SYNTHESIS OF NEW [γ-(ARYL)PYRIDINO]DIBENZO-27,28-DIAZACROWNOPHANES CONTAINING TWO PYRIDINE RINGS Текст научной статьи по специальности «Биотехнологии в медицине»

Crownophanes Краунофаны

Шкрогэтароцмклы

http://macroheterocycles.isuct.ru

Paper Статья

DOI: 10.6060/mhc190231a

Synthesis of New [y-(Aryl)pyridino]dibenzo-27r28-Diazacrownophanes Containing Two Pyridine Rings

Le Tuan Anh,a@ Nguyen T. T. Huyen,a Pham T. T. Tam,ab Nguyen T. Dat,a Truong Hong Hieu,c Tran T. T. Van,a Luong T. M. Hanh,a Anatoly T. Soldatenkov,c and Ayalew T. Wodajod

aFaculty of Chemistry, University of Science, Vietnam National University, 100000 Hanoi, Vietnam

hFaculty of Pharmacy, Thai Nguyen University of Medicine and Pharmacy, 250000 Thai Nguyen City, Vietnam

cPeoples' Friendship University of Russia, 117198 Moscow, Russian Federation

dCollege of Natural and Computational Sciences, University of Gondar, 196 Gondar, Ethiopia

@Corresponding author E-mail: huschemical.lab@gmail.com

In continuation of developing new cytotoxic compounds, six azacrownophanes containing both 2,4,6-triarylpyri-dine and 2,6-bis(phenoxymethyl)pyridine moieties were synthesized successfully by one-step domino-condensation of podand 2,6-bis[(2-acetophenyl)oxymethyl]pyridine, arylaldehydes and ammonium acetate according to the conditions of Hantzsch reactions. The compounds 5a-c were selected for cytotoxicity evaluations against human cell lines (HepG2, Lui, RD, FL and MCF-7). Compound 5b showing the highest cytotoxicity is interesting for the development of promising anticancer drugs.

Keywords: Arylpyridine, cytotoxicity, Hantzsch reaction, azacrownophane.

Синтез новых [у-(арил)пиридино]дибензо-27,28-диазокраунофанов, содержащих два пиридиновых кольца

Л. Т. Ань,а@ Н. Т. Т. Хуен,а П. Т. Т. Там,аЬ Н. Т. Дат,а Т. Х. Хиеу,с Т. Т. Т. Ван,а Л. Т. М. Хань,а А. Т. Солдатенков,с А. Т. Водайой

Факультет химии, Вьетнамский национальный университет, Университет науки, 100000 Ханой, Вьетнам ъФакультет фармации, Университет медицины и фармации Тхайнгуена, 250000 Тхайнгуен, Вьетнам сРоссийский университет дружбы народов, 117198 Москва, Россия

аКолледж естественных и компьютерных наук университета Гондора, 196 Гондор, Эфиопия @Е-таИ: huschemical.lab@gmail.com

В продолжение разработки новых цитотоксических соединений были синтезированы шесть азакраунофанов, содержащих остатки 2,4,6-триарилпиридина и 2,6-бис(феноксиметил)пиридина, путем одностадийной доминоконденсации поданда - 2,6-бис[(2-ацетофенил)оксиметил]пиридина, арилальдегидов и ацетата аммония по реакции Ганча. Для соединений 5а-с была оценена цитотоксичность в отношении клеточных линий человека (HepG2, Ьи1, RD, FL и МСЕ-7). Соединение 5Ь, проявляющее наибольшую цитотоксичность, представляет интерес для разработки перспективных противораковых лекарственных средств.

Ключевые слова: Арилпиридин, цитотоксичность, реакция Ганча, азакраунофаны.

