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of Diacylhydrazine Derivatives Possessing 1,4-Benzodioxan. Moiety as Potential Anticancer Agents1. S. Wanga, H.-Y. Liua, R.-F. Xuc, and J. Suna,b* a School ...
ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 11, pp. 2671–2677. © Pleiades Publishing, Ltd., 2017.

Synthesis, Biological Evaluation, and Molecular Docking Studies of Diacylhydrazine Derivatives Possessing 1,4-Benzodioxan Moiety as Potential Anticancer Agents1 S. Wanga, H.-Y. Liua, R.-F. Xuc, and J. Suna,b* a

School of Life Sciences, Shandong University of Technology, Zibo, 255049 China *e-mail: [email protected] b

Elion Nature Biological Technology Co. Ltd, Nanjing, 210046 China c

Shandong Experimental High School, Jinan, 250001 China Received July 17, 2017

Abstract—A series of diacylhydrazine derivatives containing 1,4-benzodioxan 1-17 has been designed, synthesized and evaluated for antitumor activity. Most of the synthesized compounds demonstrated potent antitumor activity and low toxicity. Compound 10 demonstrated the most potent biological activity against MCF-7 cancer cell line, which was comparable with the positive control 5-fluorouracil. Docking simulation by positioning compound 10 into the MetAP2 structure active site was performed to explore the possible binding model. Keywords: diacylhydrazine, benzodioxan, antitumor activity, MetAP2, molecular docking

DOI: 10.1134/S1070363217110238 The accumulated information on molecular and cell tumor biology has brought about a revolutionary change in cancer treatment: (1) technological improvement of tumor molecular profiling and (2) discovery of predictive molecular targets [1–3]. Methionine aminopeptidase (MetAP) is present in every cell and carries out co-translational modification by removing the N-terminal methionine residue from many nascent proteins [4]. MetAP is divided into two subtypes, namely types 1 and 2. Eukaryotic cells have both subtypes, and prokaryotic cells have only one [5]. Mammalian MetAP1 and MetAP2 play important roles in cells proliferation and angiogenesis [6, 7]. MetAP2 is expressed at higher concentrations in tumors as compared to normal cells [8] and plays an important role in the growth of different types of tumors [9]. A number of MetAP2 inhibitors containing 1,4-benzodioxanthe has been synthesized [10] and determined to be one of important targets of 1,4-benzodioxane derivatives. Compounds containing a 1,4-benzodioxan skeleton demonstrate a broad spectrum of biological activities [11], such as anticancer [12, 13], immunosuppressive 1

The text was submitted by the authors in English.

[14], anti-inflammatory [15], antibacterial [16], and some others [17–19]. RESULTS AND DISCUSSION Seventeen novel MetAP2 potential inhibitors containing 1,4-benzodioxan and diacylhydrazine skeletons were synthesized. Docking simulations data exhibited that the compounds could possess improved activity due to introduction of the diacylhydrazine backbone in those. The highest binding energy was determined to be between the compound 10 and MetAP2 (–54.5157 cal/mol) probably due to the electron-donating groups that could reduce electron density of the benzene ring, making the active center larger and easier for penetration by the benzene ring. Few reports have been dedicated to the synthesis and MetAP2 inhibitory activity of diacylhydrazine derivatives containing 1,4-benzodioxan fragment. Synthesis and structure–activity relationship of a series of diacylhydrazine derivatives containing 1,4benzodioxan as antitumor agents are presented herein. Biological evaluation indicated that some of the synthesized compounds were potent inhibitors of MetAP2.

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WANG et al. Scheme 1. General synthesis of compounds 1–17.

O O

O OH

O

OCH3

a

O

O

O O

b

O

A

NH . NH2 B

O HN NH .

O

c

R O

O 1−17 F

O2N

Br (1);

R=

(3);

(2); Cl

OCH3

Cl

N OCH3 (6);

(8);

(7);

(4);

(5);

C2H5O (9);

(10);

C2H5O

OCH3 OCH3

NO2

Cl (12);

(11);

(13);

O (14);

(15);

