Characterization of novel aminobenzylcantharidinimides and related imides by proton NMR spectra and their effects on NO induction

Article abstract of DOI:10.1002/jccs.201400228

Various acidic anhydrides including cantharidin were converted into corresponding aminobenzylcantharidinimide 3a and analogous imides 3b～k (at the ortho, meta, and para positions) with 35%～87% yields by reacting with aminobenzylamines and triethylamine. The two methyl side chains of cantharidinimides 3ao, 3am, and 3ap, and related imides had more than two chiral centers; the lone pair of electrons of nitrogen displayed a different chemical shift and coupling constant in H-NMR spectra when the amino group of benzylamine was in the ortho position. These cantharidinimides had parent aniline, pyridine, and naphthalene plane structures, and the primary amine nucleophilicity and basicity might reflect the inductive electron's negative effect on chemical shifts. We prepared cantharidinimides by heating the reactants cantharidin 1a, aliphatic and aromatic acid anhydrides, primary benzylic amines, and aniline derivatives to ca. 200 °C with 3 mL of dry toluene, and 1～2 mL of triethylamine in high-pressure sealed tubes (Buchi glasuster 0032) to produce cantharidinimides and their analogues in good yields. The para-aminobenzylic imides showed greater inhibition of nitric oxide (NO) synthesis by NO synthase (NOS) than did ortho- and meta-aminobenzylic imides. Compound 3fp, para-aminobenzylic norbonane-imide, had the most potent effect on inducible NOS among the tested compounds and showed 35% inhibition. Cantharidinimides and their analogue were prepared by heating the reactants cantharidin, aliphatic, aromatic acid anhydrides, and primary benzyl amines, aniline derivatives with 3 mL of dry toluene, and 1-2 mL of triethylamine in high-pressure sealed tube at 200 ^oC in good yields. The para-aminobenzylic imides showed greater inhibition of nitric oxide (NO) synthesis by NO synthase (NOS) than that of ortho- and meta-aminobenzylic imides did.

Full text of DOI:10.1002/jccs.201400228

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Characterization of Novel Aminobenzylcantharidinimides and Related Imides by
Proton NMR Spectra and Their Effects on NO Induction
Ing-Jy Tseng,a Pen-Yuan Lin,b Shiow-Yunn Sheu,b Wan-Ni Tung,c Ching-Tung Lind and
Mei-Hsiang Linb,*
aSchool of Gerontology Health Management, College of Nursing, Taipei Medical University, 250 Wuxing St., Taipei,
Taiwan 11031, R.O.C.
bSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei, Taiwan 11031, R.O.C.
cDepartment of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei, Taiwan
11031, R.O.C.
dDepartment of Chemistry, Tam-Kang University, 151 Yingzhuan Rd., Danshui Dist., New Taipei City, Taiwan 25137,
R.O.C.
(Received: May 20, 2014; Accepted: Aug. 1, 2014; Published Online: Oct. 9, 2014; DOI: 10.1002/jccs.201400228)
Various acidic anhydrides including cantharidin were converted into corresponding aminobenzylcanthari-
dinimide 3a and analogous imides 3b~k (at the ortho, meta, and para positions) with 35%~87% yields by
reacting with aminobenzylamines and triethylamine. The two methyl side chains of cantharidinimides
3ao, 3am, and 3ap, and related imides had more than two chiral centers; the lone pair of electrons of nitro-
gen displayed a different chemical shift and coupling constant in H-NMR spectra when the amino group
of benzylamine was in the ortho position. These cantharidinimides had parent aniline, pyridine, and naph-
thalene plane structures, and the primary amine nucleophilicity and basicity might reflect the inductive
electron’s negative effect on chemical shifts. We prepared cantharidinimides by heating the reactants
cantharidin 1a, aliphatic and aromatic acid anhydrides, primary benzylic amines, and aniline derivatives
to ca. 200 °C with 3 mL of dry toluene, and 1~2 mL of triethylamine in high-pressure sealed tubes (Buchi
glasuster 0032) to produce cantharidinimides and their analogues in good yields. The para-aminobenzylic
imides showed greater inhibition of nitric oxide (NO) synthesis by NO synthase (NOS) than did ortho-
and meta-aminobenzylic imides. Compound 3fp, para-aminobenzylic norbonane-imide, had the most po-
tent effect on inducible NOS among the tested compounds and showed 35% inhibition.
Keywords: Cantharidin; Cantharidinimide; Aminobenzylamine; iNOS.
Scheme 1 Synthesis of 3a
INTRODUCTION
Cantharidin is found in Mylabris caraganae and vari-
ous other insects and shows extremely high vesicant po-
tency and toxic properties.1-3 In clinical studies, it was
shown to possess antitumor and antihepatoma properties.
However, it cannot be applied in the clinic due to its high
potency and toxic properties.4-8 It is only used as a standard
in research in veterinary medicine due to its irritant and
vesicating effects. In a search for less-toxic analogues of
cantharidin or cantharidinimide derivatives, a slightly
modified structure was synthesized in an analogous man-
ner.9 Cantharidin (1a) was subjected to an oxygen-nitrogen
exchange reaction to convert it into cantharidinimide (3a)
by reaction with primary amines at 200 °C (Scheme 1). Be-
cause acidic anhydrides are recognized as a class of analo-
gous compounds, some of them, such as phthalic anhydride
(1b), 4-methylphthalic anhydride (1c), 3-methylphthalic
anhydride (1d), 1,8-naphthalenedicarboxylic anhydride
(1e), methylnorbonene-2,3-dicarboxylic acid anhydride
(1f), citraconic anhydride (1g), himic anhydride (1h), and
2,3-pyridinecarboxylic anhydride (1i), can be used to pre-
pare corresponding imides under similar conditions. We
also used diphenic anhydride (1j), 3-nitrophthalic anhy-
dride (1k), and 2,3-dimethylmaleic anhydride (1l) to inves-
tigate the results of various reactions (Scheme 2). Previous
work showed that yields depended on the basicity of com-
pound 2 and perhaps reflected the inductive effects of elec-
tron-withdrawing and -donating groups on the aminoben-
* Corresponding author. E-mail: mhl00001@tmu.edu.tw
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Tseng et al.
Scheme 2 Synthesis of 3b-l
Table 1. Conversion of acidic anhydride into the corresponding
imides by TEA
Acetic
mmol
product (% yield)[b]
anhydride
1
2[a]
1.5
o
m
1.5
1.2
1.1
1.1
-
p
3 o
46
66
70
70
35
40
85
76
37
15
7
m
71
75
65
75
-
p
1a
1b
1c
1d
1e
1f
1g
1h
1i
1.5
1.2
1.1
1.1
1.1
1.1
1.2
1.2
1.1
1.1
1.1
1.1
85
85
73
79
43
45
87
78
41
20
16
-
1.2
1.1
1.1
1.1
1.1
1.2
1.2
1.1
1.1
1.1
1.1
-
-
-
-
-
-
zylamine ring, which might have influenced the charge
density at the benzene ring and thus affected the reactivity.
The temperature was also crucial in these reactions.
-
-
1j
1k
1l
-
-
-
-
-
30
-
Nitric oxide (NO) has important roles in human regu-
latory systems such as vasodilation and platelet aggrega-
tion in the cytostatic and cytotoxic actions of macrophages
and neutrophils.10 NO-induced vasodilation is mediated by
cyclic guanosine monophosphate (c-GMP).11 In addition, it
was reported that NO increases the activity of soluble
guanylate cyclase in vascular smooth muscle, which results
in vasodilation. Our synthetic compounds exhibited a cer-
tain degree of cytotoxic activity against HL-60 and Hep3B
hepatocellular carcinomas.12 Herein, we report our system-
atic studies of various acidic anhydrides to produce imides
under a base condition (Scheme 2) and the effects of cyto-
toxicity and as inducible NO synthase (iNOS) inhibitors
for designing new drugs as future therapeutic sources.
[a] 2 o, m, p = Aminobenzylamine, ortho, meta, para.; [b] After
purification by chromatography on silica gel and then recrystil-
lized with methanol.; Conditions: TEA/toluene (1/3, mL), 200 oC,
2 h.
Table 2. Tests of Nitric oxide synthase
LPSa+
Nitrite (mM)
% of Inhibition
None
0
33.1
-0.1
24.7
24.2
23.8
15.5
0.5
100.4
25.6
26.9
28.2
53.1
98.4
65.6
75.5
72.8
91.9
43.3
81.4
80.7
44.6
35.4
Thb+-
Th+
Th-
3bo
3co
3eo
3fo
11.4
8.1
RESULTS
3lo
9.0
We treated cantharidin and various acidic anhydrides
1a~k in 3 mL of toluene with 1~2 mL of triethylamine,
ortho-, meta-, and para-aminobenzylamines, and heating
to ca. 200 °C to yield the corresponding imides 3a~k and
4a~k (Table 1). We successfully converted 1a~k into 3a~k,
respectively, in yields of 35%~87%. The 4a~k imide com-
pounds failed to yield anything, and the high regiospecific
reaction could be explained by the pKa values of the two
amino groups of aminobenzylamine. The results obtained
only with 3a-k strongly confirmed the influence of the
amine basicity. It seemed that aliphatic amines were pre-
dominant over aromatic amines, and the preparative tech-
niques and steric hindrance were also factors influencing
yields (Table 1). We found that para-aminobenzylamines
were converted into the products, 3ap~kp, in yields of
16%~87%, while ortho-aminobenzylamines gave products
3ao~3ko in yields of 7%~85%, and meta-aminobenzyl-
3bm
3em
3bp
3dp
3ep
3fp
2.7
18.8
6.2
6.4
18.3
21.4
[a] LPS: lipopolysaccharide; [b] Th: Thalidomide.
amines gave products 3am~3dm in yields of 65%~75%.
Inhibitory percentages of NO synthesis and nitrite
concentrations after treatment with synthetic compounds
3bo~3lo are shown in Table 2. All tested compounds
showed NO inhibition, and the most potent compound was
3fp, a para-aminobenzylic norbonane-imide.
DISCUSSION
In studies on cantharidin 1a, it was found that the J
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Characterization of Aminobenzylcantharidinimides
value of CHO was in the triplet at d 4.72, and the coupling
constant was 2.4 Hz. Signals of the two methyls had equal
intensities to that at d 1.23, but were nonetheless very
sharp. The identity of 2-aminobenzylcantharidinimide
(3ao) was confirmed by NMR as shown in Fig. 1. We found
that when the amino group was in the ortho position of the
benzylamine of cantharidinimide, d and J values were more
complicated, and when compared to the properties and
spectral data of 3am and 3ap, we noted one complication in
the NMR spectrum of compound 3ao, which showed two
methyl assignments that were not equivalent. They ap-
peared at d 1.13 and 1.22, with each showing one singlet.
Signals of the two benzylic protons displayed different
equivalent hydrogens in this structure of the type, N-CH2-
C, which appeared at d 4.79 and showed two doublet peaks,
with J values of 16.1 and 16.2 Hz. The proton chemical
shift of CHO was at d 4.53 and displayed two doublets; its
coupling constant was 3.6 Hz. The fact that there were
three different signals, each resulting from three different
kinds of equivalent hydrogens, suggested a high degree of
asymmetry in the structure, as if one methyl of canthari-
dinimide was on the same side with the ortho amine which
exhibited d 1.22. By a lucky chance, clear and sharp spectra
of the two species were obtained at about 25 °C (Figs. 1, 2),
i.e., at a normal temperature of the spectrometer. A part of
the crude crystal product mixture of 3ao prior to chroma-
tography gave these spectra. Despite many efforts, it was
not possible to reproduce a spectrum that indicated slow
isomerization between the two species in the absence of an
unknown catalyst or solvent. In a discussion of Fig. 1,
isomerization was accelerated by either the solvent, reac-
tion time, or temperature in the NMR determination.
shift differed between species, namely in signals for the
two methyl groups and OC-H of the ring. It was proposed
that the two species of 3ao are syn-anti isomers A (minor)
and B (major) with preferred conformations as in the for-
mula shown in Fig. 3. The conformation of A was favored
by the hydrogen bond and steric repulsion between the two
methyl groups and benzyl (phenyl), while conformation of
B possibly exhibited the least electrostatic repulsion be-
tween the lone nitrogen pair and oxygen of bridge atoms
with their partial negative charge. The difference in A rela-
tive to B was observed to be the ortho proton of benzyl
(phenyl), and this shift occurred for several possible rea-
sons: the hydrogen bond of the amino group might have en-
hanced the electro capacity of the ortho phenyl hydrogen,
thus shifting the signal downfield from the usual range. For
B this signal might have been shifted upfield by an electric
field effect arising from the lone nitrogen pair and by the
diamagnetic anisotropy of the C=O bond.
In the mass spectrum of 3ao, the molecular peak at
300 did not show the cyclization form between the car-
bonyl and amine. This might possibly have occurred due to
hydrogen bonding and have become a more-stable six-
ring-like conformation or might simply have been due to
Compared to Fig. 2, aromatic protons with a small
Fig. 2. The proton NMR (CDCl3) of compound 3ao
(type B).
Fig. 1. The proton NMR (CDCl3) of compound 3ao
(type A).
Fig. 3. Structure of aminobenzylcantharidinimide con-
formers A and B.
J. Chin. Chem. Soc. 2015, 62, 59-63
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nitrogen’s polar effects. We did not find it in compounds
3am or 3ap, as their methyl and benzylic hydrogens
seemed to be equivalent, with a sharp methyl signal at d
1.12 and benzylic H at d 4.54. We found that the benzylic
protons of compounds 3bo, 3co, 3eo, and 3io had an aro-
matic phthalic imide and an aliphatic maleic imide and re-
vealed a planar structure; their benzylic protons showed
sharp singlet peaks at d 4.92 and 4.73, and methyl groups
had singlet peaks with two different values at d 1.97 and
2.13. Compounds 3bm, 3cm, 3dm, 3em, and 3im had re-
spective sharp singlet peaks at d 4.73, 4.83, 4.83, 5.27, and
4.79, and their para derivatives, 3bp, 3dp, 3ep, and 3hp,
also had respective sharp singlet peaks at d 4.71, 4.68, 5.25,
and 4.52 that produced no special changes. The benzylic
protons of 3ho showed some coupling signals compared to
those of compound 3ao, and we found its benzylic protons
were at d 6.16 and displayed a double doublet signal. This
might be explained by both compounds having a chiral cen-
ter in their structures and different steric conformations
which might be factors influencing the NMR chemical shift
of the hydrogens, principally their molecular environ-
ments. We also found that the two methyls of o-aminoben-
zyl-2,3-dimethylmaleic imide were not equivalent and ex-
hibited two sharp singlets at d 1.97 and 2.13, but the chemi-
cal shift of its benzylic proton was within the expected po-
sition at about d 4.73 as a singlet peak.
the less slightly ability to inhibit NOS activity as unsubsti-
tuted benzene ring. It was revealed that the inhibition of
NO synthesis by NOS of N-(aminobenzyl)-1,8-naphthal-
imide derivatives decreased in the following sequence:
3em » 3ep > 3eo. It was shown that the meta/para-amino
group was better than the ortho-amino group in the high
lipophilicity of the naphthalene moiety which might have
more effect for NO inhibition. Comparing the bioactivity
of N-(2/4-aminobenzyl)norborane-imides revealed that the
para-amino group was better than the ortho-amino group
on the norborane ring which might have same effect as
cantharidinimide. Among the tested compounds, we found
that N-(4-aminobenzyl)norboraneimide (3fp) showed the
most potent effect on iNOS at 35% inhibition. We supposed
that the para-amino group and the spherical norborane
moiety might be linked at a position opposite of the recep-
tor.
EXPERIMENTAL
General: Melting points were determined with a melting
point microscope (Yanaco apparatus). Silica gel (0.063~0.200
mm, 70~230 mesh) supplied by Merck was used for column chro-
matography. Infrared (IR) spectra of KBr discs were recorded on
Bio-Ras FT-IR FTS 165 and Nicolet 510 PFT-IR spectrophotom-
eters. Mass spectra were obtained on Joel JMSHX 110 FABMS
and Joel-HX 110 high-resolution spectrometers. 1H nuclear mag-
netic resonance (NMR) spectra (CDCl3 unless otherwise stated)
were recorded at 500 MHz on a Bruker Advance DRX. Chemical
shifts are shown as d values (ppm) with tetramethylsilane (TMS)
as an internal reference.
These compounds exhibited less cytotoxicity than
other anticancer drugs currently being used; thus their de-
rivatives could be candidates for testing as NO-inhibitory
materials. Our tested compounds 3bo~3lo had structures
similar to that present in thalidomide, which has two imide
structures, phthalimide and glutarimide. It inhibited NO
synthesis by 25%~28% (Table 2). Hence, we used it as a
standard to test the inhibition of NO formation. Based on
the pharmacological results, it was also possible to make a
number of correlations between the structure and inhibition
of NO synthesis by NO synthase with the 11 imide com-
pounds. It was found that the inhibition of NO formation by
NOS of N-(aminobenzyl)phthalimide derivatives de-
creased in the following order: 3bo > 3bp > 3bm. It was
shown that the ortho-amino group of benzylphthalimide
might display some pharmacological effect better than the
others. It demonstrated that the amino group in the ortho
position might create more-stable and comformationally
fixed isomers that were predominant over the others. Com-
paring the bioactivity of N-(2-aminobenzyl)imides (3bo,
3co, 3eo, 3fo, and 3lo) revealed that naphthalene ring has
General procedure for the synthesis of cantharidinimides
and imide analogues: Cantharidinimides and imide analogues
were prepared from cantharidin and aminobenzylamines in the
presence of triethylamine and toluene in high-pressure tubes with
stirring and heating to ca. 200 °C. After being stirred for 2 h, the
mixture was evaporated, and the residue was purified by column
chromatography on silica gel and then recrystallized from metha-
nol.
Physical properties of 3ao, 3am, 3ap, 3bo, 3co, 3eo, and
3lo: N-(2-Aminobenzyl)cantharidinimide (3ao): Cantharidin
(204 mg, 1.1 mmol), amine (140 mg, 1.2 mmol), TEA (1 mL), to-
luene (3 mL); mp 133~136 °C (MeOH); IR (KBr) 1726 (amide),
3569 (NH2) cm-1; 1H NMR (CDCl3) d 1.13 (3H, s, CH3), 1.22 (3H,
s, CH3), 1.66-1.82 (4H, m, CH2 x2), 4.53 (1H, d, J = 3.6 Hz,
OCH), 4.65 (1H, d, J = 3.6 Hz, OCH), 4.79 (2H, dd, J = 16.1 , J =
16.2 Hz, benzylic H), 6.98 (1H, d, J = 7.5 Hz, H-3), 7.09 (1H, dd,
J = 3.9, 7.5 Hz, H-5), 7.18 (2H, d, J = 3.9 Hz, H-2 overlapping
62
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Characterization of Aminobenzylcantharidinimides
with H-4); MS m/z (rel. int. %) 300 (M+, 5), 281 (10), 57 (100);
HRMS (EI, 80 eV) calcd. for C17H20O3N2 300.1474, found
300.1480. N-(3-Aminobenzyl)cantharidinimide (3am): Can-
tharidin (199 mg, 1.1 mmol), amine (135 mg, 1.1 mmol), TEA (1
mL), toluene (3 mL); mp 175~179 °C (MeOH); IR (KBr) 1692
(amide), 3355, 3417 (NH2) cm-1; 1H NMR (CDCl3) d 6.61 (1H, s,
H-2), 6.54 (1H, dd, J = 1.9, 7.8 Hz, H-4), 6.67 (1H, d, J = 7.8 Hz,
H-6), 7.05 (1H, d, J = 7.8 Hz, H-5); MS m/z (rel. int. %) 300 (M+,
100), 231 (10),106 (65); HRMS (EI-80 eV) calcd. for C17H20O3N2
300.1474, found 300.1479. N-(4-Aminobenzyl)cantharidin-
imide (3ap): Cantharidin (206 mg, 1.2 mmol), amine (256 mg,
2.0 mmol), TEA (1 mL), toluene (3 mL); mp 202~205 °C
Hz, h-5’), 7.71 (1H, d, J = 3.3 Hz, H-6’); MS m/z (rel. int. %) 220
(M+, 17), 104 (22), 76 (100). Nitrite quantitation: NO2-accumu-
lation was used as an indicator of NO production in the medium as
previously described.13 Raw 264.7 cells at 4~5 mL were main-
tained in 96-well, 24-h culture plates; 20 mg/ml of compounds
was added and stimulated with lipopolysaccharide (LPS) (300
ng/mL). After 18 h, isolated supernatants were mixed with an
equal volume of Griess reagent (1% sulfanilamide, 0.1% naph-
thylethylenediamine dihydrochloride, and 5% phosphoric acid)
and incubated at room temperature for 10 min using Na2NO2 to
generate a standard curve. Nitrite production was measured with
an enzyme-linked immunosorbent assay (ELISA) reader at 530
nm.
1
(MeOH); IR (KBr) 1693 (amide), 3367, 3444 (NH2) ; H NMR
(CDCl3) d 1.11 (6H, s, CH3), 1.64-1.83 (4H, m, CH2 x 2), 4.53
(2H, d, J = 14.1 Hz, CH2N), 4.56 (2H, s, OCH), 6.57 (2H, d, J =
8.2 Hz, phenyl 3,5-H), 7.09 (2H, d, J = 8.1 Hz, phenyl 2,6-H), MS
m/z (rel. int. %) 300 (M+, 30), 106 (100). HRMS (EI-80 eV) calcd.
for C17H20O3N2 300.1474, found 300.1476. N-(2-Aminobenzyl)-
phthalimide (3bo): Phthalic anhydride (150 mg, 1.0 mmol),
amine (130 mg, 1.1 mmol), TEA (1 mL), toluene (3 mL); mp
310~313 °C (MeOH); 1H NMR (CDCl3) d 4.73 (1H, s, benzylic
H), 7.14 (1H, d, J = 7.4 Hz, H-3’), 7.22 (1H, dd, J = 9.6, 7.4 Hz,
H-5’), 7.31 (1H, t, J = 7.5 Hz, H-4’), 7.45 (1H, d, J = 7.7 Hz,
H-6’), 7.65 (1H, d, J = 7.4 Hz, H-4), 7.67 (1H, d, J = 7.4 Hz, H-5),
7.88 (1H, d, J = 7.2 Hz, H-3), 8.03 (1H, d, J = 7.4 Hz, H-6);
Cl-MS m/z (rel. int. %) 252 (M+, 17), 104 (22), 76 (100). N-(2-
Aminobenzyl)-4-methylphthalimide (3co): mp 133~135 °C
ACKNOWLEDGEMENTS
We thank Ms. Shwu-Huey Wang for help with the
mass and NMR spectra and data calculations.
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(MeOH); IR (KBr) 1714 cm-1; H NMR (CDCl3) d 2.48 (1H, s,
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1
IR (KBr) 1713 cm-1; H NMR (CDCl3) d 5.28 (2H, s, benzylic
H),7.16 (2H, dd, J = 6.5 Hz, benzylic 3,4-H), 7.24 (1H, m,
benzylic H-5), 7.36 (1H, s, benzylic H-6), 7.66 (1H, t, J = 3.8 Hz),
7.68 (1H, d, J = 7.8 Hz), 8.03 (1H, t, J = 3.8 Hz), 8.10 (1H, d, J =
3.1 Hz), 8.45 (1H, d, J = 8.1Hz), 8.83 (1H, d, J = 7.6 Hz). MS m/z
(rel. int. %) 302 (M+, 17), 104 (22), 76 (100). N-(2-Aminoben-
zyl)-2,3-dimethylmaleiimide (3lo): mp 175~178 °C (MeOH); IR
(KBr) 1713 cm-1; 1H NMR (CDCl3) d 1.97 (3H, s, 3-CH3), 2.13
(3H, s, 2-CH3), 4.73 (2H, s, benzylic CH2), 7.13 (1H, dd, J = 7.5,
7.5 Hz, H-3’), 7.26 (1H, d, J = 7.5 Hz, H-4’), 7.42 (1H, d, J = 7.1
11. Jeon, Y.-J.; Han, S.-H.; Yang, K.-H. Toxicol. Lett. 1999, 104,
195.
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J. Chin. Chem. Soc. 2015, 62, 59-63
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