Introduction

Experimental

Drug development is one of the most attractive tasks in medicinal chemistry. In this connection, pharmacophore approaches have become one of the major tools in drug discovery in the previous century. Now a days, several synthetic methods were designed for the development of new medical drugs. Among them, multicomponent condensation reactions (MCR) are highly applicable and important in synthesis of novel molecules due to their significant cost effectiveness and less reaction time. Recent studies have shown that azacrown ethers incorporating y-arylpyridine have brought strong cytotoxicity towards human cancer cell lines: Hepatocellular carcinoma (HepG2), Rhabdosarcoma (RD), Human Uterine (FL), Human Breast adenocarcinoma (MCF7), Human Prostate Cancer (PC3) (Table 1).[1-4]

The present research is focused on synthesis of an effective pharmacophores - 2,4,6-triarylpyridine and 2,6-diphenoxymethylpyridine. The combination of polyarylpyridine and azacrownophane is promising to bring a novel class of bioactive compounds. To be specific, novel [(y-aryl)pyridino]dibenzodiazacrownophanes with a y-arylpyridine subunit (5a-f) were synthesized via the domino-type condensation of three components: 2,6-bis[(2-acetophenyl)oxymethyl]pyridine (3), ammonium acetate and arylaldehyde derivatives.

The structure of the synthesized compounds was confirmed by the physico-chemical methods, such as IR, 'H NMR, 13C NMR, LCMS and HRMS. The bioactivity of all synthesized compounds was predicted by PASS[5] and some of the selected compounds (5a-c) were evaluated in vitro for their cytotoxicity against human cancer cell lines.

Reagents purchased from commercial sources (Sigma-Aldrich) were used without any additional purification. Melting points were determined in open capillary tubes on a digital Stuart SMP3 apparatus. Elemental analysis was conducted on Euro Vector EA-3000 analyzer. IR spectra were recorded in FTIR Affinity - 1S SHIMADZU. 'H and 13C NMR spectra were recorded in CDCl3 solutions at 25 °C, using a BRUKER 500 MHz NMR spectrometer at VNU University of Science and TMS as internal standard and chemical shifts are given in parts per million (5). Signal of the residual protons of the solvent (7.26 ppm for CHCl3) was used as the reference in 'H NMR spectra, while solvents signals (77.2 ppm for CDCl3) was used as the reference in 13C NMR spectra. Mass spectra were recorded on LTQ Orbitrap XL using electrospray ionization source and on instruments Finnigan MAT 95 XL (EI, ionizing energy 70 eV) at VNU University of Science.

Compound 2,6-bis(tosyloxymethyl)pyridine (2) was synthesized based on the method described earlier.[6]

Synthesis of 2,6-bis[(2-acetophenyl)oxymethyl]pyridine (3). A solution of 1.37 g (3.00 mmol) 2,6-bis(tosyloxymethyl)pyridine (2), 1.00 ml (8.30 mmol) 2'-hydroxyacetophenone and 2.00 g (14.50 mmol) K2CO3 in 10.00 ml acetonitrile was heated to reflux for 16 h. After that the mixture was cooled at ambient temperature, 500 ml ice water (0-4 °C) was added, then a slightly pink precipitate appeared. The precipitate was filtered by Buchner funnel, dried and recrystallized in ethanol to collect a white crystalline solid (3) (1.00 g, 88 %). M.p. 85-87 oC, R = 0.33 (n-hexane/ethyl acetate = 1/1). Found (%): C 73.83, H 5.34, N 3.53. Calcd. for C23H21NO4 (%): C 73.58, H 5.64, N 3.73. LCMS (m/z): 376 [M+H]+, 398 [M+Na]+. IR (KBr) vmax cm-1: 1664 (C=O), 1595 (C=N), 1236 (C-O-C), 1450.47, 1485.19,m1595.13 (C=Caryl). 1H NMR (500MHz, CDCl3, TMS) 5H ppm: 2.67 (s, 6H, 2xCH3); 5.31 (s, 4H, 2x-OCH2-); 6.99 (d, 2H, J = 8.0 Hz, H4, H4); 7.03 (t, 2H, J = 7.5 Hz, H2, H2); 7.44 (t.d, 2H, J = 8.5 Hz, 2.0 Hz, H3, H3); 7.74 (d.d, 2H, J = 8.0 Hz, 2.0 Hz, H1, H1); 7.48 (d, 2H, J = 7.5 Hz, №.„.), 7.81 (t, 1H, J = 8.0 Hz, Hy ... ).

