Mendeleev Commun., 2019, 29, 375–377
phenyl substituents occupy the sterically more favorable equatorial
C(34)
C(42)
C(43)
positions. The dihedral angles between the basal C(1)–C(21)–
C(22)–C(24) plane of the piperidone ring and planes of the two
benzene rings fused to the diaza-14-crown-2-ether moiety are
81.66(13) and 81.08(13)°. Both nitrogen atoms have a trigonal
pyramidal configuration.
The molecule of 5a possesses four asymmetric centers at the
C(1), C(21), C(22) and C(24) carbon atoms and potentially can
have sixteen diastereomers. The crystal of 5a is racemic and consists
of enantiomeric pairs with the following relative configuration of
the centers: 1RS,21SR,22RS,24SR. Such a diastereoselectivity of
multicomponent assembling of complex molecule of types 5,6 is
worthwhile of note.
C(41)
C(40)
C(35)
C(36)
C(33)
C(32)
O(23)
C(23)
C(38)
C(3)
C(37)
C(19)
C(39)
C(22)
C(24)
C(21)
C(1)
O(8)
C(18)
C(17)
C(4)
C(5)
C(20)
C(15)
N(25)
C(2)
C(7)
C(16)
O(14)
C(13)
C(6)
C(9)
C(12)
C(10)
O(2)
N(11)
S(1)
O(1)
C(30)
C(25)
In the crystal, the molecules of 5a form centrosymmetrical
dimers via the intermolecular C–H···O hydrogen bonds. The
H-bonded dimers are arranged at van der Waals distances (Table S1,
Figures S1 and S2, see Online Supplementary Materials).
In the search for new antitumor agents, some representatives
among herein synthesized g-piperidone-containing 1,7-diaza-
14-crown-4 ethers were tested towards cytotoxicity against five
human tumor cell lines, namely, Hep-G2 (Human hepatocellular
carcinoma), Lu-1 (Human lung adenocarcinoma), RD (Human
rhabdomyosarcoma), MCF-7 (Human breast adenocarcinoma),
HeLa (HeLa cervical cancer cells) and on the Vero cell line.
Compounds 5a,b,d and 6a have been selected due to their high
solubility. (Tables 1 and 2). Crown compound 5b has inhibited
the Hep-G2 and Lu-1 cell line with IC50 of 4.32 and 6.64 mg ml–1,
respectively (see Table 2). In continuation of biological evaluation
of potential antitumor agents, compound 5b was tested for cyto-
toxicity on the Vero cell line (normal African green monkey
kidney cell line) and it did not show activity on the Vero cell line.
In conclusion, we have synthesized six (g-piperidone-containing
1,7-diaza-14-crown-4 ethers by three-component domino reactions
of simple reactants, podands 3a,b, ammonium acetate and ketones.
The assembling proceeds with high diastereoselectivity. In vitro
cytotoxicity tests revealed that compound 5b could inhibit the
C(29)
C(27)
C(28)
C(31)
C(26)
Figure 1 Molecular structure of 5a (50% displacement ellipsoids). The
intramolecular N–H···O hydrogen bonds are depicted by dashed lines.
Structural features of 1,7-diaza-14-crown-4 ether 5a have been
ultimately established by single crystal X-ray diffraction study
(Figure 1).‡ The molecule of 5a possesses the idealized Cs (m)
intrinsic symmetry. However, in the crystal the geometry of
5a is slightly distinguished from the idealized one due to the
crystal packing effects. Compound 5a crystallizes as a chloroform
disolvate, i.e., 5a·2CHCl3. The molecule of 5a comprises a fused
tetracyclic system containing the diaza-14-crown-2-ether macro-
cycle, piperidone and two benzene rings. The diaza-14-crown-
2-ether ring adopts a bowl conformation which is stabilized by
the two intramolecular N–H···O hydrogen bonds (Table S1, see
Online Supplementary Materials). The configuration of the
C(7)–O(8)–C(9)–C(10)–N(11)–C(12)–C(13)–O(14)–C(15) aza-
polyether chain is t–g––g––g+–g+–t (t = trans, 180°; g = gauche,
60°). The central piperidone ring has a distorted (flattened
from a side of the carbonyl group) chair conformation. Two
Table 1 Cytotoxicity tests performed on compounds 5a, 5b, 5d, 6a (5 mg ml–1) against five cancer cell lines and Vero cell line.
