Design, synthesis and anticancer activity evaluation of aziridine-1,2,3-triazole hybrid derivatives

Article abstract of DOI:10.1515/hc-2017-0144

New 1-aryl-4-[(aziridine-1-yl)diarylmethyl]-5-methyl-1H-1,2,3-triazole derivatives 7a-i were synthesized by a one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)methanols 6a-i derived from 1-aryl-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

Full text of DOI:10.1515/hc-2017-0144

Heterocycl. Commun. 2018; aop
HDoengs-RiugDnon,g*sayndnJitahn-eGusoiWsu and anticancer activity evaluation
of aziridine-1,2,3-triazole hybrid derivatives
https://doi.org/10.1515/hc-2017-0144
Received August 1, 2017; accepted December 19, 2017
Results and discussion
Abstract: New 1-aryl-4-[(aziridine-1-yl)diarylmethyl]-5-me- 1-Aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-tria-
thyl-1H-1,2,3-triazole derivatives 7a–i were synthesized zoles 7a–i were synthesized from diaryl-1H-1,2,3-triazol-4-yl)
by a one-pot reaction of diaryl-(1-aryl-5-methyl-1H-1,2,3- methanols 6a–i. The synthetic route is shown in Scheme 1.
triazol-4-yl)methanols 6a–i derived from 1-aryl-5-me- Details of the synthesis of compounds 6a–i starting with
thyl-1H-1,2,3-triazole-4-carboxylic acids 4a–c. Structures anilines 1 through intermediaries 4 and 5 were described
of compounds 7a–i were confirmed by analysis of pro- in our previous report [19]. Structures of products 7a–i were
ton nuclear magnetic resonance (1H NMR) and carbon-13 deduced by spectral methods. In particular, a strong absorp-
nuclear magnetic resonance (13C NMR), mass spectrometry tion at 3320–3520 cm−1 for a hydroxy group, observed in the
(MS) and infrared (IR) data. The structure of compound 7f infrared (IR) spectra of substrates 6a–i, is absent in the IR
was studied by X-ray diffraction analysis. The anticancer spectra of products 7a–i. The proton nuclear magnetic reso-
activities of compounds 7a–i against human leukemia nance (1H NMR) spectra of compounds 7a–i show signals
HL-60 cells and human hepatoma G2 cells were evaluated. of the aziridine protons at δ 1.80–1.88 and δ 1.15–1.33, as
Some of the compounds are highly active.
expected. The structure of compound 7f was additionally
determined by X-ray diffraction analysis (Figure 3). Com-
pound 7f (CCDC deposit No 775599), C25H24N4, MW 380.48,
Keywords: anticancer; aziridine; human hepatoma G2;
human leukemia HL-60; 1H-1,2,3-triazole.
̅
crystallizes in the triclinic space group P1 with unit cell
parameters aꢀ=ꢀ9.3100(7), bꢀ=ꢀ13.8263(11), cꢀ=ꢀ17.4605(15) Å,
αꢀ=ꢀ107.402(4), βꢀ=ꢀ92.607(4), γꢀ=ꢀ92.829(4)°, Vꢀ=ꢀ2137.8(3) Å3,
Zꢀ=ꢀ4, Dxꢀ=ꢀ1.182 mg/cm3. The final R value was 0.0558.
Introduction
A vast majority of biologically important molecules are
heterocyclic compounds [1–3]. The biological properties
of aziridine-containing compounds such as azicemicins
[4], miraziridine [5, 6], azinomycins [7], ficellomycin
[8], FR-900482 [9] and mitomycins [10] are of significant
interest (Figure 1). In particular, mitomycin C has a broad
activity against a range of tumors and has been applied
clinically since the 1960s. 1,2,3-Triazoles are also phar-
macologically important molecules that show anticancer
[11–13], antibacterial [14, 15], antifungal [16], antiviral [17],
anti-inflammatory and analgesic activities [18] (Figure 2).
However, there is little information describing compounds
containing aziridine and 1,2,3-triazole moieties in one
molecule. Such compounds are the subject of this report.