v ' ' ' pyridine7' v ' ' ' pyridine7

General method for synthesis of [g-(phenyl)pyridino]diben-zodiazacrownophanes (5a-f). Equimolar amounts of 2,6-bis[(2-acetophenyl)oxymethyl]pyridine (3) (0.5 g, 1.30 mmol), aromatic aldehyde (4a-f) [1.30 mmol, 0.177 g (4a), 0.177 g (4b), 0.196 g (4c), 0.159 g (4d), 0.241 g (4e), 0.146 g (4f)] and ammonium acetate (5.00 g, 65.00 mmol) were refluxed in acetic acid (10 ml) for 11 hours (the reaction was monitored by TLC). The mixture was allowed to cool to room temperature and neutralized with sodium carbonate solution; then, the product was extracted with ethyl acetate (4x30 ml), dried over Na2SO4. After filtration, the solvent was evaporated in vacuo; the residue was first purified by column chromatography with a gradient elution of ethyl acetate/n-hexane affording the white solid which was then recrystallized from etha-nol to obtain the pure azacrownophane product.

Table 1. Cytotoxicity on the human cancer cell lines.

No

R

Cell lines (IC50 - ^g/ml)

RD

HepG2

MCF7

FL

PC3

Lui

1 2-OH 1 1.89 - - - N/A N/A

2 4-Cl 1 1.46 2.79 4.56 1.51 N/A N/A

3 3-Br 1 4.11 4.37 1.98 N/A 4.06 -

4 3-NO2 1 - - 4.78 N/A - -

5 4-Me 2 2.56 2.61 N/A 1.39 N/A 2.66

6 4-OH 2 6.89 7.96 N/A 6.74 N/A 6.95

7 2-OMe 2 7.53 6.59 N/A - N/A 7.90

n

All the compounds 5a-f are new and their structures were characterized by usual spectroscopic methods.

a) 25-(4-Methoxyphenyl)-8,16-dioxa-27,28-diazapentacyclo [21.3.1.11014.027.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27)-dodecaene (5a). Yield: 0.43 g (70 %), white crystals. M.p. 138-140 °C (from EtOH). Rf = 0.38 (EtOAc:MeOH = 5:1). HRMS (ESI) m/z: 473.1865 [M+H]+. Calcd. for C31H25N2O3+ m/z: 473.1860. IR (KBr) vmax cm-1: 1253 (C-O-C), 1444, 1597 (C=C ). 1H NMR (500 MHz, cba3, TMS) 5H ppm: 3.85 (s, 3H, -OCH3);y 5.12 (s, 4H, 2x-OCH-); 6.95 (d, 2H, J = 9.0 Hz, HA, HA' „ ,); 7.03 (d, 2H,

2 v ' ' ' ' methoxyphenyl7' v ' '

J = 7.5 Hz, H6, H18); 7.07 (t.d, 2H, J = 7.5 Hz, 0.5 Hz, H4, H20); 7.16 (d, 2H, J = 8.0 Hz, H5, H19); 7.35-7.40 (m, 4H, H^,H\3,H° H21); 7.45 (s, 2H, H^24, Hp26); 7.44 (m, 1H, №12); 7.61 (d, 2H, J= 8.5 Hz, HB, HB' t. . . ). 13C NMR (125 MHz, CDCl3, TMS) 5 ppm:

5 methoxyph enyl' v 5 35 / c

55.35, 73.31, 114.31, 116.29, 120.73, 121.75, 121.99, 128.35, 129.40, 130.64, 130.75, 133.76, 136.41, 155.97, 156.64, 157.44.

