Conversion of Isatins to Tryptanthrins, Heterocycles Endowed with a Myriad of Bioactivities

Article abstract of DOI:10.1002/ejoc.201900352

The numerous bioactivities exhibited by tryptanthrins led chemists to develop synthetic approaches towards this important scaffold. In particular, conversion of isatins into tryptanthrins has been the subject of several studies. In this context, by using iodine and potassium hydroxide at room temperature, we have discovered a simple way to convert isatin and seven of its 5-substituted derivatives (Bu, F, Cl, Br, I, OMe and OCF₃) into the corresponding tryptanthrins. Furthermore, a mechanism was proposed to explain this original reactivity. Finally, we evaluated the antibacterial, antifungal, antioxidant and cytotoxic properties of the synthesized tryptanthrins. The unprecedented inhibition of human 20S constitutive proteasome was finally evaluated.

Full text of DOI:10.1002/ejoc.201900352

A Journal of
Accepted Article
Title: Conversion of isatins to tryptanthrins, heterocycles endowed with
a myriad of bioactivities
Authors: Rim AMARA, Haçan AWAD, Diana CHAKER, Ghenia
BENTABED-ABABSA, Frédéric LASSAGNE, William ERB,
Floris CHEVALLIER, Thierry Roisnel, Vincent DORCET, Ziad
FAJLOUN, Joëlle VIDAL, and Florence Mongin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900352
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900352
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10.1002/ejoc.201900352
European Journal of Organic Chemistry
FULL PAPER
Conversion of isatins to tryptanthrins, heterocycles endowed
with a myriad of bioactivities
Rim Amara,[a,b] Haçan Awad,[c] Diana Chaker,[d][‖] Ghenia Bentabed-Ababsa,*[b] Frédéric Lassagne,[a]
William Erb,[a] Floris Chevallier,[a][‡] Thierry Roisnel,[a] Vincent Dorcet,[a] Ziad Fajloun,*[c,d] Joëlle Vidal*[a]
and Florence Mongin*[a]
Abstract: The numerous bioactivities exhibited by tryptanthrins led
chemists to develop synthetic approaches towards this important
scaffold. In particular, conversion of isatins into tryptanthrins has
been the subject of several studies. In this context, by using iodine
and potassium hydroxide at room temperature, we have discovered
a simple way to convert isatin and seven of its 5-substituted
derivatives (Bu, F, Cl, Br, I, OMe and OCF3) into the corresponding
tryptanthrins. Furthermore, a mechanism was proposed to explain
this original reactivity. Finally, we evaluated the antibacterial,
antifungal, antioxidant and cytotoxic properties of the synthesized
tryptanthrins. The unprecedented inhibition of human 20S
constitutive proteasome was finally evaluated.
First, tryptanthrins show biological properties such as
antibacterial, antifungal, antiprotozoal and other antiparasitic
activities. Towards Mycobacterium tuberculosis, tryptanthrin (1-
H) is as effective as isoniazid, streptomycin and ethambutol
which are powerful antitubercular agents.7 It is also effective
against bacillus (antibiotic) and dermatophytes (fungistatic
activity).8 Tryptanthrins are promising drugs against
toxoplasmosis,9 while they display antitrypanosomal activities, in
particular against Trypanosoma brucei responsible for the
African sleeping sickness,10 as well as antimalarial properties.11
Second, the anti-inflammatory activities attributed to 1-H12
can result from its ability to inhibit cyclooxygenase-2 and 5-
lipooxygenase mediated syntheses of prostaglandins and
leukotrienes
which
are
pro-inflammatory
mediators.13
Tryptanthrin (1-H) can alternately inhibit the biocatalysed nitric
oxide over-production and mast cell degranulation,14 at the origin
of several inflammatory diseases. It has potential for the
treatment of diseases such as allergic atopic dermatitis15 and
inflammatory bowel colitis.16
Some tryptanthrins are inhibitors of the indoleamine 2,3-
dioxygenase 117 and 2,18 and of the tryptophan 2,3-
dioxygenase,19 which are important therapeutic targets due to
their involvement in cancers, neurological disorders and other
diseases linked to pathological tryptophan metabolism. The
chemopreventive activity of tryptanthrin (1-H) is also reported,
for example towards tumor promotion20 or adverse effects of
environmental pollutants such as chlorinated dioxins.21 A cell
protected effect against oxidative stress has also been
proposed.22
The antineoplastic properties of tryptanthrin (1-H) have been
associated with cell cycle arrest23 and cell differentiation
promotion,1 leading to apoptosis24 and reduced proliferation.25
Furthermore, tryptanthrin (1-H) has shown some activity towards
the inhibition of angiogenesis, which plays an important role in
tumor growth, invasion and metastasis.26 It prevents the action
of topoisomerase I and II, both essential for solving DNA
topological problems, and also causes cytotoxicity in several
human cancer cell lines such as neuroblastoma and leukemia
cells.27 Finally, it is capable of reversing multidrug resistance,
one of the main causes of failure for cancer chemotherapy.28
Because of its numerous bioactivities, different synthetic
approaches to access tryptanthrin (1-H) and its substituted
derivatives have been reported.4-5,29 As unsubstituted isatin (2-
H) can be easily obtained by oxidation of indole, oxindole or
indigo,30 it constitutes the most general starting material towards
Introduction
The alkaloid tryptanthrin (unsubstituted indolo[2,1-b]quinazoline-
6,12-dione, 1-H) is present in a variety of natural sources such
as dried roots of indigo1 and leaves of Couroupita guianensis
(cannonball tree).2 It can also be found in cultures including
fungus Candida lipolytica3 and yeast.4 As traditional component
of dyes and constituent of traditional medicinal herbal
treatments,5 tryptanthrin has experienced a very rich history
since the elucidation of its structure 50 years ago.6 Indeed, the
long list of biological properties associated with this tetracycle
has justified the study of many of its derivatives.3
[a]
Dr. R. Amara, F. Lassagne, Dr. W. Erb, Dr. F. Chevallier, Dr. T.
