Synthesis of new derivatives of 3-aryl-1,5-dimethyl-1H-[1,2,4] triazolo[4′,3′:1,2]pyrimido[4,5-e][1,3,4]oxadiazines as potential antiproliferative agents

Article abstract of DOI:10.1002/jhet.509

Starting from pyrimido[4,5-e][1,3,4]oxadiazines (3a-c), a synthetic pathway to [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5-e][1,3,4]oxadiazines (5a-i) is described. The reaction of pyrimido[4,5-e][1,3,4]oxadiazines (3a-c) with hydrazine hydrate afforded the co

Full text of DOI:10.1002/jhet.509

January 2011
Synthesis of New Derivatives of 3-Aryl-1,5-dimethyl-1H-
[1,2,4]triazolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazines as
Potential Antiproliferative Agents
183
Mehdi Bakavoli,a* Mohammad Rahimizadeh,a Ali Shiri,a Marzieh
Akbarzadeh,a Seyed-Hadi Mousavi,b,c Zahra Tayarani-Najaran,b
Hoda Atapour-Mashhad,c,d and Mohsen Nikpoure
aDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436
Mashhad, Iran
bDepartment of Pharmacology and Pharmacological Research Centre of Medicinal Plants,
School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
cMedical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
dDepartment of Chemistry, Payam Noor University (PNU), Mashhad, Iran
eDepartment of Chemistry, School of Sciences, Islamic Azad University, Ahvaz Branch, Ahvaz, Iran
*E-mail: mbakavoli@yahoo.com
Received March 3, 2010
DOI 10.1002/jhet.509
Published online 7 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
Starting from pyrimido[4,5-e][1,3,4]oxadiazines (3a-c),
a synthetic pathway to [1,2,4]triazo-
lo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazines (5a-i) is described. The reaction of pyrimido[4,5-
e][1,3,4]oxadiazines (3a-c) with hydrazine hydrate afforded the corresponding hydrazino derivatives
(4a-c). Further treatment of these compounds with different orthoesters in acetic acid gave the corre-
sponding [1,2,4]triazolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazines (5a-i). Compound (3a) and (5b), as
examples, were tested on different cancer cell lines including HeLa, MCF-7, and HepG2. Malignant
cells were cultured in DMEM medium and incubated with different concentrations of the titled com-
pounds. Cell viability was quantitated by MTT assay.
J. Heterocyclic Chem., 48, 183 (2011).
INTRODUCTION
well as other oxidative reagents like chloramines T [15],
iodobenzene diacetate [16,17], iron(III) chloride [18],
and CuCl2 [19]. The synthesis of 1,2,4-triazoles through
electrochemical method [20] have also been reported.
Various triazole derivatives have also been prepared
through conversion of iminophosphoranes into triazolo-
pyrimidines by initial aza-Wittig reaction between the
iminophosphoranes and isocyanate giving a carbodimide
as intermediate, which easily undergoes ring closure
[21]. Likewise triazoles have been synthesized by reflux-
ing various substituted hydrazonoyl chlorides in the
presence of Et3N for a long time [22] or by treatment
of 2-thioxo-1,3,6-trihydropyrimidine-5-carboxylate with
appropriate hydrazonoyl halides in boiling CHCl3 [23].
In continuation of our studies towards the synthesis of
fused heterocycles of biological importance containing py-
rimidine [24] and oxadiazine [25] moieties, we describe here
the synthesis of some new derivatives of 3-aryl-1H-[1,2,4]tri-
azolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazine (5a-i).
Pyrimidine derivatives and heterocyclic annulated
pyrimidines continue to attract great interest because of
the wide variety of interesting biological activities
observed for these compounds, such as anticancer [1],
antiviral [2], antitumor [3], and anti-inflammatory activ-
ities [4]. Moreover, triazoles and especially fused tria-
zoles are an important class of heterocyclic compounds
with antifungal [5], bactericidal [5,6], anxiolytic [7,8],
anticonvulsant [9], herbicidal [10], and antidepressants
activities [11]. Keeping this in view, it was thought
worthwhile to synthesize the title compounds wherein
the biologically active 1,2,4-triazole moieties are fused
to potent, pyrimido[4,5-e][1,3,4]oxadiazine ring at 6,7
positions.