b) 25-(2-Methoxylphenyl)-8,16-dioxa-27,28-diazapentacyclo [21.3.1.11014.027.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27)-dodecaene (5b). Yield: 0.38 g (62 %), white crystals. M.p. 142-144 oC (from EtOH). Rf = 0.42 (EtOAc:MeOH = 5:1). LCMS m/z: 473 [M+H]+. HRMS (ESI) m/z: 473.1320 [M+H]+. Calcd. for C„H„N,O,+ m/z: 473.1860. IR (KBr) v cm-1: 1244.09 (C-O-C),

31 25 2 3 v ! max v

1446.61, 1597.06 (C=Caryl). 1H NMR (500 MHz, CDCl3, TMS) 5H ppm: 3.81 (s, 3H, -OCH3); 5.13 (s, 4H, 2x-OCH2-); 6^5 (d, 1H, J = 8.5 Hz, H3' .. „ ,); 7.00-7.07 (m, 5H, H5' fh „ ,, H , H,

' methoxyphenyl7' v ' ' methoxyphenyP 4' 5'

H19, H20); 7.15 (d, 2H, J = 8.5 Hz, H6, H18); 7.32-7.37 (m, 3H, H^ HL, H4' th h ,); 7.39-7.42 (m, 3H, H3, H21, H6' th h ,); 7.46 (t,

13' methoxyphenyP v ' ' V 21' methoxyphenyl7' v '

1H, J = 7.5 Hz, H12); 7.48 (s, 2H, H^24 H^26). 13C NMR (125 MHz, CDCl3, TMS) 5c ppm: 55.58, 73.10, 111.33, 116.15, 120.93, 121.73, 121.89, 123.86,c 128.01, 129.26, 129.75, 130.84, 130.91, 133.85, 136.38, 155.96, 156.55, 156.69.

c) 25-(3-Nitrophenyl)-8,16-dioxa-27,28-diazapentacyclo [21.3.1.11014.027.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27)-dodecaene (5c). Yield: 0.48 g (74 %), white crystals. M.p. 249-250 °C (from EtOH). Rf = 0.50 (EtOAc:MeOH = 5:1). Found (%): C 73.63, H 4.54, N 8.55. Calcd. for C30H21N3O4 (%): C 73.91, H 4.34, N 8.62. LCMS m/z: 488 [M+H]+. IR (KBr) vmax cm-1: 1251 (C-O-C), 1379, 1597 (C=C ), 1503, 1398 (C-NO2) 1H NMR (500 MHz, CDCl3, TMS) 5H ppm: 5.12 (s, 4H, 2x-OCH2-); 7.03 (d, 2H, J = 8.0 Hz, H6, H18); 7.10 (t, 2H, J = 7.5 Hz, H4, H20); 7.20 (d, 2H, J = 8.0 Hz, H5, H19); 7.38-7.42 (m, 4H, H^, H\3,H^ H21); 7.45 (t, 1H, J = 8.5 ^ H5nitrophenyl); 7.53 (s, 2H, H^ №26); 7.63 (t, 1H, J = 8.0 Hz, Hy12), 8.00 (d, 1H, J = 7.5Hz, H6nitrophenyl); 8.27 (d, 1H, J = 8.0 Hz, H4 , h ,); 8.52 (s, 1H, H2, „ ,)ni"" e"y

' nitropheny^^' v ' ' nitrophenyl7

d) 25-(4-Methylphenyl)-8,16-dioxa-27,28-diazapentacyclo [21.3.1.11014.027.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27)-dodecaene (5d). Yield: 0.45 g (76 %), white crystals. M.p. 158-160 °C (from EtOH). Rf = 0.24 (EtOAc:Aceton = 5:1). Found (%): C 81.83, H 5.16, N 6.35. Calcd. for C31H24N2O2 (%): C 81.56, H 5.30, N 6.14. HRMS (ESI) m/z: 457.1965 [M+H]+, 479.1317 [M+Na]+. Calc. for C31H25N2O2+: 457.1911. IR (KBr) vmax cm-1: 1047, 1249 (C-O-C), 1448, 1597, (C=C ). 1H NMR ^"(TMHZ, CDCl3, TMS) 5H ppm: 2.32 (s, 3H, -CH3);y 5.05 (s, 4H, 2x-OCH2-); 6.95-7.70 (m, 14H, Harom); 7.41 (s, 2H, H?24, H?26); 7.90 (m, 1H, HY12).