Roisnel, Dr. V. Dorcet, Prof. J. Vidal, Prof. F. Mongin
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de
Rennes) - UMR 6226, F-35000 Rennes, France
E-mails: joelle.vidal@univ-rennes1.fr,
florence.mongin@univ-rennes1.fr
https://iscr.univ-rennes1.fr/corint/joelle-vidal
https://iscr.univ-rennes1.fr/corint/florence-mongin
Dr. R. Amara, Prof. G. Bentabed-Ababsa
[b]
Laboratoire de Synthèse Organique Appliquée, Faculté des
Sciences Exactes et Appliquées, Université Oran1 Ahmed Ben
Bella, BP 1524 El M’Naouer, 31000 Oran, Algeria
E-mail: badri_sofi@yahoo.fr
https://scholar.google.com/citations?user=7c5-Bw8AAAAJ&hl=fr
Dr. H. Awad, Prof. Z. Fajloun
Faculty of Sciences 3, Lebanese University, Campus El-Kobbeh,
Tripoli, Lebanon
E-mail: ziad.fajloun@ul.edu.lb
https://scholar.google.fr/citations?user=HSaT-LAAAAAJ&hl=fr
Dr. D. Chaker, Prof. Z. Fajloun
[c]
[d]
Laboratory of Applied Biotechnology, Azm Center for Research in
Biotechnology and its Applications, EDST, Lebanese University,
1300 Tripoli, Lebanon
1-H (Schemes
1
and 2). Other approaches are less
straightforward and will not be detailed here. Isatoic anhydride is
the most commonly used partner of 2-H (reaction (i) in Scheme
1);31 one can also cite 2-nitrobenzoyl chloride (reaction (ii) for
which a reduction step is needed),32 2-azidobenzoyl chloride
(intramolecular aza-Wittig reaction (iii)),33 anthranilamide
[‖]
Present address: INSERM U935, Université Paris-Saclay
F-94800 Villejuif, France
Present address: Laboratoire de Chimie UMR 5182, CNRS-Univ.
Lyon, ENS de Lyon, Université Claude Bernard Lyon 1
F-69342, Lyon (France)
[‡]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900352
European Journal of Organic Chemistry
FULL PAPER
(reaction (iv) using POCl3),31h anthranilic acid (reaction (v) in the
disubstituted (and in principle 1,7-, 3,9-, 4,10-, etc.) analogues
bearing the same substituents (Scheme 2). In addition to the
photoredox-catalyzed reactions recently published (reaction
(viii))31a,36 and cathodic reduction (reaction ix),37 methods using
34
presence of SOCl2
or PCl5),11a and more recently 2-
aminoacetophenone and indole (reactions (vi)29g and (vii),35 both
using CuI and oxygen). These ways are in general suitable for
synthesis of tryptanthrins with different substituents on each side. POCl3 (reaction (x))38 or oxidizing agents such as KMnO4 (xi)8b,39
Self-condensation of isatin can be performed as an alternative
and t-BuO2H (xii)29e were reported to achieve such
a
method to access tryptanthrin (1-H), as well as its 2,8-
dimerization.
Scheme 1. Methods for converting isatin (2-H) into tryptanthrin (1-H) that can be extended to tryptanthrins with different substituents on each benzo ring.
proteasome inhibitors,42 we evaluated their ability to inhibit
human 20S proteasome.
Results and Discussion
Synthesis
Scheme 2. Methods for converting isatin (2-H) into tryptanthrin (1-H) that can
be extended to its 2,8-disubstituted (and in principle 1,7-, 3,9-, 4,10-, etc.)
analogues bearing the same substituents.
Intrigued by the conditions reported in the literature to
convert isatin (2-H) into its 5-iodo derivative 2-I,40 we simply
treated 2-H by iodine and potassium hydroxide in DMF.41 By this
way, we obtained a bright yellow compound for which the
structure of tryptanthrin (1-H) was unambiguously attributed by
X-ray diffraction (Scheme 3, top). This result prompted us to
extend the reaction to substituted isatins 1-R (Table 1; R =
substituent), and to assess some of their biological properties.
Particularly, in the course of our search for new non-peptide
Scheme 3. Conversion of isatin (2-H) into tryptanthrin (1-H) or 3 by using
iodine and potassium hydroxide in DMF or ethylene glycol, respectively.
ORTEP diagrams (30% probability) of 1-H and 3. [a] 1-H also formed in <20%
yield.
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First, we tried to get clues on the conversion of 2-H to 1-H.
Without iodine or potassium hydroxide, the reaction did not
occur, indicating that both are playing a role in the reaction
mechanism. When DMF was replaced by ethylene glycol to
Given the ease with which N-C2 (lactam) cleavage of isatin
can occur through nucleophilic attack of hydroxides (e.g.
aqueous KOH, r.t., 0.5 h),43 it seemed to us that it could be the
first step of both reaction pathways. Next, nucleophilic attacks at
C3 are well-known, and could here take place with the
potassium salt of isatin (Scheme 4) or ethylene glycol (Scheme
5). An oxidation step is then needed, step probably performed
by iodine. Even if N-I bonds are sometimes put forward,44 and
can be here advanced as key step in the pathway giving 1-H
(Scheme 4, bottom), O-I bonds would allow a common way to 1-
H and 3. In addition, the latter were proposed to rationalize
favour
a polar mechanism, the competitive formation of
compound 3 was observed; it was isolated in 11% yield while
tryptanthrin was also formed in a <20% yield under these
conditions (Scheme 3, bottom). These results led us to propose
the pathways shown in Schemes 4 and 5 in which potassium
hydroxide and iodine are involved.
oxidative
cleavage
of
C2-C3
isatin
bonds
using
(diacetoxyiodo)benzene.45 It is not obvious to decide which of
the oxygens (that of the alkoxide or carboxylate group) interacts
with iodine in this decarboxylative oxidation.46 As no cyclization
can occur in the case of 3, the amino group is finally engaged in
a carbamoylation step with carbon dioxide in ethylene glycol
(Scheme 5).
Table 1. Synthesis of substituted tryptanthrins.
Entry
2-R[a]
Conditions
1-R,[a] Yields[b] (%)
1
2
2-H
r.t., 4 days
r.t., 4 days
1-H, 73
2-Bu (5-Bu)
1-Bu (2,8-diBu), 70%
r.t., 8 days then
100 °C, 3 h
3
2-F (5-Cl)
1-F (2,8-diF), 58
4
5
6
2-Cl (5-Cl)
2’-Cl (7-Cl)
2-Br (5-Br)
r.t., 4 days
r.t., 4 days
r.t., 3 days
1-Cl (2,8-diCl), 53
1’-Cl, 0
Scheme 4. Mechanism proposed for the conversion of isatin (2-H) into 1-H by
using iodine as oxidant and potassium hydroxide.
1-Br (2,8-diBr), 15[b]
r.t., 4 days then
100 °C, 19 h
7
2’-Br (4-Br)
1’-Br, 0[b]
8
2-I (5-I)
r.t., 4 days
r.t., 4 days
r.t., 4 days
1-I (2,8-diI), 40
9
2-OMe (5-OMe)
2-OCF3 (5-OCF3)
1-OMe (2,8-diOMe), 80
1-OCF3 (2,8-diOCF3), 34
10
[a] The substituent location is given into brackets. [b] After purification
(see experimental part). [c] Degradation noticed.
