ureas via the Ugi Reaction. Tetrahedron Lett. 2000,
41, 1889–1893.
7
8
9
(25) Patil, B. S.; Vasanthakumar, G.; Babu, V. V. S. Synthesis of Peptidyl Ureas Using Pꢀ
Nitrophenylꢀ(9ꢀFluorenylmethoxy Carbonylamino)methyl Carbamate Derivatives. Synth.
Commun. 2004, 34, 2313–2321.
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48
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50
51
52
53
54
55
56
57
58
59
60
(26) Diness, F.; Beyer, J.; Meldal, M. SolidꢀPhase Synthesis of TetrahydroꢀβꢀCarbolines and
Tetrahydroisoquinolines by Stereoselective Intramolecular NꢀCarbamyliminium Pictetꢀ
Spengler Reactions. Chem. Eur. J. 2006, 12, 8056–8066.
(27) Zhang, D.; Xing, X.; Cuny, G. D. Synthesis of Hydantoins from Enantiomerically Pure Rꢀ
Amino Amides without Epimerization. J. Org. Chem. 2006, 71, 1750–1753.
(28) Muccioli, G. G.; Poupaert, J. H.; Wouters, J.; Norberg, B.; Poppitz, W.; Scriba, G. K. E.;
Lambert, D. M. A Rapid and Efficient MicrowaveꢀAssisted Synthesis of Hydantoins and
Thiohydantoins. Tetrahedron 2003, 59, 1301–1307.
(29) Volonterio, A.; Zanda, M. Domino Condensation / AzaꢀMichael / O–N Acyl Migration of
Carbodiimides with Activated α,βꢀUnsaturated Carboxylic Acids to Form Hydantoins. J.
Org. Chem. 2005, 70, 2161–2170.
(30) Law, V.; Knox, C.; Djoumbou, Y.; Jewison, T.; Guo, A. C.; Liu, Y.; Maciejewski, A.;
Arndt, D.; Wilson, M.; Neveu, V.; Tang, A.; Gabriel, G.; Ly, C.; Adamjee, S.; Dame, Z.
T.; Han, B.; Zhou, Y.; Wishart, D. S. DrugBank 4.0: Shedding New Light on Drug
Metabolism. Nucleic Acids Res. 2014, 42, D1091–D1097.
(31) Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Combinatorial Chemistry of
Hydantoins. Bioorg. Med. Chem. Lett. 1998, 8, 2375–2380.
(32) Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y. Solid Phase Synthesis of
Hydantoin Library Using a Novel Cyclization and Traceless Cleavage Step. Tetrahedron
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Lett. 1997, 38, 4603–4606.
5
6
7
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(33) Lu, Y.; Zhang, W. Fluorous Parallel Synthesis of a Hydantoin/thiohydantoin Library. Mol.
Divers. 2005, 9, 91–98.
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(34) Colacino, E.; Lamaty, F.; Martinez, J.; Parrot, I. MicrowaveꢀAssisted SolidꢀPhase
Synthesis of Hydantoin Derivatives. Tetrahedron Lett. 2007, 48, 5317–5320.
(35) Olimpieri, F.; Bellucci, M. C.; Marcelli, T.; Volonterio, A. Regioselective
Multicomponent Sequential Synthesis of Hydantoins. Org. Biomol. Chem. 2012, 10,
9538–9555.
(36) Hanessian, S.; Yang, R.ꢀY. Solution and Solid Phase Synthesis of 5ꢀAlkoxyhydantoin
Libraries with a ThreeꢀFold Functional Diversity. Tetrahedron Lett. 1996, 37, 5835–5838.
(37) Nefzi, A.; Dooley, C.; Ostresh, J. M.; Houghten, R. A. Combinatorial Chemistry: From
Peptides and Peptidomimetics to Small Organic and Heterocyclic Compounds. Bioorg.
Med. Chem. Lett. 1998, 8, 2273–2278.
(38) Zhang, W.; Lu, Y.; Chen, C. H.ꢀT.; Curran, D. P.; Geib, S. Fluorous Synthesis of
Hydantoinꢀ, Piperazinedioneꢀ, and BenzodiazepinedioneꢀFused Tricyclic and Tetracyclic
Ring Systems. Eur. J. Org. Chem. 2006, 2055–2059.