e) 25-(3-Bromophenyl)-8,16-dioxa-27,28-diazapentacyclo [21.3.1.11014.027.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27)-

dodecaene (5e). Yield: 0.41 g (60 %), white crystals. M.p. 205-207 °C (from EtOH). Rf = 0.36 (EtOAc:MeOH = 5:1). Found (%): C 68.87, H 4.35, N 5.68. Calcd. for C3()H21BrN2O2 (%): C 69.11, H 4.06, N 5.37. LCMS m/z: 521 [M+H]+(Bi,=79)find 523 [M+H]+(Br=79). IR (KBr) vmax cm-1: 1051, 1245 (C-O-C),' 1450, 1588 (C=C ). 1H NMR (500 MHz, CDCl3, TMS) 5H ppm: 5.15 (s, 4H, 2x-OCH2-); 7.07-7.62 (m, 15H, H , H12); 7.83 (s, 2H, HL HL).

' ' arom' 127' ' ' 24, 267

f) 25-(2-Thienyl)-8,16-dioxa-27,28-diazapentacyclo[21.3.1. jio, 14.02,7.01722]octacosa-2,4,6,10,12,14,17,19,21,23,25,1(27) -dode-caene (5f). Yield: 0.45 g (77 %), white crystals. M.p. 158-160 °C (from EtOH). Rf = 0.23 (EtOAc). Found (%): C 75.23, H 4.34, N 6.56. Calcd. for C28H20N2O2S (%): C 74.98, H 4.49, N 6.25. LCMS m/z: 449 [M+H]+. IR (KBr) vmax cm-1: 1161, 1408, 1593 (C=C ). 1H NMR (500 MHz, CDCl3, •flVIS) 5H ppm: 5.11 (s, 4H); 7.061(1, 2H, J = 8.0 Hz, H6, H18); 7.1(5 (d, 2H, J= 8.0 Hz, H5, H19); 7.04-7.10 (m, 3Hthienyl); 7.36-7.46 (m, 7H, H3, H4, HM, H21, H^, №n), 7.47

(s, 2H, HM>M).

Cytotoxicity Assay

Five human cancer cell lines were obtained from the American Type Culture Collection (Manassas, VA) ATCC as FL (human cervix carcinoma), Rb (human rhabdomyosarcoma), Lu1 (human lung adenocarcinoma), HepG2 (human hepatocellular carcinoma), MCF-7 (Human breast adenocarcinoma). The cells were grown in DMEM (bulbecco's Modified Eagle Medium) supplemented with L-glutamine, Sodium pyruvate, NaHCO3, PSF (Penicillin - Streptomycin sulfate - Fungizone); NAA (Non-Essential Amino Acids); 10 % BCS (Bovine Calf Serum). All incubations were performed at 37 oC for 72 hours in a CO2 (5 %) incubator with the plates capped in the normal fashion.

The MTT is based on the protocol described by Skehan & etc. (1990)[7] and Likhiwitayawuid & etc. (1993).[8] This method has worldwide application and recommended by National Cancer Institute (NCI) and College of Medicine, University of Illinois at Chicago for routine drug screening.

Results and Discussion

The parent compound (3) was effectively prepared from 2'-hydroxyacetophenone and 2,6-bis(tosyloxymethyl) pyridine (2) by using a known procedure[6] (Scheme 1).

The structure of 2,6-bis[(2-acetophenyl)oxymethyl] pyridine (3) was confirmed by IR and 'H NMR spectra. More precise, IR spectrum showed a strong signal of C=O at 1664.57 cm-1. In NMR spectrum, the product gave two sharp signals assignable to six protons of the methyl group at 5 = 2.67 ppm (s, 6H, 2xCH3) and to four protons of ether group at 5 = 5.31 ppm (s, 4H, 2x-OCH2-). Signals of eight protons of aromatic rings were corresponded to ABCD system at 5 = 6.99-7.75 ppm and three signals of pyridine protons at 5 = 7.48 ppm (2№ ) and 5 = 7.81 ppm (HY ... ).