We next studied the impact of isatin substituents on the
efficiency of the reaction (Table 1). Unlike 5-substituted isatins,
the 7-chloroisatin (2’-Cl) and 4-bromoisatin (2’-Br) did not
furnish the expected tryptanthrins 1’-Cl and 1’-Br (entries 5 and
7). As previously observed in the reaction of 5,7-dichloroisatin
with phosphorus(V) oxychloride,38a the presence of an electron-
withdrawing group next to the isatin nitrogen could reduce its
ability to act as a nucleophile. Probably for a similar reason, the
presence of electron-withdrawing groups such as halogens
(entries 3, 4, 6 and 8) and trifluoromethoxy (entry 10; Figure 1)
at the 5-position of the starting isatin led to the expected
tryptanthrins in yields ranging from 15 to 58%, lower than with
bare isatin (73%; entry 1). In contrast, while a similar yield was
Scheme 5. Mechanism proposed for the conversion of isatin (2-H) into 3 by
using iodine as oxidant and potassium hydroxide in ethylene glycol.
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10.1002/ejoc.201900352
European Journal of Organic Chemistry
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recorded from 5-butylisatin (70%, entry 2; Figure 1), an
increased reactivity was noticed in the presence of a methoxy
group at C5 (entry 9; Figure 1). Thus, our method is perfectly
suitable to synthesize tryptanthrins 2,8-disubstituted by electron-
donating groups under very mild conditions. However, as
noticed when using POCl3,38a it is not appropriate to prepare
monosubstituted derivatives of tryptanthrin; indeed, treating a
1:1 mixture of isatin and 5-chloroisatin under the same reaction
conditions furnished a mixture of the tryptanthrins 1-H and 1-Cl
in addition to monochlorinated tryptanthrins (~1:1:1 ratio).
radical scavenging properties was also analysed, but no
reduction of the diphenylpicrylhydrazyl (DPPH) radical was
observed.17 Besides, 2,8-dibromotryptanthrin (1-Br) showed
promising antitumor activity against lung and gastric cancer.47 Its
antibacterial and antifungal activities were determined (0.6
μg.mL-1 minimum inhibitory concentration (MIC) against the
gram-positive methicillin-resistant Staphylococcus aureus, and 4
μg.mL-1 MIC against Malassezia furfur), and although good,
proved similar to those exhibited by 1-H.48
In search for improved bioactivities conferred by our
substituents, it was of interest to evaluate the synthesized
compounds in various biological assays. They were first
screened for their antibacterial and antifungal activity (Table 2).
None of the tested compounds inhibit the growth of E. coli, P.
aeruginosa and L. monocytogenes. When compared with parent
1-H, the 1-I and 1-OMe derivatives have a similar effect on the
growth of S. aureus whereas 1-F, 1-Cl and 1-Br show a more
significant inhibition. The compound 1-F also inhibits E. faecium
while 1-Br is more active on C. albicans. The in vitro antioxidant
activity of the synthesized tryptanthrins is immediate and does
not exceed 60% of DPPH radical scavenger activity (RSA),
except for the halogenated compounds 1-F and 1-Cl that
respectively show 74 and 82% scavenging (Table 3).
Figure 1. ORTEP diagrams (30% probability) of 1-Bu (top), 1-OMe (bottom
left) and 1-OCF3 (bottom right).
Recently, human mesenchymal stem cells were confidently
used in the area of toxicology.49 Particularly, adipose human
mesenchymal stem cells were considered as a potential new cell
substrate for expecting preliminary chemical doses for toxicity
assays.50 We thus evaluated the cytotoxicity of four compounds,
1-H, 1-Cl, 1-I and 1-OMe, against human mesenchymal stem
cells proliferation and viability. To this purpose, their
antiproliferative activity was assessed by calculating the index of
growth inhibition [1 - (number of cells in treated well/number of
cells in control well)] at different concentrations.
Table 3. Antioxidant activity of the tryptanthrins 1-R (R = substituent).
Compound
RSA (%)[a] at t = 0 min RSA (%)[a] at t = 30 min
1-H
1-Bu
1-F
1-Cl
1-Br
1-I
40
30
74
82
48
55
49
60
40
39
81
82
49
58
51
65
1-OMe
1-OCF3
The results depicted in Figure 2 show an antiproliferative
effect of all the tested compounds. However, the effect of 1-OMe
and 1-I is already marked at a low 0.1 mg.mL-1 concentration
while 1-H and 1-Cl show less toxicity effects when used at low
doses. The viability of the human mesenchymal stem cells in the
presence of 1-H, 1-Cl, 1-I and 1-OMe at different concentrations
was also determined (Figure 3). While the viability (assessed
using the trypan blue stain) does not exceed 60% when cells are
treated over 48 h with 0.01 mg.mL-1, 1-I and 1-OMe show a high
toxicity effect when used concentrated at 0.1 mg.mL-1.
Interestingly, the microscopy examination confirmed these
results (Figure 4).
[a] At a concentration of 5 mg.mL-1 in DMSO at room temperature.
Bioactivity
As discussed in the introduction, if the biological activities of
bare tryptanthrin (1-H) has been extensively studied, 2,8-
disubstituted derivatives similar to those prepared here were
scarcely studied. 2,8-Difluorotryptanthrin (1-F) was evaluated for
its ability to inhibit indoleamine 2,3-dioxygenase (IDO) 117 and
2,18 but did not prove better than 1-H. In order to see if the IDO1
inhibitory activity of 1-H was related to its redox potential, its
Table 2. Antibacterial and antifungal activity of the tryptanthrins 1-R (R = substituent).[a]
Compound
Amount (μg dissolved in DMSO)
Staphylococcus aureus
Enterococcus faecium
Listeria monocytogenes
Candida albicans
[d]
1-H[b]
450
150
150
450
150
450
450
150
-
10
0
0
0
10
0
0
0
0
0
0
24
-
0
0
5
0
13
0
0
0
1-Bu[c]
1-F[c]
0
0
23
19
21
10
10
5
[d]
1-Cl[b]
1-Br[c]
1-I[b]
-
0
[d]
-
[d]
1-OMe[b]
1-OCF3[c]
DMSO
-
0
0
30
0
18
0
13
Reference compound
Vancomycin (30 μg)
Ampicillin (25 μg)
Nystatin (416 Ul)
[a] The diameters of zones of inhibition are given in mm. [b] 50 μL/well. [c] 30 μL/well. [d] Not tested.
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10.1002/ejoc.201900352
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Figure 2. Antiproliferative activity of 1-H, 1-Cl, 1-I and 1-OMe at 0.01, 0.03
and 0.10 mg.mL-1. 5.103 human mesenchymal stem cells were treated for 24
h (left) and 48 h (right). The proliferation activity was assessed by the
calculation of the index of growth inhibition.
Figure 4. Microscopy examination after 48
h treatment of human
mesenchymal stem cells treated with 1-H, 1-Cl, 1-I and 1-OMe at 0.00, 0.01,
0.03 and 0.1 mg.mL-1.
Figure 3. Cell viability of human mesenchymal stem cells treated with 1-H, 1-
Cl, 1-I and 1-OMe at 0.01, 0.03 and 0.10 mg.mL-1 for 24 h (left) and 48 h
(right).