Cell line with cell survival (%)
Entry Compound
Result
Hep-G2
LU-1
RD
100
MCF-7
HeLa
Vero
1
2
3
4
5
6
DMSO
Taxol (+)
5a
5b
5d
100
100
100
100
100
1.34 0.82
97.65 2.21
31.29 2.09
98.06 1.28
99.12 0.57
1.66 0.95
98.16 0.39
48.61 1.65
97.92 1.55
96.89 2.51
2.12 0.38
4.71 1.55
99.30 0.87
84.12 2.27
96.14 1.62
98.77 1.60
3.42 1.63
99.14 0.72
97.33 0.91
97.56 1.70
99.60 0.14
30.07 1.51
93.56 1.98
95.79 1.57
85.34 2.32
92.98 2.08
Positive
96.33 1.41
99.22 0.34
99.02 0.67
98.39 1.12
Negative
Positive with Hep-G2. LU-1
Negative
6a
Negative
(m, 10H, 2×Ph), 6.78 (d, 2H, H-3, H-19, 3J 8.0 Hz), 6.75 (br.d, 2H, H-6,
H-16, 3J 6.5 Hz), 6.61 (br.t, 2H, H-5, H-17, 3J 6.5 Hz), 4.89 (br.d,
2H, H-1, H-21, J 8.5 Hz), 4.38–4.45 (br.m, 7H, H-22, H-24, 2×H-9,
was determined by direct methods and refined by full-matrix least squares
technique on F2 with anisotropic displacement parameters for non-hydrogen
atoms. The crystal was found to contain two solvate chloroform molecules
in the asymmetric unit. All attempts to model and refine positions of the
solvate chloroform molecules were unsuccessful. Therefore, their con-
tribution to the total scattering pattern was removed using the utility
SQUEEZE in PLATON16.13 The hydrogen atom of the NH group was
localized in the difference-Fourier map and included into the refinement
with fixed positional and isotropic displacement parameters [Uiso(H) =
= 1.2Ueq(N)]. The other hydrogen atoms were placed in calculated positions
and refined within riding model with fixed isotropic displacement para-
meters [Uiso(H) = 1.5Ueq(C) for the methyl groups and 1.2Ueq(C) for the
other groups]. The final divergence factors were R1 = 0.118 for 4201
independent reflections with I > 2s(I) and wR2 = 0.289 for all independent
reflections, S = 0.953. The calculations were carried out using the SHELXTL
program.14
3
2×H-13, NH-25), 3.76 (br.s, 2H, 2×H-10), 3.61 (br.m, 2H, 2×H-12),
2.42 (s, 3H, Me). 13C NMR (125 MHz, CDCl3) d: 156.22, 131.79, 130.01,
129.50, 128.53, 127.77, 126.35, 121.28, 51.15, 21.51. HRMS, m/z: 703.2441
[M+HCOO–] (calc. for C41H39N2O7S, m/z: 703.2483).
‡
Crystal data for 5a. The crystal of –5a (C40H38N2O5S·2CHCl3, M =
= 897.52) is triclinic, space group P1, at T = 100 K: a = 11.606(2),
b = 13.856(3) and c = 14.920(3) Å, a = 83.37(3)°, b = 67.38(3)°, g =
= 71.40(3)°, V = 2099.0(9) Å3, Z = 2, dcalc = 1.420 g cm–3, F(000) = 928,
m = 1.261 mm–1. X-ray diffraction data were collected on the ‘Belok’
beamline (l = 0.96330 Å) of the National Research Center ‘Kurchatov
Institute’ using a Rayonix SX165 CCD detector. A total of 720 images
for two orientations of the crystal (21088 reflections, 8513 independent
reflections, Rint = 0.117) were collected using an oscillation range of 1.0°
(j scan mode, 2qmax = 76.76°) and corrected for absorption using the ‘Scala’
program (Tmin = 0.830, Tmax = 0.880).11 The data were indexed, integrated
and scaled using the utility iMOSFLM in CCP4 program.12 The structure
CCDC 1888670 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
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