O Cl

(16); Br

The synthetic approach to target compounds 1–17 (Scheme 1) included 2,3-dihydrobenzo[b][1,4]dioxine6-carboxylic acids transformation into 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylates A, catalyzed by concentrated sulfuric acid in methanol. This was followed by preparation of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazides by treatment of compound A with hydrazine hydrate (85%) in ethanol. Finally, diacylhydrazine derivatives 1–17 were prepared by refluxing of B with substituted benzoic acids in dichloromethane (Scheme 1). Antiproliferation assay. All synthesized 1,4-benzodioxan derivatives 1–17 were evaluated for their antiproliferative activity against the HELA (human cervical cancer cell) and MCF-7 (human breast cancer) (see the table). Among the synthesized compounds, the product 10 demonstrated the most significant anticancer activity against MCF-7 (IC50 = 2.13 μg/mL). Compounds 6, 8, 10, and 15 demonstrated a broad-

(17).

spectrum antitumor activity with IC50 concentration range of 2.13–11.35 μg/mL against the cancer cell lines involved. Binding model of compound 10 into MetAP2. In an effort to elucidate the possible mechanism of inducing anticancer activity in the two cells and conducting further SAR studies, molecular docking of the potent inhibitor 10 into the ATP binding site of MetAP2 (Figs. 1, 2) was considered using the binding model based on the MetAP2 (2EA4.pdb). In the binding model, compound 10 was nicely bound to the amino hydrogen of MetAP2 forming one H-bond. According to the molecular docking data the compound 10 exhibited potential inhibiting activity for MetAP2 Besides, a further study between the anti-proliferative activity against MCF-7 cell line and the CDOCKER INTERACTION ENERGY of MetAP2 was analyzed and the result indicated that there was a moderate correlation, as evidenced in Fig. 3.

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SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES MET A:384

ALA A:414 HIS A:331

HIS A:339 ASN A:329

PRO A:220 PHE A:219

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O

H

TYR A:444

ILE A:338

PHE A:252

GLY A:222

HIS A:231

O

N

O

HIS A:282

GLU LEU A:364 A:328

O

N

O

O VAL A:374

GLU A:459 ASP A:262

ASP A:251

ALA A:230 LEU A:447

ASN A:327

Fig. 1. Molecular docking modeling of compound 10 with MetAP2. Interactions: electrostatic (grey color), van der Waals (black color).

EXPERIMENTAL All chemicals and reagents used were of analytical grade. The reactions were monitored by TLC on Merck pre-coated silica GF254 plates. Melting points (uncorrected) were determined on a Digital Melting Point apparatus (Shenguang., Shanghai, China). ESI mass spectra were measured on a Mariner System 5304 mass spectrometer. 1H NMR spectra were measured in DMSO-d6 on a Bruker DPX500 spectrometer with

TMS used as a standard. Elemental analyses were performed on a CHN-O-Rapid instrument. Synthesis of methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (A). A mixture of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (1 mmol) with concentrated sulfuric acid (0.5 mL) in methanol (30 mL) was heated at 65°C overnight. The solvent was removed in vacuo, the oil was dissolved in ethyl acetate (20 mL) and extracted with water (40 mL).

Antiproliferative activity of the synthesized compounds 1–17 Comp. no.

IC50 ±SD, μg/mL MCF-7

HELA

1

12.12±0.03

17.24±0.06

2

13.13±0.07

3

Comp. no.

IC50 ±SD, μg/mL MCF-7

HELA

10

2.13±0.04

11.35±0.07

10.96±0.02

11

12.82±0.03

12.35±0.09

22.79±0.07

18.79±0.03

12

21.27±0.08

18.53±0.06

4

13.15±0.02

16.54±0.04

13

12.15±0.06

9.76±0.05

5

10.86±0.03

22.41±0.19

14

27.27±0.08

28.53±0.07

6

7.56±0.05

5.67±0.06

15

6.13±0.07

7.76±0.03

7

21.87±0.03

14.55±0.04

16

>50

>50

8

5.84±0.06

4.09±0.04

17

>50

>50

9

13.79±0.09

18.25±0.11

9.19±0.03

11.82±0.08

5-Fuorouracil

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IC50, μg/mL

60

20

E, kcal/mol

0

Fig. 2. 3D model of the interaction between compound 10 and MetAP2 binding site. MetAP2 is represented by molecular surface. Compound 10 is depicted by sticks and balls.

After drying the organic layer with anhydrous Na2SO4 and evaporating the solvent under reduced pressure a solid precipitate was formed. It was recrystallized from ethanol. Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-6carbohydrazide (B). To a solution of compound A (0.1 mol) in ethanol (50 mL) was added 85% hydrazine hydrate (1 mL) and the mixture was refluxed for 8–10 h. The reaction mixture was cooled down and the precipitated solid was filtered off and washed with small quantity of ethanol to give intermediate compound B. Synthesis of N-substituted 2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazides (1–17) (general procedure). A stirred solution of compound B (0.1 mol) in CH2Cl2 (50 mL) was treated with an appropriate substituted benzoic acid, EDC·HCl (0.15 mol) and HOBt (0.05 mol), and refluxed overnight. Following purification with recrystallisation afforded the corresponding compound as a white powder. N'-[2-(4-Fluorophenyl)acetyl]-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (1). mp 204–207°C. 1 H NMR spectrum, δ, ppm: 3.46–3.47 d (J = 6.5 Hz, 2H), 4.27–4.31 m (4H), 6.90–6.96 d (J = 9.0 Hz, 1H), 7.14–7.18 d (J = 9.3 Hz, 2H), 7.20–7.25 m (1H), 7.36– 7.40 m (3H), 10.11 s (1H), 10.21 s (1H). MS (ESI), m/z: 331.1 [M + H]+. Found, %: C 61.90; H 4.63; N 8.34. C17H15FN2O4. Calculated, %: C 61.82; H 4.58; N 8.48. N'-[2-(4-Bromophenyl)acetyl]-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (2). mp 198–202°C. 1 H NMR spectrum, δ, ppm: 3.51 s (2H), 4.27–4.30 m (4H), 6.95–6.96 d (J = 3.5 Hz, 1H), 7.29–7.31 d (J =

2

40

–20

1 → 17 Comp. no.

–40 1 –60 Fig. 3. The CDOCKER interaction energy E of (1) MetAP2 (2EA4) and (2) the antiproliferation activity IC50 of MCF-7.

8.5 Hz, 2H), 7.36–7.40 d (J = 15.5 Hz, 2H), 7.52–7.54 d (J = 9.0 Hz, 2H), 10.13 s (1H), 10.20 s (1H). MS (ESI), m/z: 391.02 [M + H]+. Found, %: C 52.07; H 3.92; N 7.23. C17H15BrN2O4. Calculated, %: C 52.19; H 3.86; N 7.16. N'-(4-Chlorobenzoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (3). mp 154–158°C. 1H NMR spectrum, δ, ppm: 4.30–4.33 m (4H), 6.97–6.99 d (J = 9.0 Hz, 1H), 7.44–7.48 m (3H), 7.50–7.52 d (J = 10.0 Hz, 1H), 7.56–7.59 m (2H), 10.31 s (1H), 10.46 s (1H). MS (ESI), m/z: 333.06, [M + H]+. Found, %: C 57.56; H 3.87; N 8.68. C16H13ClN2O4. Calculated, %: C 57.75; H 3.94; N 8.42. N'-(2-Phenylacetyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (4). mp 195–197°C. 1H NMR spectrum, δ, ppm: 3.52 s (2H), 4.27–4.30 m (4H), 6.95–6.96 d (J = 3.5 Hz, 1H), 7.23–7.26 m (2H), 7.46–7.49 m (3H), 7.50–7.51 d (J = 3.0 Hz, 2H), 10.21 s (1H), 10.25 s (1H). MS (ESI), m/z: 313.11, [M + H]+. Found, %: C 65.47; H 5.05; N 8.99. C17H16N2O4. Calculated, %: C 65.38; H 5.16; N 8.97. N'-(3-Nitrobenzoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (5). mp 217–220°C. 1H NMR spectrum, δ, ppm: 4.30–4.33 m (4H), 6.99–7.00 d (J = 9.5 Hz, 1H), 7.46–7.48 d (J = 10.0 Hz, 2H), 7.83–7.87 m (1H), 8.35–8.36 d (J = 7.5 Hz, 1H), 8.45– 8.47 d (J = 9.5 Hz, 1H), 8.74 (s,1H), 10.48 (s,1H), 10.86 (s,1H). MS (ESI), m/z: 344.1, [M + H]+. Found, %: C 55.77; H 3.93; N 12.37. C16H13N3O6. Calculated, %: C 55.98; H 3.82; N 12.24. N'-(3,4,5-Trimethoxybenzoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (6). mp 212–216°C. 1 H NMR spectrum, δ, ppm: 3.85 s (9H), 4.30–4.33 m

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SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES

(4H), 7.26 s (3H), 7.46–7.47 d (J = 3.0 Hz, 2H), 10.33 s (1H), 10.39 s (1H). CalMS (ESI), m/z: 389.13, [M + H]+. Found, %: C 58.63; H 5.53; N 7.01. C19H20N2O7. Calculated, %: C 58.76; H 5.19; N 7.21. (E)-N'-Cinnamoyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (7). mp 220–224°C. 1H NMR spectrum, δ, ppm: 4.29–4.32 m (4H), 6.72–6.75 d (J = 16.0 Hz, 1H), 6.96–6.98 d (J = 8.5 Hz, 1H), 7.40–7.41 m (5H), 7.55–7.58 d (J = 15.5 Hz, 1H), 7.82–7.84 d (J = 6.5 Hz, 2H), 10.15 s (1H), 10.35 s (1H). MS (ESI), m/z: 325.11, [M + H]+. Found, %: C 66.52; H 4.85; N 8.90. C18H16N2O4. Calculated, %: C 66.66; H 4.97; N 8.64. N'-(2,3-Dihydrobenzo[b][1,4]dioxine-6-carbonyl)nicotinohydrazide (8). mp 231–236°C. 1H NMR spectrum, δ, ppm: 4.28–4.33 m (4H), 6.98–7.00 d (J = 9.0 Hz, 1H), 7.44–7.47 d (J = 16.0 Hz, 2H), 7.57–7.98 m (1H), 8.25–8.27 m (1H), 8.38–8.39 d (J = 6.5 Hz, 1H), 9.07 s (1H), 10.43 s (1H), 10.67 s (1H). MS (ESI), m/z: 300.09, [M + H]+. Found, %: C 60.28; H 4.25; N 14.09. C15H13N3O4. Calculated, %: C 60.20; H 4.38; N 14.04. N-[2-(3-Chlorophenyl)acetyl]-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (9). mp 207–209°C. 1 H NMR spectrum, δ, ppm: 3.56 s (2H), 4.27–4.31 m (4H), 6.94–6.96 d (J = 13.5 Hz, 1H), 7.29–7.33 m (2H), 7.36–7.36 d (J = 2.0 Hz, 1H), 7.36–7.43 m (3H), 10.16 s (1H), 10.22 s (1H). MS (ESI), m/z: 347.07, [M + H]+. Found, %: C 58.76; H 4.33; N 8.23. C17H15ClN2O4. Calculated, %: C 58.88; H 4.36; N 8.08. N'-[2-(3,4-Diethoxyphenyl)acetyl]-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (10). mp 174– 176°C. 1H NMR spectrum, δ, ppm: 1.29–1.35 m (6H), 3.42 s (2H), 3.96–4.04 m (4H), 4.27–4.31 m (4H), 6.81– 6.83 m (1H), 6.87–6.89 d (J = 9.0 Hz, 1H), 6.93–6.97 m (2H), 7.39–7.41 m (2H), 10.19 s (1H), 10.40 s (1H). MS (ESI), m/z: 401.16, [M + H]+. Found, %: C 62.76; H 6.12; N 6.84. C21H24N2O6. Calculated, %: C 62.99; H 6.04; N 7.00. N'-[2-(3-Methoxyphenyl)acetyl]-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazid (11). mp 158– 161°C. 1H NMR spectrum, δ, ppm: 3.49 s (2H), 3.76 s (3H), 4.27–4.31 m (4H), 6.81–6.82 d (J = 7.5 Hz, 1H), 6.90–6.96 m (3H), 7.22–7.25 m (1H), 7.39–7.44 m (2H), 10.10 s (1H), 10.20 s (1H). MS (ESI), m/z: 343.12, [M + H]+. Found, %: C 63.23; H 5.36; N 8.04. C18 H18N2O5. Calculated, %: C 63.15; H 5.30; N 8.18.