As proteasome is a target for cancer therapy, very important
efforts have been made in recent years in order to discover new
inhibitors of this complex, multi-catalytic and proteolytic
enzyme.51 Three peptide proteasome inhibitors bearing an
electrophilic warhead are currently marketed for the treatment of
multiple myeloma, a blood cancer.51 In order to circumvent
peptide limitations in therapy, the development of non-peptide
inhibitors, especially heterocyclic compounds, is growing.42,51a-
d,52
Figure 5. Effects of tryptanthrins on human 20S constitutive proteasome (pH 8,
37 °C). a. Inhibition of the ChT-L and PA activities by 50 µM tryptanthrins 1-R.
b. Inhibition profile of the PA activity (substrate Z-LLE-NA, 50 µM) by 1-OMe
showing an IC50 of 8.0 ± 0.5 µM. c. Double-reciprocal Lineweawer-Burk plot
for the inhibition of the ChT-L activity by tryptanthrin 1-OMe; [20S proteasome]
= 0.3 nM; [1-OMe] = 0 µM (□); [1-OMe] = 10 µM (○); [1-OMe] = 20 µM (•); [1-
OMe] = 38 µM (◊); F.U., fluorescence arbitrary unit; S, substrate Suc-LLVY-
AMC.
The heterocyclic structure of the prepared tryptanthrins 1-R
and their described cytotoxicity prompted us to test their ability
to inhibit purified human constitutive 20S proteasome in vitro. At
first, their effect on the three proteasome proteolytic activities
was evaluated by following the hydrolysis of the corresponding
fluorogenic specific substrate in the presence of 50 µM solution
of 1-R or in their absence (see Eq. (1) in the experimental
section and Figure 5a.).
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No inhibition of the trypsin-like (T-L) activity was detected,
whereas the chymotrypsin-like (Ch-TL) and the post-acid (PA)
activities were moderately to strongly inhibited by compounds 1-
H, 1-Bu, 1-Cl, 1-I, and 1-OMe (Figure 5a.). For the most potent
tryptanthrin 1-OMe, the concentrations leading to 50% inhibition
(IC50 value) were determined, showing that the PA activity (IC50
=
7.0 ± 0.5 µM) was more efficiently inhibited than the ChT-L
activity (IC50 = 15.0 ± 0.8 µM) (Figure 5b.). This is an interesting
feature, since co-inhibition of ChT-L and PA activities was
shown to enhance cytotoxicity of proteasome inhibitors.53 As the
detection of the ChT-L activity was easier, a kinetic study was
realized at a fixed enzyme concentration and various substrate
(Suc-LLVY-AMC) and tryptanthrin 1-OMe concentrations. It was
analyzed by Lineweawer-Burk plots that showed a mixed
inhibition mechanism (Figure 5c.). Such an allosteric modulation
of the proteasome activity, already observed with non-peptide
inhibitors42b,54 and also peptide inhibitors,55 indicated that binding
occurred at a site other than the ChT-L active site, while
resulting in inhibition of enzyme activity.
Figure 6. ORTEP diagrams (30% probability) and visualizations of the
intermolecular hydrogen bonds of 4a (1.981 Å; left) and 4b (1.993 Å; right).
Blue: nitrogen; Red: oxygen; Green: chlorine.
Conclusions
Experimental Section
Thus, in view of the numerous potential applications of
tryptanthrins, we reported an original route towards 2,8-
disubstituted derivatives under mild conditions and proposed a
mechanism to explain this unexpected reactivity. The early
biological evaluation of our compounds 1-R was done, and
those substituted with halogeno and methoxy groups proved to
be more bioactive than the reference 1H. The antibacterial (S.
aureus), antifungal (C. albicans) and antioxidant activities were
higher for 1-F, 1-Cl and 1-Br substituted tryptanthrins.
Tryptanthrins 1-OMe and 1I were shown to be cytotoxic and
antiproliferative agents. This last feature might be due to their
ability to inhibit the ChT-L and PA activities of the 20S
proteasome, with IC50 values in the micromolar range (15 µM
and 7 µM, respectively) for 1-OMe.
If substituted tryptanthrins are of interest by themselves, as
disclosed all through this article, they also constitute a promising
tetracyclic scaffold to access natural products such as
phaitanthrin A and cephalanthrin A,38b compounds that can be
obtained by nucleophilic attack onto the tryptanthrin ketone.56 To
highlight how such additions can easily happen, we could cite
cite the non-optimized formation of compounds 4a and 4b.
The dichloro derivative of phaitanthrin A 4a was obtained in
the course of an attempt to dissolve 1-Cl in acetone and obtain
crystals suitable for X-ray diffraction (Figure 6, left). As to 4b
(right), it was formed as undesirable product in the course of an
attempt to deprotometallate 1-H in tetrahydrofuran at room
temperature by using a metal amide formed from butyllithium (a
slight excess of the latter is enough to rationalize the formation
of the butylated alcohol 4b). Interestingly, both structures
obtained by X-ray diffraction show intermolecular hydrogen
bonds at the crystal state.
General synthetic and analytical details. Column chromatography
separations were achieved on silica gel (40-63 μm). Melting points were
measured on a Kofler apparatus. IR spectra were taken on a Perkin-
Elmer Spectrum 100 spectrometer. Unless otherwise cited in the product
description, 1H and 13C Nuclear Magnetic Resonance (NMR) spectra
were recorded on a Bruker Avance III spectrometer at 300 MHz and 75
MHz, respectively. 1H chemical shifts (δ) are always given in ppm relative
to the solvent residual peak and 13C chemical shifts are relative to the
central peak of the solvent signal.57 7-Chloroisatin (2’-Cl) and 5-
butylisatin (2-Bu) were prepared as described previously58 while the
other isatins were purchased.
General crystallographic details. The samples were studied using Mo-
K radiation ( = 0.71073 Å) at the temperature given in the crystal data.
For compounds 1-H and 3, the X-ray diffraction data were collected using
APEXII Bruker-AXS diffractometer (graphite monochromatized). The
structure was solved by direct methods using the SIR97 program,59 and
then refined with full-matrix least-square methods based on F2 (SHELX-
97)60 with the aid of the WINGX program.61 All non-hydrogen atoms were
refined with anisotropic atomic displacement parameters. For 1-Bu, 1-
OMe, 1-OCF3, 4a and 4b, the X-ray diffraction data were collected using
D8 VENTURE Bruker AXS diffractometer (multilayer monochromatized).
The structure was solved by dual-space algorithm using the SHELXT
program,62 and then refined with full-matrix least-square methods based
on F2 (SHELXL-2014).63 All non-hydrogen atoms were refined with
anisotropic atomic displacement parameters. Except oxygen linked
hydrogen atoms that was introduced in the structural model through
Fourier difference maps analysis in the case of 4a and 4b, H atoms were
finally included in their calculated positions. The molecular diagrams
were generated by ORTEP-3 (version 2.02).64
Biological evaluation.