Conclusions
New 1-aryl-4-[(aziridin-1-yl)diaryl-methyl]-5-methyl-1H-1,2,3-
triazoles 7a–i were synthesized and their anticancer
activities were evaluated. The anticancer activity was
investigated under our previously reported conditions
[20, 21] using the MTT assay. Compounds 7b,c and 7i are
highly active against human leukemia cells and com-
pounds 7c,d, 7f,g inhibit human hepatoma G2 cells.
Experimental
1H NMR spectra were obtained in deuterated chloroform (CDCl3) at
300 MHz. Starting materials 4–6 were synthesized as previously
reported [19].
*Corresponding author: Hong-Ru Dong, School of Chemical
Engineering, Lanzhou University of Arts and Science, Lanzhou
730000, Gansu, P.R. China, e-mail: donghr@luas.edu.cn
Jian-Guo Wu: School of Chemical Engineering, Lanzhou University of
Arts and Science, Lanzhou 730000, Gansu, P.R. China
Synthesis of compounds 7a–i
Dry hydrogen chloride was bubbled through a hot solution of com-
pounds 6a–i (0.04 mol) in benzene (20 mL) in a 50-mL flask equipped
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2ꢀ ꢀH.-R. Dong and J.-G. Wu: Aziridine-1,2,3-triazole hybrid derivatives
N
O
O
OH
O
O
R
H
H
O
N
N
OMe
HO
N
H
N
OH
OH
H
HO
MeO
N
O
O
H
OH
O
H
NH
OH OH
H2N
NH
Azicemicin A: R = H
Azicemicin B: R = Me
Miraziridine
O
O
H
O
O
O
N
H
N
N
O
H2N
OH
O
N
O
H
N
O
O
HN
NH
NH2
O
HO
Azinomycin A
O
Ficellomycin
O
NH2
NH2
O
O
O
O
OH
OH
X
OCH3
N
N R
O
NH
H3C
R
N
Mitomycin A: X = OMe; R = H
Mitomycin C: X = NH2; R = H
FR-900482 R = CHO
FR-66979 R = CH2OH
Figure 1ꢀFused aziridine-containing natural products.
S
O
HO
N
N
S
N
O
F
N
NH
N
N
N
O
N
O
N
O
Figure 2ꢀAnticancer compounds containing 1,2,3-triazole.
with an automatic water separator, a reflux condenser and a calcium 0.39), 428 (6), 426 (6), 154 (32), 152 (100); IR: 3425, 3061, 2987, 2926,
chloride guard-tube. After 1 h, the solution was concentrated to 2844, 1734, 1496, 1442, 1422, 1400, 1264, 1117, 1092, 1010, 922, 867, 829,
+
10 mL and treated with aziridine (0.06 mol) with rapid stirring fol- 818 cm−1. HRMS (ESI). Calcd for C24H19Cl3N4, [Mꢀ+ꢀH] : m/z 469.0748.
lowed by the addition of triethylamine (0.08 mol). After the mixture Found: m/z 469.0755.
was stirred at 45°C for an additional 1 h, the solvent was evaporated
and the residue was crystallized from ethyl acetate or purified by 4-[(Aziridin-1-yl)-bis(3-chlorophenyl)methyl]-5-methyl-1-(4-
column chromatography on silica gel and eluted with ethyl acetate/ chlorophenyl)-1H-1,2,3-triazole (7b)ꢁWhite flakes; yield 65%; mp
1
petroleum ether.