Numerous methods for the synthesis of 1,2,4-triazoles
have been reported in the literature, which includes uti-
lizing toxic reagents such as phosphorus oxychloride
[12], lead tetraacetate [12,13], and bromine [13,14] as
C
V
2010 HeteroCorporation

184
M. Bakavoli, M. Rahimizadeh, A. Shiri, M. Akbarzadeh, S.-H. Mousavi, Z. Tayarani-Najaran,
H. Atapour-Mashhad, and M. Nikpour
Vol 48
Scheme 1
RESULTS AND DISCUSSION
bovine serum, 100 units/mL penicillin, and 100 lg/mL
streptomycin. Cells were seeded overnight, and then
incubated with various concentrations of different
extracts for 24 h and 48 h.
For MTT assay, cells were seeded at 5000 cell/well
onto 96-well culture plates. For assay of apoptosis, cells
were seeded at 100,000 cell/well onto a 24-well plate.
For each concentration and time course study, there was
a control sample which remained untreated and received
the equal volume of medium.
The cell viability was determined using a modified 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT)
assay [27,28]. Briefly, cells were seeded (5000 cell/well)
onto flat-bottomed 96-well culture plates and allowed to
grow 24 h followed by treatment with a typical heterocy-
clic derivative (5b). After removing the medium, cells
were labeled with MTT solution (5 mg/mL in PBS) for 4 h
and resulting formazan was dissolved in DMSO (100 lL).
The absorption was measured at 570 nm (620 nm as a ref-
erence) in an ELISA reader.
Chemistry. 5-Bromo-2-chloro-6-methyl-4-(1-methylhy-
drazino)pyrimidine (2) was prepared from the reaction of 5-
bromo-2,4-dichloro-6-methyl pyrimidine (1) with methyl
hydrazine according to our previous published method [26].
Treatment of the latter compound with aromatic acyl halides
in the presence of K2CO3 in boiling acetonirile afforded the
pyrimido[4,5-e][1,3,4]oxadiazines (3a-c). Subsequent reaction
of these compounds with hydrazine led to the replacement of
the chorine atom to give the hydrazino derivatives quantita-
tively (4a-c). The latter products subsequently under-
went cyclocondensation with triethylorthoesters in boiling
acetic acid to give the desired tricyclic [1,2,4]triazolo
[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazines (5a-i). (Scheme 1)
The structural assignment of compounds (5a-i) is based upon
spectroscopic and microanalytical data. For example, the
1H-NMR spectrum of (5b) did not show the NH2 and NH
signals of the precursor (4a) at d 3.8 and 5.8 ppm, but
1
instead showed a sharp H signal at d 8.3 ppm belonging
To investigate the potential antitumor activities of fused
heterocyclic compounds with pyrimidooxadiazine moiety,
compound (3a) and (5b), as example, were selected and
tested for their antiproliferative activities in HeLa cell line.
Structural changes at the C-7 and the addition of a triazole
ring on pyrimido [4,5-e][1,3,4] oxadiazines appear to have
a considerable effect on the biological activity. This may
indicate that triazole ring is a crucial component of the
antiproliferation pharmacophore.
to the triazole ring indicating the formation of the tricyclic
compound (5b). The IR spectrum was devoid of the NH2
and NH absorption bands at m ¼ 3360, 3335, and 3260
cmꢀ1 of the precursor. The mass spectrum of (5a) showed
a molecular ion peak at m/z ¼ 294 (Mþ) corresponding to
the molecular formula C15H14N6O.