A A v pyridine' A A v pyridine'

In this study, we continue to develop new compounds possessing both the polysubstituted pyridine and ether frag-

OH OH

+ 2TsCl

OTs OTs +2 r^

(1)

NaOH, THF/H20, -5 —*-0°C

OH

K2C03, MeCN 3

(2)

Scheme 1. Synthesis of podand 2,6-bis[(2-acetophenyl)oxymethyl]pyridine (3).

Scheme 2. Synthesis of new [g-(aryl)pyridino]dibenzo-27,28-diazacrownophanes (5a-f).

ments. The synthesis of novel dibenzodiazacrownophane with two pyridine subunits (5a-f), via a domino-type condensation of three components - 2,6-bis[(2-acetophenyl) oxymethyl]pyridine (3), benzaldehyde derivatives (4a-f) and ammonium acetate, is proposed (Scheme 2). The reactions take place with good yields 60-77 % depending on the type of starting benzaldehydes (4a-f) used in the reaction.

The structures of all synthesized compounds were confirmed by spectral data (IR, NMR and MS). All [g-(aryl) pyridino]dibenzo-27,28-diazacrownophanes (5a-f) contained charactisitic peaks of singlet signal (4H, 2*-OCH2-) in 5 = 5.05-5.15 ppm region and singlet signal of two ¿^-protons (H24, H26) in 5 = 7.41-7.83 ppm region of the 1H NMR spectrum. For example, the 1H NMR spectrum of [ y-(4-methoxyphenyl)pyridino]dibenzo-27,28-diazacrownophane (5a) showed two singlets at 5 = 3.85 ppm and 5.12 ppm which are assigned to the three protons of methyl groups (s, 3H, -OCH3) and to the four protons of two methylene groups (s, 4H, 2*-OCH2-), respectivelly. Two ¿^-protons of g-(methoxyphenyl)pyridine subunit (H24, H26) appeared as a singlet signal at 7.45 ppm in the 'H NMR spectrum. The spectrum of 13C NMR and HRMS (473.1865 [M+H]+) also indicated the suitable structure of proposed [y-(4-methoxyphenyl)pyridino]dibenzo-27,28-diazacrownophane (5a) (see Experimental part). Protons of methoxyphenyl fragment appears as two doublets in system AABB at 5 = 6.95 ppm and 7.61 ppm.

PASS[6] was used to evaluate the general bioactivity potential of an organic drug-like molecule. Therefore, computer-aided drug discovery program was applied to predict the biological activities of synthesized compounds before in vitro testing (Table 2).

The selected synthesized compounds (5a-c) were evaluated in vitro for their biological activity against five human tumor cell lines: FL (human cervix carcinoma), RD (human rhabdomyosarcoma), Lu1 (human lung adeno-carcinoma), HepG2 (human hepatocellular carcinoma) and MCF-7 (human breast adenocarcinoma). The bioactivi-

Table 2. Prediction of several bioactivities of compounds (5a-f) by PASS program (Pa > 70 %).

Compound Predicted activities Pa (%)

Aspulvinone dimethylallyltransferase inhibitor 87.5

Gluconate 2-dehydrogenase (acceptor) inhibitor 83.2

5a Nitrate reductase (cytochrome) inhibitor 74.7

Chlordecone reductase inhibitor 72.5

Taurine dehydrogenase inhibitor 72.2

4-Nitrophenol 2-monooxygenase inhibitor 71.1

5b Aspulvinone dimethylallyltransferase inhibitor 82.8

Gluconate 2-dehydrogenase (acceptor) inhibitor 79.5

Acrocylindropepsin inhibitor 78.9

Chymosin inhibitor 78.9

5c Saccharopepsin inhibitor 78.9

Ubiquinol-cytochrome-c reductase inhibitor 75.9

Hyponitrite reductase inhibitor 75.2

Lysase inhibitor 70.3

Nitrate reductase (cytochrome) inhibitor 84.1

5d CYP2B5 substrate 73.6

Aspulvinone dimethylallyltransferase inhibitor 74.2

Membrane permeability inhibitor 71.2

5e Aspulvinone dimethylallyltransferase inhibitor 85.2

5f CYP2A6 inhibitor 73.5

Anaphylatoxin receptor antagonist 74.4

ties of synthesized compounds towards human cancer cell lines are shown in Table 3. Azacrown ether 5a showed positive results in cytotoxicity test against HepG2, Lu1 and RD cell lines. The similar synthesized compound 5c exhibited potent cytotoxicity only against HepG2 cell lines. Compound 5b containing g-(2-methoxyphenyl)pyridine showed significant activity against four cancer cell lines (HepG2, Lu1, RD and MCF-7). Based on these results,

Table 3. Cytotoxicity tests performed on compounds 5a-c in human cancer cell lines.

Entry Conc. (p.g/ml)

Cell line, cell survival (%)

HepG2

Lu1

RD

FL

MCF-7

Conclusion

DMSO Taxol(+) 5a 5b 5c

0.5% 5 10 10 10

100 3.46 ± 0.28 48.63 ± 1.47 32.23 ± 2.2 35.69 ± 0.5

100 2.14 ± 0.3 36.49 ± 1.33 30.18 ± 2.24 91.01 ± 1.3

100 3.28 ± 0.31 47.21 ± 1.33 12.01 ± 2.14 51.95 ± 0.4

100 0 N/A N/A 80.18±0.3

100 5.01 ± 0.95 60.83 ± 1.26 39.64 ± 2.78 N/A

+ (03 cell lines) + (04 cell lines) + (01 cell lines)

Table 4. Results of ICc„ test.

Entry

HepG2

Cell lines IC50 (ng/ml)

Lu-1

RD

MCF-7

Conclusion

Taxol (+)

5a 5b 5c

0.275 10.86 1.15 8.983

0.48 3.32 1.41

0.25 6.92 3.28

0.47

2.47

+ (03 cell lines) + (04 cell lines) + (01 cell lines)

+

[g-(aryl)pyridino]dibenzo-27,28-diazacrownophanes (5a-c) were selected for further evaluation on IC50 test.

To investigate the effectiveness of 5a-c in inhibiting cancer cell lines, inhibitory tests (IC50) were conducted. The synthesized compound 5c exhibited potent cyto-toxicity against the HepG2 cell line with an IC50 value of 8.983 ^g/ml (equivalent 18.441 3 ^M). The analogue 5a inhibited the HepG2, Lu1 and RD cell lines with IC50 values of 10.86 ^g/ml (equivalent 23.0040 3 ^M), 3.32 ^g/ml (equivalent 7.0340 3 ^M), 9.92 ^g/ml (equivalent 21.0110 3 ^M), respectively. Azacrownophane 5b showed the highest activity against all of four human cell lines in IC50 test with the value in the 1.15-3.28 ^g/ml (equivalent (2.44-6.95)40 3 ^M) (Table 4).

Conclusion

In conclusion, a number of [g-(aryl)pyridino]dibenzo-27,28-diazacrownophanes containing two pyridine rings have been successfully synthesized through the domino one-pot reaction of a new parent compound 2,6-bis[(2-acetophenyl)oxymethyl]pyridine. Diazacrownophane 5b showed significant cytotoxic activity against human cancer HepG2, Lu1, RD and MCF-7 cell lines whereas the similar synthesized compound 5a possessed cytotoxicity against HepG2, Lu1, RD cell lines. Compound 5c exhibited cyto-toxicity only against HepG2 cell line.

Acknowledgements. This research was funded by the Vietnam National University, Hanoi (VNU), under grant number TN.18.11.

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Received 21.02.2019 Accepted 16.05.2019

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