96–98°C; H NMR: δ 7.61 (s, 2H), 7.52 (q, 2H, Jꢀ=ꢀ2.4 Hz), 7.38 (m, 4H),
7.23 (m, 4H), 2.04 (s, 3H), 1.84 (d, 2H, Jꢀ=ꢀ2Hz), 1.17 (d, 2H, Jꢀ=ꢀ2 Hz); 13C
4-[(Aziridin-1-yl)-bis(4-chlorophenyl)methyl]-5-methyl-1-(4- NMR (CDCl3-d1), δ 145.3, 144.8, 135.6, 134.7, 133.7, 133.2, 129.6, 128.9,
+
chlorophenyl)-1H-1,2,3-triazole (7a)ꢁWhite flakes; yield 86%; mp 128.8, 127.4, 127.3, 126.8, 69.5, 21.8, 10.6; MS: m/z 468 (M , 0.71), 428
1
90–92°C; H NMR: δ 7.52 (d, 1H, Jꢀ=ꢀ3 Hz), 7.50 (d, 1H, Jꢀ=ꢀ3 Hz), 7.48 (5), 154 (27), 152 (100), 111 (29), 75 (12); IR: 3449, 3088, 3063, 2990,
(d, 2H, Jꢀ=ꢀ3 Hz), 7.45 (d, 2H, Jꢀ=ꢀ3 Hz), 7.40 (d, 1H, Jꢀ=ꢀ3.6 Hz), 7.37 (d, 2931, 2869, 1734, 1590, 1572, 1496, 1469, 1422, 1368, 1256, 1202, 1148,
1H, Jꢀ=ꢀ3Hz), 7.29 (d, 2H, Jꢀ=ꢀ3 Hz), 7.26 (d, 2H, Jꢀ=ꢀ3.6 Hz), 2.10 (s, 3H), 1120, 1091, 1049, 1006, 978, 940, 893, 875, 845, 785, 753, 728, 699,
+
1.81 (s, 2H), 1.15 (s, 2H); 13C NMR (CDCl3-d1), δ 145.7, 141.6, 135.6, 134.7, 681 cm−1; HRMS (ESI). Calcd for C24H19Cl3N4, [Mꢀ+ꢀH] : m/z 469.0748.
+
133.1, 132.9, 130.4, 129.6, 127.8, 126.8, 69.3, 21.7, 10.6; MS: m/z 468 (M , Found: m/z 469.0751.
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H.-R. Dong and J.-G. Wu: Aziridine-1,2,3-triazole hybrid derivativesꢂ ꢂ3
4-[(Aziridin-1-yl)-bis(3-chlorophenyl)methyl]-5-methyl-1-p-tolyl-
1H-1,2,3-triazole (7e)ꢁWhite needles; yield 82%; mp 103–105°C;
1H NMR: δ 7.65 (s, 2H), 7.42 (m, 2H), 7.30 (s, 4H), 7.22 (m, 4H), 2.42 (s, 3H),
1.95 (s, 3H), 1.85 (d, 2H, Jꢀ=ꢀ2 Hz), 1.18 (d, 2H, Jꢀ=ꢀ2 Hz); 13C NMR (CDCl3-
d1), δ 145.8, 143.8, 139.7, 133.8, 133.7, 133.3, 129.9, 128.9, 128.7, 127.3, 127.2,
COOH
COOEt
N
N
i
H2SO4
EtOH
N
N
H2N Ar1
Me
Me
N
N
Ar1
Ar1
1a–c
4a–c
5a–c
+
125.4, 69.4, 21.8, 21.2, 10.6; MS: m/z 448 (M , 0.54), 406 (5), 133 (10), 132
Ar2
Ar2
Me
Ar2
Ar2
Me
(100), 91 (30), 65 (13); IR: 3449, 3062, 2990, 2923, 2865, 1735, 1590, 1571,
1515, 1469, 1420, 1368, 1256, 1235, 1203, 1179, 1147, 1121, 1102, 1078, 1048,
1010, 939, 883, 826, 785, 754, 729, 698, 682 cm−1; HRMS (ESI). Calcd for
HO
N
N
N
(i) 1. Et2O, PhMgBr
2. NH4Cl, H2O
ii
One-pot
N
N
(ii) 1. Benzene, dry HCl
2. Benzene, aziridine,
Et3N, acetonitrile
+
N
N
C25H22Cl2N4, [Mꢀ+ꢀH] : m/z 449.1294. Found: m/z 449.1301.
Ar1
Ar1
6a–i
7a–i
4-[(Aziridin-1-yl)-diphenylmethyl]-5-methyl-1-p-tolyl-1H-1,2,3-
triazole (7f)ꢁWhite needles; yield 91%; mp 151–152°C; 1H NMR: δ 7.57
(m, 4H), 7.37 (m, 10H), 2.42 (s, 3H), 1.98(s, 3H), 1.82 (d, 2H, Jꢀ=ꢀ2 Hz),
1.22 (d, 2H, Jꢀ=ꢀ2 Hz); 13C NMR (CDCl3-d1), δ 145.7, 143.8, 139.4, 133.9,
132.9, 129.8, 129.1, 127.4, 126.8, 125.5, 69.9, 21.8, 21.2, 10.5; MS: m/z 380
7a: Ar1 = 4-ClC6H4; Ar2 = 4-ClC6H4
7b: Ar1 = 4-ClC6H4; Ar2 = 3-ClC6H4
7c: Ar1 = 4-ClC6H4; Ar2 = Ph
7f: Ar1 = 4-MeC6H4; Ar2 = Ph
7g: Ar1 = Ph; Ar2 = 4-ClC6H4
7h: Ar1 = Ph; Ar2 = 3-ClC6H4
7i: Ar1 = Ar2 = Ph
7d: Ar1 = 4-MeC6H4; Ar2 = 4-ClC6H4
7e: Ar1 = 4-MeC6H4; Ar2 = 3-ClC6H4
+
(M , 1.0), 33 (13), 178 (6), 133 (10), 132 (100), 91 (34), 77 (6), 65 (14);
IR: 3430, 3055, 3021, 2983, 2926, 2864, 1594, 1516, 1488, 1444, 1420,
1387, 1259, 1208, 1181, 1120, 1104, 1031, 1006, 987, 935, 898, 859, 838,
818, 798, 767, 748, 700, 662, 640, 553, 529 cm−1. HRMS (ESI). Calcd for
Scheme 1
+
C24H24N4, [Mꢀ+ꢀH] : m/z 381.2074. Found: m/z 381.2079.
4-[(Aziridin-1-yl)-bis(4-chlorophenyl)methyl]-5-methyl-1-phe-
nyl-1H-1,2,3-triazole (7g)ꢁWhite flakes; yield 90%; mp 83–85°C;
1H NMR: δ 7.52 (m, 5H), 7.47 (m, 2H), 7.42 (m, 2H), 7.29 (m, 2H), 7.26 (s,
2H), 2.05 (s, 3H), 1.82 (d, 2H, Jꢀ=ꢀ3 Hz), 1.16 (d, 2H, Jꢀ=ꢀ3 Hz); 13C NMR
(CDCl3-d1), δ 145.1, 141.9, 136.2, 133.0, 132.9, 130.4, 129.5, 129.4, 127.8,
+
125.6, 69.3, 21.7, 10.6; MS: m/z 434 (M , 0.7), 394 (5), 392 (9), 332 (11),
129 (11), 119 (11), 118 (100), 104 (10), 91 (13), 77 (21), 57 (11); IR: 3429,
3060, 2987, 2955, 2924, 2854, 1595, 1485, 1416, 1398, 1264, 1113, 1092,
1072, 1011, 921, 867, 817, 763, 694, 565, 531 cm−1. HRMS (ESI). Calcd for
+
C24H20Cl2N4, [Mꢀ+ꢀH] : m/z 435.1138. Found: m/z 435.1144.
4-[(Aziridin-1-yl)-bis(3-chlorophenyl)methyl]-5-methyl-1-phe-
nyl-1H-1,2,3-triazole (7h)ꢁWhite flakes; yield 40%; mp 141–143°C;
1H NMR: δ 7.65 (s, 2H), 7.52 (m, 3H), 7.40 (m, 4H), 7.23 (m, 4H), 1.99
(s, 3H), 1.85 (t, 2H, Jꢀ=ꢀ2 Hz), 1.19 (t, 2H, Jꢀ=ꢀ2 Hz); 13C NMR (CDCl3-d1),
δ 145.7, 144.1, 136.2, 133.8, 133.3, 129.5, 129.4, 128.9, 128.7, 127.3, 127.2,
Figure 3ꢀView of the molecular structure of 7f (CCDC, 2005).
+
125.6, 69.4, 21.8, 10.5; MS: m/z 434 (M , 0.3), 176 (5), 118 (100), 77
(69), 5 1 (16); IR: 3429, 3058, 2985, 2926, 2844, 1592, 1571, 1501, 1471,
1265, 1119, 1144, 1120, 1100, 1015, 976, 940, 893, 813, 784, 761, 747, 713,
4-[(Aziridin-1-yl)diphenylmethyl]-5-methyl-1-(4-chlorophenyl)-
1
1H-1,2,3-triazole (7c)ꢁWhite needles; yield 90%; mp 92–94°C; H
+
695 cm−1. HRMS (ESI). Calcd for C24H20Cl2N4, [Mꢀ+ꢀH] : m/z 435.1138.
NMR: δ 7.50 (m, 6H), 7.50 (m, 2H ), 7.26 (m, 6H), 2.08 (s, 3H), 1.80
(s, 2H), 1.19 (d, 2H, Jꢀ=ꢀ2 Hz); 13C NMR (CDCl3-d1), δ 146.6, 143.3, 135.3,
134.9, 132.8, 129.5, 129.2, 127.4, 126.8, 126.7, 69.9, 21.7, 10.5; MS: m/z 400
Found: m/z 435.1145.
4-[(Aziridin-1-yl)-diphenylmethyl]-5-methyl-1-phenyl-1H-1,2,3-
+
(M , 1.2), 358 (11), 178 (5), 154 (32) 152 (100), 11 (26), 77 (8), 75 (11), 51
1
triazole (7i)ꢁWhite needles; yield 89%; mp 203–206°C; H NMR: δ
(5), 43 (7); IR: 3459, 3088, 3059, 2987, 2928, 1738, 1594, 1495, 1445, 1422,
1402, 1371, 1262, 1235, 1202, 1177, 1120, 1090, 1042, 1004, 938, 902, 848,
7.56 (m, 4H), 7.51 (m, 3H), 7.43 (m, 2H), 7.26 (m, 6H), 2.03 (s, 3H), 1.81 (s,
2H), 1.21 (s, 2H); 13C NMR (CDCl3-d1), δ 145.9, 143.6, 136.4, 132.9, 129.3,
+
821, 765, 744, 700, 639 cm−1. HRMS (ESI). Calcd for C24H21ClN4, [Mꢀ+ꢀH] :
+
129.1, 127.4, 126.8, 125.6, 69.9, 21.7, 10.5; MS: m/z 366 (M , 0.4), 324 (8),
m/z 401.1528. Found: m/z 401.1532.
178 (5), 119 (8), 118 (100), 77 (46); IR: 3424, 3070, 3051, 3022, 2988,
2925, 2890, 1594, 1496, 1444, 1416, 1387, 1261, 1207, 1077, 1033, 993, 937,
903, 854, 767, 747, 697, 646, 561 cm−1. HRMS (ESI). Calcd for C24H22N4,
4-[(Aziridin-1-yl)-bis(4-chlorophenyl)methyl]-5-methyl-1-p-
tolyl-1H-1,2,3-triazole (7d)ꢁWhite flakes; yield 89%; mp 86–88°C;
1H NMR: δ 7.48 (m, 4H), 7.28 (m, 8H), 2.43 (s, 3H), 2.00 (s, 3H), 1.80 (d,
2H, Jꢀ=ꢀ2 Hz), 1.15 (d, 2H, Jꢀ=ꢀ2 Hz); 13C NMR (CDCl3-d1), δ 144.8, 142.1,
139.6, 133.7, 133.1, 132.8, 130.3, 129.9, 127.8, 125.4, 69.2, 21.7, 21.1, 10.5;
+
[Mꢀ+ꢀH] : m/z 367.1917. Found: m/z 367.1924.
Biological evaluation
+
MS: m/z 448 (M , 0.52), 406 (8), 152 (22), 133 (11), 132 (100), 125 (7),
111 (12), 97 (8), 91 (11), 83 (12), 74 (11), 55 (15); IR: 3429, 3060, 2987,
2923, 2856, 1517, 1486, 1443, 1421, 1400, 1264, 1205, 1180, 1094, 1011,
The effects of the synthesized compounds on cell viability were inves-
tigated under previously reported conditions with human leukemia
cells and human hepatoma G2 cells [20, 21] using the MTT assay.
+
923, 867, 819, 559 cm−1. HRMS (ESI). Calcd for C25H22Cl2N4, [Mꢀ+ꢀH] : m/z
449.1294. Found: m/z 449.1299.
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4ꢀ ꢀH.-R. Dong and J.-G. Wu: Aziridine-1,2,3-triazole hybrid derivatives
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