Pharmacology. HeLa, MCF-7 and HepG2 were
obtained from Pasteur Institute (Tehran, Iran) and main-
tained at 37ꢁC in a humidified atmosphere (90%) con-
taining 5% CO2. Cell lines were cultured in Dulbecco’s
modified Eagle’s medium (DMEM) with 5% (v/v) fetal
To further improve the antiproliferative activity, our
effort was focused on determining the effect of the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis of New Derivatives of 3-Aryl-1,5-dimethyl-1H-[1,2,4]triazolo[40,30:1,2]-
pyrimido[4,5-e][1,3,4]oxadiazines as Potential Antiproliferative Agents
185
spectra were scanned on a Varian Mat CH-7 at 70 eV. Elemental
analysis was performed on a Thermo Finnigan Flash EA micro-
analyzer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
(MTT), were purchased from Sigma (St. Louis, MD). RPMI and
FCS were purchased from Gibco (Grand Island, NY). General
procedure for the synthesis of 3-aryl-7-chloro-1,5-dimethyl-1H-
pyrimido[4,5-e][1,3,4]oxadiazine (3a-c).
To a magnetically stirred solution of 5-bromo-2-chloro-6-
methyl-4-(1-methylhydrazino)pyrimidine(2) (1 mmol, 0.25 g) and
an appropriate acyl halide (1 mmol) in dry acetonitrile (20 mL),
K2CO3 (2 mmol, 0.28 g) was added and stirred at room tempera-
ture for 1 h. Then, the mixture was refluxed for 6–7 h and the pro-
gress of the reaction was monitored by TLC using petroleum
ether: ethylacetate (7:3). After the completion of the reaction, the
mixture was cooled and the solvent was removed under reduced
pressure. Water (5 mL) was added to the resulting precipitate, and
the mixture was neutralized by 0.1N HCl solution. The crude
solid was filtered and recrystallized from ethanol: water.
Figure 1. Dose-dependent growth inhibition of HeLa cells by compounds
3c and 5b (62.5 to 250 lM) for 24 h. Viability was quantitated by MTT
assay. The dose inducing 50% cell growth inhibition (IC50) against HeLa
was calculated 106.3 lM. Results are Mean 6 SEM (n ¼ 3). *P < 0.05,
**P < 0.01, and ***P < 0.001 compared with control (C).
7-Chloro-1,5-dimethyl-3-phenyl-1H-pyrimido[4,5-e][1,3,4]oxa-
diazine (3a). yield ¼ 70%, mp ¼ 156–157ꢁC, 1H-NMR (CDCl3,
ppm) d 2.22 (s, 3H, CH3-pyrimidine), 3.21 (s, 3H, CH3AN), 7.1–
7.8 (m, 5H, phenyl); ir (KBr disc) m 3010, 2950, 1154 cm–1
(CAO), ms (m/z) 274 (Mþ), 276 (Mþ þ 2). Anal. Calcd. for
C13H11ClN4O: C, 56.84; H, 4.04; N, 20.39; Found: C, 55.48; H,
3.20; N, 21.97.
triazole ring. Therefore, the tricyclic compound (5b)
was also evaluated for its inhibitory activity on HepG2
and MCF-7 cell lines.
7-Chloro-1,5-dimethyl-3-(4-methylphenyl)-1H-pyrimido[4,5-
1
e][1,3,4]oxadiazine (3b). yield ¼ 60%, mp ¼ 150–151ꢁC, H-
Cytotoxicity of compound (5b) was examined on malig-
nant cell lines. At first, malignant cells were incubated with
various concentrations of (5b) (25–400 lM) for 24 h. The
result showed compound (5b) decreased cell viability of
cells as a concentration-dependent manner. The toxicity
started as little as 50 lM and during the 24 h, the dose
inducing 50% cell growth inhibition (IC50) against HeLa,
MCF-7 and HepG2 were calculated 106.3, 555.8, and
294.1 lM, respectively (Figs. 1 and 2).
NMR (CDCl3, ppm) d 2.23 (s, 3H, CH3-pyrimidine), 2.40 (s,
3H, CH3-phenyl), 3.21 (s, 3H, CH3AN), 7.3 (d, J ¼ 7 Hz, 2H,
phenyl), 7.8 (d, J ¼ 7 Hz, 2H, phenyl); ir (KBr disc) m 3015,
2930, 1152 cm–1 (CAO), ms (m/z) 288 (Mþ), 290 (Mþ þ 2).