(39) Maiti, B.; Chanda, K.; Sun, C.ꢀM. Traceless Synthesis of Hydantoin Fused Tetrahydroꢀβꢀ
Carboline on Ionic Liquid Support in Green Media. Org. Lett. 2009, 11, 4826–4829.
(40) Olimpieri, F.; Volonterio, A.; Zanda, M. ThreeꢀComponent, OneꢀPot Sequential Synthesis
of 1,3ꢀDisubstituted 5ꢀArylhydantoins. Synlett 2008, 2008, 3016–3020.
(41) GeronaꢀNavarro, G.; GonzálezꢀMuñiz, R.; FernándezꢀCarvajal, A.; GonzálezꢀRos, J. M.;
FerrerꢀMontiel, A.; Carreño, C.; Albericio, F.; Royo, M. SolidꢀPhase Synthesis of a
Library of Amphipatic Hydantoins. Discovery of New Hits for TRPV1 Blockade. ACS
Comb. Sci. 2011, 13, 458–465.
24
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Page 25 of 28
ACS Combinatorial Science
1
2
3
4
5
6
(42) Nieto, M. J.; Philip, A. E.; Poupaert, J. H.; McCurdy, C. R. SolutionꢀPhase Parallel
Synthesis of Spirohydantoins. J. Comb. Chem. 2005, 7, 258–263.
7
8
9
(43) Firth, J. D.; Zhang, R.; Morgentin, R.; Guilleux, R.; Kalliokoski, T.; Warriner, S.; Foster,
R.; Marsden, S. P.; Nelson, A. Exploitation of the Ugi–Joullié Reaction in the Synthesis of
Libraries of DrugꢀLike Bicyclic Hydantoins. Synthesis 2015, 47, 2391–2406.
(44) KucwajꢀBrysz, K.; Warszycki, D.; Podlewska, S.; Witek, J.; Witek, K.; Gonzalez
Izquierdo, A.; Satala, G.; Loza, M. I.; Lubelska, A.; Latacz, G.; Bojarski, A. J.; Castro, M.;
KiecꢀKononowicz, K.; Handzlik, J. Rational Design in Search for 5ꢀPhenylhydantoin
Selective 5ꢀHT7R Antagonists. Molecular Modeling, Synthesis and Biological Evaluation.
Eur. J. Med. Chem. 2016, 112, 258–269.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(45) Prevet, H.; Flipo, M.; Roussel, P.; Deprez, B.; Willand, N. MicrowaveꢀAssisted Synthesis
of Functionalized Spirohydantoins as 3D Privileged Fragments for Scouting the Chemical
Space. Tetrahedron Lett. 2016, 57, 2888–2894.
(46) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Microwave Assisted Synthesis of 1,5ꢀ
Disubstituted Hydantoins and Thiohydantoins in SolventꢀFree Conditions. Synthesis 2002,
75–78.
(47) Kuster, G. J. T.; van Berkom, L. W. A.; Kalmoua, M.; van Loevezijn, A.; Sliedregt, L. A.
J. M.; van Steen, B. J.; Kruse, C. G.; Rutjes, F. P. J. T.; Scheeren, H. W. Synthesis of
Spirohydantoins and Spiroꢀ2,5ꢀDiketopiperazines via ResinꢀBound Cyclic Α,αꢀ
Disubstituted αꢀAmino Esters. J. Comb. Chem. 2006, 8, 85–94.
(48) Kita, R.; Svec, F.; Fréchet, J. M. J. Hydrophilic Polymer Supports for SolidꢀPhase
Synthesis: Preparation of Poly(ethylene Glycol) Methacrylate Polymer Beads Using
“Classical” Suspension Polymerization in Aqueous Medium and Their Application in the
SolidꢀPhase Synthesis of Hydantoins. J. Comb. Chem. 2001, 3, 564–571.
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Page 26 of 28
1
2
3
4
5
6
7
8
9
(49) Bhalay, G.; Cowell, D.; Hone, N. D.; Scobie, M.; Baxter, A. D. Multiple SolidꢀPhase
Synthesis of Hydantoins and Thiohydantoins. Mol. Divers. 1997, 3, 195–198.
(50) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Solid Phase Synthesis of Hydantoins
Using a Carbamate Linker and a Novel Cyclization / Cleavage Step. Tetrahedron Lett.