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4-Chlorophenyl 2-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)hydrazinecarboxylate (12). mp 201–204°C. 1H NMR spectrum, δ, ppm: 4.28–4.31 m (4H), 6.96–6.97 d (J = 4.0 Hz, 1H), 7.04–7.07 d (J = 14.5 Hz, 2H), 7.36–7.43 m (4H), 10.19 s (1H), 10.25 s (1H). MS (ESI), m/z: 348.05, [M + H]+. Found, %: C 55.33; H 3.68; N 8.12. C16H13ClN2O5. Calculated, %: C 55.10; H 3.76; N 8.03. N'-(3-Phenylpropanoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (13). mp 175–177°C. 1 H NMR spectrum, δ, ppm: 2.86–2.89 m (2H), 3.35 s (2H), 4.22–4.33 m (4H), 6.94–6.97 d (J = 6.5 Hz, 1H), 7.19–7.31 m (5H), 7.40–7.42 d (J = 9.0 Hz, 2H), 9.86 s (1H), 10.15 s (1H). MS (ESI), m/z: 327.13, [M + H]+. Found, %: C 66.49; H 5.39; N 8.51. C18H18N2O4. Calculated, %: C 66.25; H 5.56; N 8.58. N'-(2-Nitrobenzoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (14). mp 222–226°C. 1H NMR spectrum, δ, ppm: 4.29–4.33 m (4H), 6.97–6.98 d (J = 6.0Hz, 1H), 7.46–7.48 m (2H), 7.76–7.78 m (2H), 7.86–7.90 m (1H), 8.07–8.11 d (J = 18.5 Hz, 1H), 10.57 s (1H), 10.61 s (1H). MS (ESI), m/z: 327.13, [M + H]+. Found, %: C 55.64; H 4.02; N 12.38. C16H13N3O6. C 55.98; H 3.82; N 12.24. N'-(2-Phenoxyacetyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (15). mp 190–193°C. 1H NMR spectrum, δ, ppm: 4.26–4.31 m (4H), 4.64 s (2H), 6.96–7.03 m (4H), 7.31–7.34 m (2H), 7.41–7.42 m (2H), 10.17 s (1H), 10.18 s (1H). MS (ESI), m/z: 329.11, [M + H]+. Found, %: C 62.38; H 5.01; N 8.24. C17H16N2O5. Calculated, %: C 62.19; H 4.91; N 8.53. N'-(2-Chloroacetyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbohydrazide (16). mp 198–202°C. 1H NMR spectrum, δ, ppm: 3.34 s (2H), 4.28–4.31 m (4H), 6.96– 6.99 d (J = 9.0 Hz, 1H), 7.40–7.42 m (2H), 10.30 s (1H), 10.31 s (1H). MS (ESI), m/z: 271.04, [M + H]+. Found, %: C 48.63; H 4.03; N 10.61. C11H11ClN2O4. Calculated, %: C 48.81; H 4.10; N 10.35. N'-(2-Bromoacetyl)-2,3-dihydrobenzol[b][1,4]dioxine-6-carbohydrazide (17). mp 206–208°C. 1H NMR spectrum, δ, ppm: 3.97 s (2H), 4.28–4.31 m (4H), 6.94– 6.97 d (J = 12.5 Hz, 1H), 7.39–7.41 m (2H), 10.31– 10.36 m (2H). MS (ESI), m/z: 314.99, [M + H]+. Found, %: C 41.75; H 3.41; N 9.18. C11H11BrN2O4. Calculated, %: C 41.93; H 3.52; N 8.89. Cell proliferation assay. Antiproliferative activity of the title compounds 1–17 against two cell lines, HELA (human cervical cancer cell) and MCF-7

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(human breast cancer), were evaluated using a standard MTT-based colorimetric assay. Ten thousand corresponding cells per well were seeded into 96-well plates (Corning, New York, USA) and incubated at 37°C, 5% CO2 for 24 h. Then a series of 100 μL of drug-containing media were dispensed into wells to maintain the final concentrations to be 50, 25, 12.5, 6.25, 3.125, and 1.5625 μg/mL. Each concentration was prepared in triplicate. 5-Fluorouracil (Sigma– Aldrich, St. Louis, USA) was used as the positive control. After 48 h of incubation, cell survival was determined by addition of 25 μL of MTT (Sigma– Aldrich, St. Louis, USA) work solution (5 mg/mL MTT dissolved in PBS). After post-incubation at 37°C for 4 h, the medium was discarded and 100 μL of DMSO (Sigma–Aldrich, St. Louis, USA) were added. The plates were then vortexed for 10 min for complete dissolution. The optical absorbance was measured at 570 nm. The data represented the mean of three independent experiments were expressed as mean ± SD. The IC50 value was defined as the concentration at which 50% of the cells could survive. Docking study. The automated docking studies were carried out using Auto Dock version 3.1. A threedimensional grid of interaction energies based on the macromolecular target using the AMBER force field was approached. Then automated docking studies were carried out to evaluate the binding free energy of the inhibitors within the macromolecules. Three-dimensional structures of the aforementioned compounds were constructed using Chem 3D ultra 11.0 software [Chemical Structure Drawing Standard; Cambridge Soft corporation, USA (2009)], then those were energetically minimized by using MOPAC with 100 iterations and minimum RMS gradient of 0.10. The Gasteiger-Hückel charges of ligands were assigned. The crystal structures of MetAP2 (PDB code: 2EA4) complex were retrieved from the RCSB Protein Data Bank (http://www.rcsb.org/pdb/home/home.do). The bound water and ligands were eliminated from the protein, and the polar hydrogens and the Kollmanunited charges were added to the proteins. CONCLUSIONS Seventeen compounds were synthesized and evaluated for their antitumor activity. Compound 10 demonstrated the most potent inhibitory activity for the growth of MCF-7 cells with IC50 of 2.13±0.04 μg/mL, which was somewhat comparable with the positive

control 5-fluorouracil (IC50 = 9.19±0.03 μg/mL). Interaction of the most potent inhibitor 10 with the binding site of MetAP2 was simulated by means of molecular docking. It demonstrated that compound 10 was stabilized by hydrogen bonding interaction with ASN 329. According to the accumulated data, the CDOCKER interaction energy was inversely proportional to the degree of antiproliferation activity. ACKNOWLEDGMENTS This work is granted by Natural Science Foundation of Jiangsu Province (BK20160570) and Jiangsu Planned Projects for Postdoctoral Research Funds (1601041A). REFERENCES 1. Rasool, I., Ahmad, M., Khan, Z.A., Mansha, A., Maqbool, T., Zahoor, A.F., and Aslam, S., Trop. J. Pharm. Res., 2017, vol. 16, no. 3, p. 723. doi 10.4314/ tjpr.v16i3.30 2. Wani, Z.A., Guru, S.K., Subba Rao, A.V., Sharma, S., Mahajan, G., Behl, A., Kumar, A., Sharma, P.R., Kamal, A., Bhushan, S., and Mondhe, D.M., Food Chem. Toxicol., 2016, vol. 87, p. 1. doi 10.1016/ j.fct.2015.11.016 3. Mioc, M., Soica, C., Bercean, V., Avram, S., BalanPorcarasu, M., Coricovac, D., Ghiulai, R., Muntean, D., Andrica, F., Dehelean, C., Spandidos, D.A., Tsatsakis, A.M., and Kurunczi, L., Int. J. Oncol., 2017, vol. 50, p. 1175. doi 10.3892/ijo.2017.3912 4. Bradshaw, R.A., Brickey, W.W., and Walker, K.W., Trends Biochem. Sci., 1998, vol. 23, p. 263. doi 10.1016/S0968-0004(98)01227-4 5. Lu, J.P., Yuan, X.H., Yuan, H.W., Wang, L., Wan, B J., Franzblau, S.G., and Ye, Q.Z., Chem. Med. Chem., 2011, vol. 6, p. 1041. doi 10.1002/cmdc.201100003 6. Griffith, E.C., Su, Z., Turk, B.E., Chen, S., Chang, Y.H., Wu, Z., Biemann, K., and Liu, J.O., Chem. Biol., 1997, vol. 4, p. 461. doi 10.1016/S1074-5521(97)90198-8 7. Hu, X., Addlagatta, A., Lu, J., Matthews, B.W., and Liu, J.Q., Proc. Natl. Acad. Sci. U.S.A., 2006, vol. 103, p. 18148. doi 10.1073/pnas.0608389103 8. Matsuzawa, T., Hasugai, H., and Moriguchi, K., J. Vet. Med. Sci., 1992, vol. 54, p. 1157. doi 10.1292/ jvms.54.1157 9. Selvakumar, P., Lakshmikuttyamma, A., Dimmock J.R., and Sharma, R.K., Biochim. Biophys. Acta, 2006, vol. 1765, p. 148. doi 10.1016/j.bbcan.2005.11.001 10. Hou, Y.P., Sun, J., Pang, Z.H., Lv, P.C., Li, D.D., Yan, L., Zhang, H.J., Zheng, E.X., Zhao, J., and Zhu, H.L., Bioorg. Med. Chem., 2011, vol. 19, p. 5948. doi 10.1016/j.bmc.2011.08.063

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