Anal. Calcd. for C14H13ClN4O: C, 58.24; H, 4.54; N, 19.40;
Found: C, 58.32; H, 4.60; N, 19.61.
7-Chloro-3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrimido[4,5-
1
e][1,3,4]oxadiazine (3c). yield ¼ 50%, mp ¼ 175–176ꢁC, H-
NMR (CDCl3, ppm) d 2.22 (s, 3H, CH3-pyrimidine), 3.21 (s, 3H,
CH3AN), 7.3 (d, J ¼ 8 Hz, 2H, phenyl), 7.7 (d, J ¼ 8 Hz, 2H,
phenyl); ir (KBr disc) m 3060, 2950, 1153 cm–1 (CAO), ms (m/z)
CONCLUSION
In summary, we have described the synthesis of new
3-aryl-1H-[1,2,4]triazolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxa-
diazines (5a-i) through heterocyclization of hydrazino deriva-
tives (4a-c) with triethylorthoesters in boiling acetic acid.
Moreover, we have found that these heterocyclic compounds
containing the triazolopyrimidooxadiazine moiety can be
considered as a novel class of antiproliferative agents on the
basis of a cell-based screening method. Further work is in
progress in our laboratory to explain the mechanism of the
cell death in cancer cell lines. The results will be reported
elsewhere.
EXPERIMENTAL
Figure 2. Dose-dependent growth inhibition of malignant cell lines by
compounds 5b (25 to 400 lM) for 24 h. Viability was quantitated by
Melting points were recorded on an Electrothermal type 9100
melting point apparatus and are not corrected. The 1H-NMR (100
MHz) spectra were recorded on a Bruker AC 100 spectrometer.
Chemical shifts are reported in ppm downfield from TMS as in-
ternal standard; coupling constants J are given in Hertz. The mass
MTT assay. The dose inducing 50% cell growth inhibition (IC50
)
against Hep-G2 and MCF-7 was calculated 294.1 and 555.8 lM,
respectively. Results are Mean 6 SEM (n ¼ 3). *P < 0.05, **P <
0.01, and ***P < 0.001 compared with control (C).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

186
M. Bakavoli, M. Rahimizadeh, A. Shiri, M. Akbarzadeh, S.-H. Mousavi, Z. Tayarani-Najaran,
H. Atapour-Mashhad, and M. Nikpour
Vol 48
Table 1
Physical, spectral, and microanalytical data of 3-aryl-1H-[1,2,4]triazolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxadiazine (5a-i).
Yield
Entry (%)
mp
(ꢁC)
C%
Molecular formula (Calcd) (Calcd) (Calcd)
H%
N%
Spectral dataa
5a
5b
5c
65 270–271 1H NMR: d 2.19 (s, 3H, CH3-pyrimidine), 3.45 (s, 3H, CH3AN),
7.42–7.83 (m, 5H, ph), 8.33 (s, 1H, triazol). ir: m 3005, 2920,
1610, 1550, 1490, 1005 cm–1, m/z 280 (Mþ).
C14H12N6O
C15H14N6O
C16H16N6O
59.89
(59.99) (4.32) (29.98)
4.30
29.88
72 324–326 1H NMR: d 2.60 (s, 3H, CH3-pyrimidine), 2.75 (s, 3H,CH3-tria-
zol), 3.42(s, 3H, CH3AN), 7.32–7.81 (m, 5H, ph), ir: m 3000,
2900, 1610, 1550, 1490, 1005 cm–1, m/z 294 (Mþ).
61.10
4.72
28.48
(61.22) (4.79) (28.55)
50
330 1H NMR: d 1.53 (t, 3H, CH3), 2.64 (s, 3H, CH3-pyrimidine),
3.25 (q, 2H, CH2-triazol), 3.51 (s, 3H, CH3AN), 7.43–7.94 (m,
5H, ph). ir: m 3015, 2940, 1605, 1555, 1500, 1015 cm–1, m/z
308 (Mþ).