1996, 37, 937–940.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(51) Bogolubsky, A. V.; Ryabukhin, S. V.; Pipko, S. E.; Lukin, O.; Shivanyuk, A.; Mykytenko,
D.; Tolmachev, A. A Facile Synthesis of Unsymmetrical Ureas. Tetrahedron 2011, 67,
3619–3623.
(52) Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Granat, D. S.; Pipko, S. E.;
Konovets, A. I.; Doroschuk, R.; Tolmachev, A. Bis(2,2,2ꢀTrifluoroethyl) Carbonate as a
Condensing Agent in OneꢀPot Parallel Synthesis of Unsymmetrical Aliphatic Ureas. ACS
Comb. Sci. 2014, 16, 303–308.
(53) Instant JChem, Version 15.3.16.0. ChemAxon ((http://www.chemaxon.com) 2015.
(54) Shivanyuk, A.; Ryabukhin, S. V.; Bogolubsky, A. V.; Tolmachev, A. Enamine Real
Database: Making Chemical Diversity Real. Chem. Today 2007, 25, 58–59.
(55) Rogers, D.; Hahn, M. ExtendedꢀConnectivity Fingerprints. J. Chem. Inf. Model. 2010, 50,
742–754.
(56) Crane, R.; Gadea, B.; Littlepage, L.; Wu, H.; Ruderman, J. V. Aurora A, Meiosis and
Mitosis. Biol. Cell 2004, 96, 215–229.
(57) Chou, C. H.; Yang, N. K.; Liu, T. Y.; Tai, S. K.; Hsu, D. S. S.; Chen, Y. W.; Chen, Y. J.;
Chang, C. C.; Tzeng, C. H.; Yang, M. H. Chromosome Instability Modulated by BMI1ꢀ
AURKA Signaling Drives Progression in Head and Neck Cancer. Cancer Res. 2013, 73,
953–966.
(58) Tanaka, M.; Ueda, A.; Kanamori, H.; Ideguchi, H.; Yang, J.; Kitajima, S.; Ishigatsubo, Y.
26
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2
3
4
5
6
7
8
9
CellꢀCycleꢀDependent Regulation of Human Aurora A Transcription Is Mediated by
Periodic Repression of E4TF1. J. Biol. Chem. 2002, 277, 10719–10726.
(59) Dobson, T.; Chen, J.; Krushel, L. A. Dysregulating IRESꢀDependent Translation
Contributes to Overexpression of Oncogenic Aurora A Kinase. Mol. Cancer Res. 2013,
11, 887–900.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(60) Pollard, J. R.; Mortimore, M. Discovery and Development of Aurora Kinase Inhibitors as
Anticancer Agents. J. Med. Chem. 2009, 52, 2629–2651.
(61) Bavetsias, V.; Linardopoulos, S. Aurora Kinase Inhibitors: Current Status and Outlook.
Front. Oncol. 2015, 5, 1–10.
(62) Heron, N. M.; Anderson, M.; Blowers, D. P.; Breed, J.; Eden, J. M.; Green, S.; Hill, G. B.;
Johnson, T.; Jung, F. H.; McMiken, H. H. J.; Mortlock, A. A.; Pannifer, A. D.; Pauptit, R.
A.; Pink, J.; Roberts, N. J.; Rowsell, S. SAR and Inhibitor Complex Structure
Determination of a Novel Class of Potent and Specific Aurora Kinase Inhibitors. Bioorg.
Med. Chem. Lett. 2006, 16, 1320–1323.
(63) McMartin, C.; Bohacek, R. S. QXP: Powerful, Rapid Computer Algorithms for Structureꢀ
Based Drug Design. J. Comput. Aided. Mol. Des. 1997, 11, 333–344.
(64) Warren, G. L.; Andrews, C. W.; Capelli, A.ꢀM.; Clarke, B.; LaLonde, J.; Lambert, M. H.;
Lindvall, M.; Nevins, N.; Semus, S. F.; Senger, S.; Tedesco, G.; Wall, I. D.; Woolven, J.
M.; Peishoff, C. E.; Head, M. S. A Critical Assessment of Docking Programs and Scoring
Functions. J. Med. Chem. 2006, 49, 5912–5931.
(65) Sudakov, O. O.; Balinskyi, O. M.; Platonov, M. O.; Kovalskyy, D. B. Geometric Filters
for Protein–ligand Complexes Based on Phenomenological Molecular Models. Biopolym.
Cell 2013, 29, 395–401.
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