Therefore, combining our mild-formation of tryptanthrins with
nucleophilic additions will allow the exploration of the chemical
space around this tetracyclic indoloquinazolinedione derivative,
in search for original biologically active molecules.
The antibacterial, antifungal and antioxidant activity was determined as
described previously.65
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900352
European Journal of Organic Chemistry
FULL PAPER
Antiproliferative activity. Healthy human adult adipose-derived
mesenchymal stem cells cell line MSCs (ATCC, PCS-500-011) was used
at passage 4. Cells were seeded to a density of 5.103 cells.cm-2 in each
well of a six-well plate (Corning). Cells were treated with the synthesized
compounds 1-H, 1-Cl, 1-I and 1-OMe at concentrations of 0.01, 0.03 and
0.10 mg.mL-1. All the molecules were reconstituted in DMSO. After 24
and 48 h, cells were counted and the inhibition growth index was
calculated. The viability was assessed using the trypan blue stain. The
viability of adipose-derived MSCs, solubilized in the same DMSO
concentration used for synthetic compounds, is considered as reference
control. The toxicity effect of 1-H, 1-Cl, 1-I and 1-OMe compounds was
assessed also by evaluating the apoptotic features of MSCs by
microscopy examination (Nikon inverted microscope).
converged at ωR(F2) = 0.1094 (R(F) = 0.0481) for 1732 observed
reflections with I > 2σ(I). CCDC 1898458. These data are close to those
reported previously.68
2,8-Dibutylindolo[2,1-b]quinazoline-6,12-dione (1-Bu). To 5-butylisatin
(2-Bu; 1.3 g, 6.4 mmol) and KOH (0.73 g, 13 mmol) in DMF (14 mL) was
added dropwise at room temperature a solution of I2 (1.3 g, 6.4 mmol) in
DMF (14 mL). After stirring for 4 days, the reaction mixture was poured
onto iced water (90 mL) containing NH4OH (4 mL) and Na2S2O3 (6 g).
The precipitate formed after 10 h in a fridge was collected by filtration
and chromatographed over silica gel (eluent: AcOEt-heptane 50:50) to
afford 1-Bu in 70% yield (0.80 g) as a yellow powder: mp 160 °C; IR
(ATR): 706, 759, 787, 839, 847, 863, 1044, 1102, 1119, 1135, 1207,
1315, 1350, 1431, 1478, 1588, 1603, 1662, 1725, 2858, 2870, 2930,
2959, 3052 cm-1; 1H NMR (CDCl3)  0.95 (t, 3H, J = 7.4 Hz), 0.96 (t, 3H,
J = 7.4 Hz), 1.31-1.46 (m, 4H), 1.59-1.75 (m, 4H), 2.70 (t, 2H, J = 7.7 Hz),
2.80 (t, 2H, J = 7.8 Hz), 7.57 (dd, 1H, J = 8.3 and 2.0 Hz), 7.65 (dd, 1H, J
= 8.4 and 2.1 Hz), 7.70 (d, 1H, J = 1.5 Hz), 7.92 (d, 1H, J = 8.1 Hz), 8.22
(d, 1H, J = 1.8 Hz), 8.49 (d, 1H, J = 8.1 Hz); 13C NMR (CDCl3)  14.0
(CH3), 14.0 (CH3), 22.3 (CH2), 22.4 (CH2), 33.4 (CH2), 33.4 (CH2), 35.2
(CH2), 35.8 (CH2), 117.8 (CH), 122.3 (C), 123.7 (C), 124.9 (CH), 126.8
(CH), 130.7 (CH), 135.8 (CH), 138.4 (CH), 142.5 (C), 144.2 (C), 144.6
(C), 144.9 (C), 146.2 (C), 158.2 (C), 182.9 (C). Crystal data for 1-Bu.
C23H24N2O2, M = 360.44, T = 150(2) K, triclinic, P -1, a = 5.1503(12), b =
13.656(3), c = 13.902(3) Å, α = 74.392(7), β = 89.234(8), γ = 85.397(7) °,
V = 938.7(3) Å3, Z = 2, d = 1.275 g cm-3, μ = 0.082 mm-1. A final
refinement on F2 with 4316 unique intensities and 246 parameters
converged at ωR(F2) = 0.2119 (R(F) = 0.0856) for 3008 observed
reflections with I > 2σ(I). CCDC 1898459.
Proteasome inhibition. Purified human 20S constitutive proteasome
was purchased from Boston Biochem. Proteasome activities were
determined as previously described.66 Briefly, the enzyme-catalyzed
hydrolysis of the appropriate fluorogenic substrate (Suc-LLVY-AMC,
concentration 20 µM for the ChT-L activity; Z-LLE-NA concentration 50
µM for the PA activity; Boc-LRR-AMC, concentration 50 µM for the T-L
activity) was followed in microplates for 45 min, at 37 °C and pH 8, by
monitoring the fluorescence emission of the released fluorophore (exc
=
360 nm and em = 460 nm for 7-amino-4-methyl-coumarin AMC and exc
= 340 nm and em = 404 nm for -naphtylamine NA). Substrates were
dissolved in DMSO. Tryptanthrins were also dissolved in DMSO in order
to obtain 5 mM stock solutions except for 1-I (3.5 mM), 1-OMe (3.8 mM)
and 1-OCF3 (4.3 mM). The DMSO percentage was maintained to 2%
(v/v) in all experiments, except for those related to 1-I, 1-OMe and 1-
OCF3 (2.5 %). The mixtures of the enzyme and the tryptanthrins were
incubated for 15 min prior treatment by the substrate. The initial rates in
the presence of DMSO (control, V0) or of the tested tryptanthrin at
concentration [I] (Vi) were used to determine the inhibition percentage
and IC50 values according to equations (1) and (2). Data were fitted to
equation (2) using the Kaleidagraph software.
2,8-Difluoroindolo[2,1-b]quinazoline-6,12-dione
(1-F).
To
5-
fluoroisatin (2-F; 0.82 g, 5.0 mmol) and KOH (0.57 g, 10 mmol) in DMF
(10 mL) was added dropwise at room temperature a solution of I2 (1.3 g,
5.0 mmol) in DMF (10 mL). After stirring for 8 days at r.t. and 3 h at
100 °C, the reaction mixture was poured onto iced water (70 mL)
containing NH4OH (3 mL) and Na2S2O3 (5 g). The precipitate formed
after 10 h in a fridge was collected by filtration and chromatographed
over silica gel (eluent: AcOEt-heptane 60:40) to afford 1-F in 58% yield
(0.41 g) as a greenish powder: mp > 260 °C (lit.35 295-297 °C); IR (ATR):
704, 744, 776, 814, 835, 888, 1037, 1099, 1120, 1162, 1206, 1242, 1270,
1306, 1350, 1470, 1568, 1606, 1678, 1729, 3081, 3130 cm-1; 1H NMR
(CDCl3)  7.50 (td, 1H, J = 8.6 and 2.7 Hz), 7.53-7.60 (m, 2H), 8.01-8.10
(m, 2H), 8.63 (dd, 1H, J = 8.9 and 4.1 Hz); 13C NMR (CDCl3)  112.3 (CH,
d, J = 24 Hz), 113.5 (CH, d, J = 25 Hz), 119.9 (CH, d, J = 7 Hz), 123.7
(CH, d, J = 24 Hz), 125.0 (CH, d, J = 24 Hz), 125.8 (C, d, J = 9 Hz),
133.4 (CH, d, J = 9 Hz), 142.4 (C, d, J = 3 Hz), 143.3 (C), 143.3 (C),
143.9 (C), 157.1 (C, d, J = 4 Hz), 161.4 (C, d, J = 249 Hz), 163.4 (C, d, J
= 253 Hz), 181.5 (C, d, J = 3 Hz). The spectral data are analogous to
those described previously.35
Synthesis of the tryptanthrins from the corresponding isatins.
Indolo[2,1-b]quinazoline-6,12-dione or tryptanthrin (1-H). To isatin (2-
H; 2.1 g, 14 mmol) and KOH (1.6 g, 28 mmol) in DMF (30 mL) was
added dropwise at room temperature a solution of I2 (3.6 g, 14 mmol) in
DMF (30 mL). After stirring for 4 days, the reaction mixture was poured
onto iced water (200 mL) containing NH4OH (8 mL) and Na2S2O3 (14 g).
The precipitate formed after 10 h in a fridge was collected by filtration
and washed by AcOEt (4 x 30 mL) before drying under vacuum to afford
1-H in 73% yield (1.3 g) as a yellow powder: mp 260-262 °C (lit.67 261-
262 °C); IR (ATR): 689, 755, 777, 867, 925, 1039, 1103, 1116, 1165,
1185, 1311, 1353, 1457, 1593, 1680, 1724, 3036, 3070, 3438, 3750 cm-1;
1H NMR (CDCl3)  7.41 (t, 1H, J = 7.5 Hz), 7.66 (td, 1H, J = 7.7 and 0.9
Hz), 7.77 (td, 1H, J = 7.8 and 1.2 Hz), 7.84 (td, 1H, J = 7.7 and 1.5 Hz),
7.90 (d, 1H, J = 7.5 Hz), 8.01 (d, 1H, J = 7.8 Hz), 8.41 (dd, 1H, J = 8.0
and 1.1 Hz), 8.60 (d, 1H, J = 8.1 Hz); 13C NMR (CDCl3)  118.1 (CH),
122.0 (C), 123.8 (C), 125.5 (CH), 127.3 (CH), 127.7 (CH), 130.4 (CH),
130.8 (CH), 135.3 (CH), 138.4 (CH), 144.4 (C), 146.4 (C), 146.7 (C),
158.2 (C), 182.7 (C). The spectral data are analogous to those described
previously.67 Crystal data for 1-H. C15H8N2O2, M = 248.23, T = 150(2) K,
monoclinic, P 21/n, a = 7.2839(5), b = 7.5706(5), c = 19.4214(14) Å, β =
91.033(3) °, V = 1070.79(13) Å3, Z = 4, d = 1.54 g cm-3, μ = 0.105 mm-1.
A final refinement on F2 with 2455 unique intensities and 172 parameters
2,8-Dichloroindolo[2,1-b]quinazoline-6,12-dione
(1-Cl).
To
5-
chloroisatin (2-Cl; 2.5 g, 14 mmol) and KOH (1.6 g, 28 mmol) in DMF (30
mL) was added dropwise at room temperature a solution of I2 (3.6 g, 14
mmol) in DMF (30 mL). After stirring for 4 days, the reaction mixture was
poured onto iced water (200 mL) containing NH4OH (8 mL) and Na2S2O3
(14 g). The precipitate formed after 10 h in a fridge was collected by
filtration and chromatographed over silica gel (eluent: AcOEt-heptane
60:40) to afford 1-Cl in 53% yield (1.2 g) as a yellow powder: mp >
260 °C (lit.35 289-291 °C); IR (ATR): 700, 709, 760, 781, 845, 1015, 1024,
1038, 1133, 1170, 1187, 1214, 1255, 1335, 1437, 1462, 1554, 1590,
1603, 1671, 1722, 1734, 2841, 2943, 2971, 3075 cm-1; 1H NMR (CDCl3)
 7.75 (dd, 1H, J = 8.6 and 2.3 Hz), 7.66 (dd, 1H, J = 8.4 and 2.4 Hz),
7.88 (d, 1H, J = 2.1 Hz), 7.97 (d, 1H, J = 8.7 Hz), 8.40 (d, 1H, J = 2.4 Hz),
8.58 (d, 1H, J = 8.7 Hz); 13C NMR (CDCl3)  119.4 (CH), 123.3 (C), 124.9
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10.1002/ejoc.201900352
European Journal of Organic Chemistry
FULL PAPER
(C), 125.5 (CH), 127.4 (CH), 132.4 (CH), 133.8 (C), 135.8 (CH), 137.1
(C), 138.0 (CH), 144.1 (C), 144.3 (C), 145.2 (C), 156.9 (C), 181.2 (C).
The spectral data are analogous to those described previously.35 Crystal
data for 4a. Due to our efforts to solubilize 1-Cl in acetone in order to get
suitable crystals for X-ray diffraction, we observed in the structure the
addition of an acetone molecule onto the tryptanthrin ketone
(cetolization) to afford 4a56a (the other acetone molecule co-crystallized
with the product: C18H12Cl2N2O3,C3H6O, M = 433.27, T = 150(2) K;
triclinic, P -1, a = 8.7184(8), b = 9.5852(7), c = 13.7891(11) Å, α =
72.409(3), β = 88.633(3), γ = 64.794(2) °, V = 986.48(14) Å3, Z = 2, d =
1.459 g cm-3, μ = 0.360 mm-1. A final refinement on F2 with 4509 unique
intensities and 268 parameters converged at ωR(F2) = 0.1826 (R(F) =
0.0702) for 3617 observed reflections with I > 2σ(I). CCDC 1898460.
(CH), 125.5 (C), 132.5 (CH), 140.4 (C), 141.0 (C), 142.9 (C), 157.6 (C),
158.9 (C), 161.5 (C), 182.7 (C). The spectral data are analogous to those
described previously.35 Crystal data for 1-OMe. C17H12N2O4, M = 308.29,
T = 295 K, monoclinic, P 21/n, a = 18.012(7), b = 3.8582(15), c =
20.150(7) Å, β = 100.88(2) °, V = 1375.1(9) Å3, Z = 4, d = 1.489 g cm-3, μ
= 0.108 mm-1. A final refinement on F2 with 3109 unique intensities and
210 parameters converged at ωR(F2) = 0.2482 (R(F) = 0.0904) for 1838
observed reflections with I > 2σ(I). CCDC 1898461.
2,8-Bis(trifluoromethoxy)indolo[2,1-b]quinazoline-6,12-dione
(1-
OCF3).36 To 5-(trifluoromethoxy)isatin (0.46 g, 2.0 mmol) and KOH (0.23
g, 4.0 mmol) in DMF (5 mL) was added dropwise at room temperature a
solution of I2 (0.51 g, 2.0 mmol) in DMF (5 mL). After stirring for 4 days,
the reaction mixture was poured onto iced water (30 mL) containing
NH4OH (1 mL) and Na2S2O3 (2 g). The precipitate formed after 10 h in a
fridge was collected by filtration and chromatographed over silica gel
(eluent: AcOEt-heptane 60:40) to afford 1-OCF3 in 34% yield (0.14 g) as
a yellow powder: mp 246-247 °C; IR (ATR): 677, 781, 801, 837, 852, 863,
1040, 1104, 1125, 1160, 1210, 1256, 1292, 1474, 1605, 1683, 1741,
2852, 2924, 2958, 3081 cm-1; 1H NMR (CDCl3)  7.65 (ddd, 1H, J = 8.9,
2.6 and 0.8 Hz), 7.69 (ddd, 1H, J = 8.9, 2.7 and 0.7 Hz), 7.77-7.78 (m,
1H), 8.09 (d, 1H, J = 9.0 Hz), 8.26 (dd, 1H, J = 2.4 and 0.9 Hz), 8.69 (d,
1H, J = 8.7 Hz); 1H NMR ((CD3)2SO)  7.92 (dd, 1H, J = 9.0 and 1.5 Hz),
7.96 (d, 1H, J = 1.3 Hz), 7.98 (dd, 1H, J = 9.0 and 2.5 Hz), 8.13 (d, 1H, J
= 8.5 Hz), 8.18 (d, 1H, J = 1.5 Hz), 8.56 (d, 1H, J = 8.5 Hz); 13C NMR
(125 MHz, (CD3)2SO, 378 K)  116.6 (CH), 117.3 (CH), 118.4 (CH),
119.5 (CF3, q, J = 257 Hz), 119.6 (CF3, q, J = 256 Hz), 123.3 (C), 124.3
(C), 127.3 (CH), 129.3 (C), 132.1 (CH), 143.7 (C), 144.7 (C), 144.9 (C),
146.3 (C), 148.3 (C), 156.2 (C), 180.2 (C). Crystal data for 1-OCF3.
C17H6F6N2O4, M = 416.24, T = 150(2) K, triclinic, P -1, a = 6.9024(9), b =
2,8-Dibromoindolo[2,1-b]quinazoline-6,12-dione
(1-Br).
To
5-
bromoisatin (2-Br; 0.90 g, 4.0 mmol) and KOH (0.46 g, 8.0 mmol) in DMF
(9 mL) was added dropwise at room temperature a solution of I2 (1.0 g, 4
mmol) in DMF (9 mL). After stirring for 3 days, the reaction mixture was
poured onto iced water (60 mL) containing NH4OH (2 mL) and Na2S2O3
(4 g). The precipitate formed after 10 h in a fridge was collected by
filtration and chromatographed over silica gel (eluent: AcOEt-heptane
60:40) to afford 1-Br in 15% yield (0.12 g) as a yellow powder: mp >
260 °C (lit.38a 319-321 °C); IR (ATR): 741, 782, 803, 845, 1037, 1182,
1262, 1301, 1330, 1459, 1585, 1674, 1730, 2852, 2921 cm-1; 1H NMR
(CDCl3)  7.89 (d, 1H, J = 8.4 Hz), 7.91 (dd, 1H, J = 8.4 and 2.1 Hz), 7.96
(dd, 1H, J = 8.6 and 2.3 Hz), 8.03 (d, 1H, J = 1.8 Hz), 8.52 (d, 1H, J = 8.7
Hz), 8.56 (d, 1H, J = 2.1 Hz); 13C NMR (CDCl3)  118.2 (C), 120.7 (C),
121.9 (CH), 122.8 (C), 125.3 (CH), 130.1 (CH), 130.5 (CH), 136.3 (C),
137.4 (CH), 137.7 (CH), 141.8 (C), 145.8 (C), 151.0 (C), 157.6 (C), 185.0
(C). The spectral data are analogous to those described previously.38a
7.5517(10),
c = 14.893(2) Å, α = 85.430(5), β = 78.965(5), γ =
89.996(5) °, V = 759.42(18) Å3, Z = 2, d = 1.820 g cm-3, μ = 0.178 mm-1.
A final refinement on F2 with 3466 unique intensities and 262 parameters
converged at ωR(F2) = 0.1114 (R(F) = 0.0464) for 2593 observed
reflections with I > 2σ(I). CCDC 1898462.
2,8-Diiodoindolo[2,1-b]quinazoline-6,12-dione (1-I). To 5-iodoisatin (2-
I; 1.9 g, 7.0 mmol) and KOH (0.80 g, 14 mmol) in DMF (15 mL) was
added dropwise at room temperature a solution of I2 (1.8 g, 7.0 mmol) in
DMF (15 mL). After stirring for 4 days, the reaction mixture was poured
onto iced water (100 mL) containing NH4OH (4 mL) and Na2S2O3 (7 g).
The precipitate formed after 10 h in a fridge was collected by filtration
and washed by AcOEt (4 x 15 mL) before drying under vacuum to afford
1-I in 40% yield (0.70 g) as a yellow powder: mp > 270 °C (lit.38a 338-
340 °C); IR (ATR): 733, 845, 856, 1036, 1051, 1117, 1178, 1188, 1303,
1341, 1422, 1458, 1544, 1583, 1678, 1725, 2921, 3024, 3058, 3081 cm-1;
1H NMR (CDCl3)  7.73 (d, 1H, J = 8.7 Hz), 8.10 (dd, 1H, J = 8.7 and 1.2
Hz), 8.14 (dd, 1H, J = 8.4 and 1.8 Hz), 8.22 (d, 1H, J = 1.8 Hz), 8.38 (d,
1H, J = 8.4 Hz), 8.77 (d, 1H, J = 1.8 Hz); 13C NMR (CDCl3)  91.3 (C),
96.5 (C), 119.8 (CH), 119.8 (C), 123.4 (C), 124.9 (C), 132.2 (CH), 134.1
(CH), 136.6 (CH), 143.7 (C), 144.3 (CH), 145.9 (C), 146.6 (CH), 156.4
(C), 180.8 (C). The spectral data are analogous to those described
previously.38a
2-Hydroxyethyl [2-((2-hydroxyethoxy)carbonyl)amino]benzoate (3).
To a stirred solution of isatin (0.15 g, 1.0 mmol) in ethylene glycol (5 mL)
at room temperature was added KOH (0.11 g, 2.0 mmol), followed by I2
(0.25 g, 1.0 mmol). After stirring for 1 day, the reaction mixture was
poured onto a saturated aqueous solution of Na2S2O3 (50 mL) and
extracted with AcOEt. The organic layer was washed with brine, dried
over Na2SO4 and evaporated. Purification was achieved by column
chromatography over silica gel using AcOEt-Heptane 70:30 as eluent.
Compound 3 was obtained (Rf = 0.24) in 11% yield (30 mg) as a white
powder: 100-102 °C; IR (ATR): 1218, 1247, 1261, 1452, 1530, 1594,
1690, 1717, 1735, 2886, 2962, 3270, 3299 cm-1; 1H NMR (CDCl3)  2.17
and 3.41 (br s, 2H, OH), 3.82 (dd, 2H, J = 5.6 and 3.6 Hz, CH2), 3.90 (dd,
2H, J = 5.7 and 3.8 Hz, CH2), 4.24-4.27 (m, 2H, CH2), 4.38-4.41 (m, 2H,
CH2), 7.00 (td, 1H, J = 7.7 and 1.1 Hz), 7.49 (ddd, 1H, J = 8.7, 7.2 and
1.7 Hz), 8.01 (dd, 1H, J = 8.0 and 1.7 Hz), 8.31 (dd, 1H, J = 8.5 and 1.1
Hz), 10.35 (s, 1H, NH); 13C NMR (CDCl3)  60.7 (CH2), 61.2 (CH2), 66.8
(CH2), 67.0 (CH2), 114.9 (C), 119.0 and 119.1 (CH), 122.0 (CH), 131.2
(CH), 134.8 (CH), 141.2 and 141.4 (C), 153.9 (C, C=O), 168.1 and 168.2
(C, C=O). Crystal data for 3. C12H15NO6, M = 269.25, T = 150(2) K,
monoclinic, P 21/c, a = 8.0584(8), b = 19.9778(15), c = 8.5074(9) Å, β =
111.608(3) °, V = 1273.3(2) Å3, Z = 4, d = 1.404 g cm-3, μ = 0.114 mm-1.
A final refinement on F2 with 2905 unique intensities and 174 parameters
converged at ωR(F2) = 0.1356 (R(F) = 0.0546) for 2187 observed
reflections with I > 2σ(I). CCDC 1898463.
2,8-Dimethoxyindolo[2,1-b]quinazoline-6,12-dione (1-OMe). To 5-
methoxyisatin (2-OMe; 2.5 g, 14 mmol) and KOH (1.6 g, 28 mmol) in
DMF (30 mL) was added dropwise at room temperature a solution of I2
(3.6 g, 14 mmol) in DMF (30 mL). After stirring for 4 days, the reaction
mixture was poured onto iced water (200 mL) containing NH4OH (8 mL)
and Na2S2O3 (14 g). The precipitate formed after 10 h in a fridge was
collected by filtration and chromatographed over silica gel (eluent:
AcOEt-heptane 60:40) to afford 1-OMe in 80% yield (1.7 g) as a yellow
powder: mp > 270 °C (lit.35 285-288 °C); IR (ATR): 703, 732, 780, 807,
843, 1014, 1023, 1073, 1108, 1137, 1168, 1219, 1256, 1285, 1319, 1345,
1436, 1464, 1479, 1556, 1603, 1665, 1721, 2841, 2943, 2973, 3027,
3053 cm-1; 1H NMR (CDCl3)  3.89 (s, 3H), 3.98 (s, 3H), 7.29 (dd, 1H, J =
9.0 and 2.7 Hz), 7.36-7.40 (m, 2H), 7.81 (d, 1H, J = 2.7 Hz), 7.93 (d, 1H,
J = 8.7 Hz), 8.50 (d, 1H, J = 8.7 Hz); 13C NMR (CDCl3)  56.1 (CH3), 56.2
(CH3), 108.3 (CH), 108.4 (CH), 119.3 (CH), 123.5 (C), 124.3 (CH), 124.9
6-Butyl-6-hydroxy-6H-indolo[2,1-b]quinazolin-12-one (4b).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900352
European Journal of Organic Chemistry
FULL PAPER
The white solid was isolated as
a
by-product in an attempt to
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deprotometallate 1-H using lithium 2,2,6,6-tetramethylpiperidine. It was
identified by comparison of its NMR data with those described
previously:56b 1H NMR (CDCl3)  0.73 (t, 3H, J = 7.3 Hz, CH3), 0.82-0.89
(m, 2H, CH2), 1.16-1.21 (m, 2H, CH2), 2.20-2.36 (m, 2H, CH2), 4.02 (br s,
1H, OH), 7.16 (td, 1H, J = 7.4 and 1.4 Hz), 7.23 (td, 1H, J = 7.8 and 1.8
Hz), 7.48 (ddd, 1H, J = 8.2, 6.7 and 1.7 Hz), 7.51-7.54 (m, 1H), 7.74 (td,
1H, J = 7.4 and 1.5 Hz), 7.77-7.80 (m, 1H), 8.23 (dd, 1H, J = 7.9 and 1.4
Hz), 8.30 (dd, 1H, J = 7.5 and 1.4 Hz); 13C NMR (CDCl3)  13.8 (CH3),
22.6 (CH2), 25.5 (CH2), 39.6 (CH2), 78.4 (CH), 116.4 (CH), 121.3 (C),
123.7 (CH), 127.1 (CH), 127.2 (CH), 127.3 (CH), 127.7 (CH), 129.9 (CH),
132.8 (C), 134.5 (CH), 138.3 (C), 147.2 (C), 159.9 (C), 160.9 (C). Crystal
data for 4b. C19H18N2O2, M = 306.35, T = 150(2) K, triclinic, P -1, a =
9.5244(18), b = 11.009(2), c = 16.485(3) Å, α = 72.146(6), β = 84.597(7),
γ = 69.590(6) °, V = 1541.8(5) Å3, Z = 4, d = 1.320 g cm-3, μ = 0.087 mm-1.
A final refinement on F2 with 6873 unique intensities and 424 parameters
converged at ωR(F2) = 0.1969 (R(F) = 0.0938) for 5521 observed
reflections with I > 2σ(I). CCDC 1898464.
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
Bioactive heterocycles
Rim Amara, Haçan Awad, Diana
Chaker, Ghenia Bentabed-Ababsa,*
Frédéric Lassagne, William Erb,
Floris Chevallier, Thierry Roisnel,
Vincent Dorcet, Ziad Fajloun,*
Joëlle Vidal* and Florence Mongin*
A straightforward and versatile synthetic approach to tryptanthrins is developed.
Starting from isatins, through addition of iodine and potassium hydroxide, the
method is shown to be an efficient route to these indoloquinazoline alkaloids,
whose in vitro bioactivities are investigated.
Page No. – Page No.
Conversion of isatins to
tryptanthrins, heterocycles endowed
with a myriad of bioactivities
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