62.21
(62.32) (5.23) (27.26)
5.17
27.03
5d
5e
5f
74 290–291 1H NMR: d 2.42 (s, 3H, CH3-pyrimidine), 2.50 (s, 3H, CH3-ph),
3.47 (s, 3H, CH3AN), 7.27 (d, J ¼ 7.5 Hz, 2H, ph), 7.70 (d, J
¼ 7.5 Hz, 2H, ph), 8.32 (s, 1H, triazol). ir: m 3000, 2950,
1605, 1540, 1480, 1000 cm–1, m/z 294 (Mþ).
C15H14N6O
C16H16N6O
C17H18N6O
61.14
4.68
28.45
(61.21) (4.79) (28.55)
68
314 1H NMR: d 2.42 (s, 3H, CH3-pyrimidine), 2.59 (s, 3H, CH3-ph),
2.75 (s, 3H, CH3- triazol), 3.42 (s, 3H, CH3AN), 7.32 (d, J ¼
7.5 Hz, 2H, ph), 7.73 (d, J ¼ 7.5 Hz, 2H, ph). ir: m 3010,
2910, 1630, 1560, 1500, 1020 cm–1, m/z 308 (Mþ).
62.29
(62.32) (5.23) (27.26)
5.17
27.20
46 340–343 1H NMR: d 1.43 (t, 3H, CH3), 2.43 (s, 3H, CH3-pyrimidine),
2.60 (s, 3H, CH3-ph), 2.75 (s, 3H, CH3- triazol), 3.42 (s, 3H,
CH3AN), 7.34 (d, J ¼ 7.5 Hz, 2H, ph), 7.73 (d, J ¼ 7.5 Hz,
2H, ph). ir: m 3015, 2920, 1620, 1565, 1515, 1025 cm–1, m/z
322 (Mþ).
63.31
(63.34) (5.63) (26.07)
5.57
25.89
5g
5h
5i
62 293–295 1H NMR: d 2.44 (s, 3H, CH3-pyrimidine), 3.30 (s, 3H, CH3AN),
7.52 (d, J ¼ 7.3 Hz, 2H, ph), 7.91 (d, J ¼ 7.3 Hz, 2H, ph),
8.82 (s, 1H, triazol). ir: m 3050, 2900, 1625, 1560, 1480, 1010
cm–1, m/z 314 (Mþ), 316 (Mþ þ 2).
C14H11ClN6O
C15H13ClN6O
C16H15ClN6O
53.40
3.48
(53.43) (3.52) (26.70)
26.65
57 319–320 1H NMR: d 2.44 (s, 3H, CH3-pyrimidine), 2.76 (s, 3H, CH3- tria-
zol), 3.30 (s, 3H, CH3AN), 7.53 (d, J ¼ 7.3 Hz, 2H, ph), 7.94
(d, J ¼ 7.3 Hz, 2H, ph), ir: m 3090, 2990, 1650, 1600, 1550,
1490, 1080 cm–1, m/z 328 ( Mþ), 330 (Mþ þ 2).
54.76
(54.80) (3.99) (25.56)
3.87
25.54
41 331–333 1H NMR: d 1.53 (t, 3H, CH3), 2.44 (s, 3H, CH3-pyrimidine),
2.88 (q, 2H, CH2), 3.30 (s, 3H, CH3AN), 7.53 (d, J ¼ 7.3 Hz,
2H, ph), 7.95 (d, J ¼ 7.3 Hz, 2H, ph). ir: m 3100, 2950, 1660,
1590, 1550, 1470, 1065 cm–1, m/z 342 ( Mþ), 344 (Mþ þ 2).
55.98 4.39
(56.06) (4.41) (24.52)
24.47
a The solvent for 1H NMR is CDCl3 and the chemical shifts are in ppm.
308 (Mþ), 310 (Mþ þ 2), 312 (Mþ þ 4). Anal. Calcd. for
C13H10Cl2N4O: C, 50.51; H, 3.26; N, 18.12; Found: C, 50.60; H,
3.23; N, 18.15.
CH3), 3.21 (s, 3H, CH3), 3.85 (br s, 2H, NH2, D2O exchange-
able), 5.89 (br s, 1H, NH, D2O exchangeable), 7.21 (d, J ¼
7.7 Hz, 2H, Ph), 7.69 (d, J ¼ 7.7 Hz, 2H, Ph); ir (KBr disc) m
3345, 3270, 3260, 1110 cm–1; ms (m/z) 284 (Mþ); Anal.
Calcd. for C14H16N6O (%): C, 59.14; H, 5.67; N, 29.56.
Found: C, 59.06; H, 5.64; N, 29.45.
General procedure for the preparation of 3-aryl-1,5-dimethyl-
7-hydrazino-1H-pyrimido[4,5-e][1,3,4]oxadiazine (4a-c). To
a
solution of 3-aryl-1,5-dimethyl-7-chloro-1H-pyrimido[4,5-e]
[1,3,4]oxadiazine (3a-c) (3.7 mmol) in ethanol (20 mL), hydra-
zine hydrate (2 mL) was added, and the solution was refluxed
for 5 h. The resulting precipitate was filtered off and recrystal-
lized from ethanol.
3-(4-Chlorophenyl)-1,5-dimethyl-7-hydrazino-1H-pyrimido
[4,5-e][1,3,4]oxadiazine (4c). yield ¼ 72 %, mp ¼ 241–
1
243ꢁC, H-NMR (DMSO-d6, ppm): d 2.19 (s, 3H, CH3), 3.20
(s, 3H, CH3), 3.89 (br s, 2H, NH2, D2O exchangeable), 5.92
(br s, 1H, NH, D2O exchangeable), 7.35 (d, J ¼ 7.9 Hz, 2H,
Ph), 7.73 (d, J ¼ 7.9 Hz, 2H, Ph); ir (KBr disc) m 3320, 3305,
3280, 1105 cm–1; ms (m/z) 304 (Mþ), 306 (Mþ þ 2); Anal.
Calcd. for C13H13ClN6O (%):C, 51.24; H, 4.30; N, 27.58.
Found: C, 51.14; H, 4.22; N, 27.51.
General procedure for the synthesis of 3-aryl-1,5-di-
methyl-1H-[1,2,4]triazolo[40,30:1,2]pyrimido[4,5-e][1,3,4]oxa-
diazines (5a-i). To a solution of 3-aryl-1,5-dimethyl-7-hydra-
zino-1H-pyrimido[4,5-e][1,3,4]oxadiazine (4a-c) (1 mmol) in
HOAc (2 mL), the respective triethylorthoester (2 mmol) was
added. The reaction solution was heated under reflux for 4 h.
1,5-Dimethyl-7-hydrazino-3-phenyl-1H-pyrimido[4,5-e][1,3,4]oxa-
200–202ꢁC, 1H-NMR
diazine (4a). yield
¼
77%, mp
¼
(DMSO-d6, ppm): d 2.21 (s, 3H, CH3), 3.22 (s, 3H, CH3AN),
3.95 (br s, 2H, NH2, D2O exchangeable), 5.93 (br s, 1H, NH,
D2O exchangeable), 7.31–7.50 (m, 3H, Ph), 7.74–7.89 (m, 2H,
Ph); ir (KBr disc) m 3360, 3335, 3260, 1115 cm–1; ms (m/z)
270 (Mþ); Anal. Calcd. for C13H14N6O (%): C, 57.77; H,
5.22; N, 31.09. Found: C, 57.73; H, 5.05; N, 30.89.
1,5-Dimethyl-7-hydrazino-3-(4-methylphenyl)-1H-pyrimido
[4,5-e][1,3,4]oxadiazine (4b). yield ¼ 68%, mp ¼ 196–198ꢁC,
1H-NMR (DMSO-d6, ppm): d 2.19 (s, 3H, CH3), 2.38 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis of New Derivatives of 3-Aryl-1,5-dimethyl-1H-[1,2,4]triazolo[40,30:1,2]-
pyrimido[4,5-e][1,3,4]oxadiazines as Potential Antiproliferative Agents
187
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet