A short and highly convergent approach for the synthesis of rutaecarpine derivatives

Article abstract of DOI:10.1039/c4ra14093a

A novel and highly convergent approach has been developed for the synthesis of quinazolinocarboline alkaloid, rutaecarpine, analogues by the condensation of anthranilamide with chloroaldehyde derived from tryptophol. This method also provides direct access to benzimidazocarbolines and quinazolinoisoquinolines. It is a shorter and metal-free approach which does not require any catalyst or additive to facilitate the reaction.

Full text of DOI:10.1039/c4ra14093a

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A short and highly convergent approach for the
synthesis of rutaecarpine derivatives†
Cite this: RSC Adv., 2015, 5, 27476
B. V. Subba Reddy, a R. Anji Babu,ae B. Jagan Mohan Reddy,e B. Sridhar,b T. Ramalinga
*
Murthy,c P. Pranathi,c Shasi V. Kalivendic and T. Prabhakar Raod
A novel and highly convergent approach has been developed for the synthesis of quinazolinocarboline
alkaloid, rutaecarpine, analogues by the condensation of anthranilamide with chloroaldehyde derived
from tryptophol. This method also provides direct access to benzimidazocarbolines and
quinazolinoisoquinolines. It is a shorter and metal-free approach which does not require any catalyst or
additive to facilitate the reaction.
Received 8th November 2014
Accepted 10th March 2015
DOI: 10.1039/c4ra14093a
www.rsc.org/advances
anthranilamide with
condensation proceeds smoothly in DMF through haloamide
cyclization (Scheme 1).
The requisite chloroaldehyde was prepared from the trypto-
phol through a sequential N-protection and Vilsmeier–Haack
reaction (Scheme 2).
Initially, we attempted the coupling of 2a with anthranil-
amide (3) in DMF. The reaction was performed at different
temperatures in various solvents and the results are presented
in Table 1. The reaction was found to be sluggish at ambient
temperature and the product 4a was isolated only in 35% yield
aer a long reaction time (12 h). By increasing the temperature
from 25 to 120 ꢀC, the desired product 4a was obtained in 90%
yield (entry e, Table 1). Of various solvents like DMF, DMSO,
and 1,2-dichlorobenzene tested, DMF gave the best results
(Table 1).
a bifunctional chloroaldehyde. The
Introduction
Rutaecarpine, a naturally occurring quinazolinocarboline alka-
loid isolated from the fruits of Evodia rutaecarpa1 is known to
possess a diverse range of pharmacological properties such as
anticancer, anti-inammatory and anti-obesity behaviour
(Fig. 1).2,3
It has also been used as a hypertensive, antiallergic, diuretic
and platelet aggregation inhibitor.4 Indeed, analogues of rutae-
carpine are found to display superior activity than rutaecarpine
when evaluated against several tumour cell lines.5–7 Generally,
rutaecarpine derivatives were synthesized by structurally modi-
fying the A or D or E rings.8 Therefore, the development of novel
approaches to access rutaecarpine analogues may lead to ther-
apeutic applications. Consequently, several methods have been
reported for the synthesis of various analogues of rutaecarpine.9
However, many of them involve multi-step synthetic sequences,
stringent conditions, and expensive reagents.
Following our interest on quinazolinone alkaloids,10 we
herein report a highly convergent approach for the synthesis of
rutaecarpine analogues through the condensation of
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka,
500 007, Hyderabad, India. E-mail: basireddy@iict.res.in; Web: http://www.iictindia.
org; Fax: +91-40-27160512
bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Tarnaka, 500 007, Hyderabad, India
cCentre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka,
500 007, Hyderabad, India
dCentre for Nuclear Magnetic Resonance, CSIR-Indian Institute of Chemical
Technology, Tarnaka, 500 007, Hyderabad, India
eDepartment of Organic Chemistry, Adikavi Nannaya University, Rajahmundry,
533105, India
† Electronic supplementary information (ESI) available: Detailed procedures and
spectroscopic data for novel compounds, copies of 1H NMR, 13C NMR of novel
compounds prepared are available. CCDC 1023835. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ra14093a
Fig. 1 Biologically active natural products.
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Fig. 2 ORTEP diagram of 4a.
Scheme
1 Synthesis of quinazolinocarbolines and benzimidazo-
carbolines.
Table 2). In addition, 2-(2-bromoethyl)benzaldehyde (2g)13 also
worked well for this conversion to produce the corresponding
4g in 86% yield (entry g, Table 2). Inspired by the above results,
we extended this approach to the condensation of chlor-
oaldehydes with o-phenylenediamines (5). Interestingly, this
reaction proceeded well under similar conditions to furnish the
corresponding benzimidazocarbolines (6) in good yields
(Table 3).
Scheme 2 Synthesis of chloroaldehyde 2a/2e. Reagents & conditions:
(a) TBAHS, CH3I, CH2Cl2 for (1a) (b) (i) imidazole, DMF, TBDMSCl, 0 ꢀC
to r.t. (ii) NaH in DMF, BnBr (iii) TBAF in THF for (1b) (c) POCl3/DMF,
60 ꢀC for 12 h.
No signicant effect of the substituents that are present on
haloaldehyde (2), o-amino-carboxamide (3) or o-phenylenedi-
amine (5) was observed under present reaction conditions. It is
noteworthy to mentioned that only one regioisomer is formed,
in which the substituent is meta to imine functionality as
1
conrmed by H NMR spectrum (entries a and b, Table 3).14a
Table 1 Optimization of solvent and temperature in the formation of
4aa
This is due to electronic effects of the substituents. Further-
more, pyridine-2,3-diamine also afforded a single regioisomer
as reported earlier in literature (entry d, Table 3).14b The reaction
was quite successful with both N-methyl and N-benzyl chlor-
oaldehydes. Thus this method is very useful for the synthesis of
a diverse range of carbolines in a simple way. Mechanistically,
the reaction is expected to proceed via the formation of imi-
nium ion. This is attacked by the internal amido group to give
the desired product (Scheme 3).
Entry
Solvent
Temp. ꢀC
Time (h)
Yield (%)
a
b
c
d
e
f
DMF
DMF
DMF
DMF
25
25
25
65
120
25
120
120
3
6
12
24
5
12
12
12
10
20
35
75
90
NR
55
50
DMF
DMSO
DMSO
o-DCB
g
h
a
o-DCB ¼ ortho-dichlorobenzene.
In vitro anticancer activity
The end products were evaluated for their anti-proliferative
activity against three human tumor cell lines; A549, HeLa and
Under optimized conditions, the required product 4a was MCF-7. In order to examine the anti-proliferative effects,
isolated in 90% yield. The structure of 4a was established by different concentrations of test compounds (1–100 mM) were
X-ray crystallography (Fig. 2).11
incubated with three cell lines for 48 h along with the positive
Similarly, the coupling of chloroaldehyde (2a) with 5-amino- control (rutaecarpine) and examined the cell viability employing
1-methyl-3-propyl-1H-pyrazole-4-carboxamide afforded the MTT assay.
product 4c in 87% yield (entry c, Table 2). Furthermore, the
The results indicate that while rutaecarpine exhibited an
cyclization of 2a with 2-aminopyridine-3-carboxamide gave the IC50 value of 53.8 mM in HeLa cells, compound 4a exhibited
respective product 4d in 85% yield (entry d, Table 2). Likewise, 33.3 mM. However, for all other compounds in the series, the
1-benzyl-3-(2-chloroethyl)-1H-indole-2-carbaldehyde (2e) also values obtained were more than 70 mM. In SK-N-SH cells, while
participated well in this cyclization (entry e, Table 2).
the compounds 4e and 6e exhibited ꢁ92 mM, the values were
The scope of this method is further exemplied with nearly 50 mM for compounds 4d and 6d. The rest of the
2-(2-chloroethyl)-4,5-dimethoxybenzaldehyde 2f12 with anthra- compounds in the series exhibited the IC50 values almost
nilamide afforded the corresponding 4f in 89% yield (entry f, comparable to that of rutaecarpine (ꢁ67 mM). However, in
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Table 2 Synthesis of polycyclic quinazolinones
Entry
Haloaldehyde (2)
Amino-carboxamide (3)
Quinazolinone (4)
Time (h)
5
Yielda (%)
90
a
b
c
6
6
89
87
d
e
f
5
6
5
85
90
89
g
4
86
a
Yield refers to pure products aer chromatography.
MCF-7 breast cancer cells, except for compound 6d (IC50 of (d ¼ 77.27) was used as internal standard and spectra were
94 mM), all other compounds in the series including the positive obtained with complete proton decoupling. Low-resolution MS
control rutaecarpine exhibited the IC50 values much more than and HRMS data were obtained using ESI ionization. Melting
the maximum employed concentration i.e., 100 mM. The points were measured on micro melting point apparatus.
obtained values indicate that the compounds in the series are Reaction progress was monitored by thin layer chromatography
less cytotoxic, however, their precise physiological effects needs (TLC) on precoated silica gel GF254 plates and the spots were
to be examined further (Table 4).
detected under UV light (254 nm).
In summary, we have developed a simple and convenient
strategy for the synthesis of several analogues of rutaecarpine.
This method also provides a direct access to benzimidazo-
carbolines and quinazolinoisoquinolines of biological
importance.
Materials and methods
Cell cultures, maintenance and evaluation of cytotoxicity
All the cell lines used in this study were purchased from the
American Type Culture Collection (ATCC, United States). A549,
HeLa and MCF-7 were grown in Dulbecco's modied Eagle's
medium (DMEM) containing 10% FBS in a humidied atmo-
Experimental
IR spectra were recorded on FT-IR spectrometer (KBr) and sphere of 5% CO2 at 37 ꢀC. SK-N-SH neuroblastoma cells
reported in reciprocal centimetres (cmꢂ1). 1H NMR spectra were were cultured in Eagle's minimal essential medium (MEM)
recorded at 600 MHz, 500 MHz, 300 MHz and 13C NMR at 150, containing non-essential amino acids, 1 mM sodium pyruvate,
1
125 MHz, 75 MHz. For H NMR, tetramethylsilane (TMS) was 10 mg mLꢂ1 bovine insulin, and 10% FBS. Cells were trypsi-
used as internal standard (d ¼ 0) and the values are reported as nized when sub-conuent from T25 asks/60 mm dishes and
follows: chemical shi, integration, multiplicity (s ¼ singlet, seeded in 96-well plates. The cytotoxicity of test compounds
d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br ¼ broad), were evaluated based on their in vitro anti-proliferative effects in
and the coupling constants in Hz. For 13C NMR, CDCl3 the above mentioned cell lines. The cell lines were grown in
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Table 3 Synthesis of benzimidazocarbolines
Entry
Haloaldehyde (2)
o-Phenylenediamine (5)
Benzimidazocarboline (6)
Time (h)
5
Yielda (%)
91
a
b
c
6
5
5
92
89
90
d
e
5
89
a
Yield refers to pure products aer chromatography.
(PerkinElmer, Inspire model) at a wavelength of 560 nm.
Percent viability was calculated on a plate by plate basis for test
wells relative to control wells. The growth inhibitory effects of
the compounds were analyzed by generating dose response
curves as a plot of the percentage surviving cells versus
compound concentration. The sensitivity of the cancer cells to
the test compound was expressed in terms of IC50, the
concentration of compound that produced 50% reduction in
viability as compared to the control cells.
General procedure for the preparation of (4)/(6)
To a solution haloaldehyde (2) (0.5 mmol) in anhydrous DMF
(4 mL) was added o-amino-carboxamide (3) or o-phenylenediamine
Scheme 3 A plausible reaction pathway.
their respective media containing 10% FBS and were seeded
into 96-well microtiter plates in 200 mL aliquots at plating
densities depending on the doubling time of individual cell
Table 4 Cytotoxicity of compounds on A549, HeLa and MCF-7 cell
lines
Compound
HeLa
SK-N-SH
MCF-7
ꢀ
lines. The microtiter plates were incubated at 37 C, 5% CO2,
95% air, and 100% relative humidity for 24 h prior to addition of
experimental drugs. Aliquots of 2 mL of the test compounds
(DMSO concentration was kept <1%) were added to the wells
already containing 198 mL of media resulting in the required
nal concentrations of test compounds. For each compound,
ve concentrations (1, 10, 25, 50 and 100 mM) were evaluated
and each was done in triplicate wells. Plates were incubated
further for 48 h, and the experiment was terminated by the
addition of 10 mL of 5% MTT and incubated further for 60 min
at 37 ꢀC. Later, the plates were washed and air-dried and bound
stain was subsequently dissolved using 100 mL of DMSO. The
absorbance was monitored in a multimode plate reader
4a
4b
4c
4d
4e
4f
4g
6a
6b
6c
6d
6e
33.3
93
1323 (>100)
89.1
89.9
72.9
68.7
70.9
53.8
92.8
67.6
70.6
72.9
69.3
70.9
54.1
92.8
67.2
219 (>100)
650 (>100)
474 (>100)
1164 (>100)
654 (>100)
1831 (>100)
283 (>100)
198 (>100)
378 (>100)
754 (>100)
94
73.9
297.6 (>100)
247 (>100)
319 (>100)
1012 (>100)
294 (>100)
ND
170 (>100)
749 (>100)
Rutaecarpine
53.8
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ꢀ
(5) (0.5 mmol) and the reaction mixture was stirred at 120 C for
5–6 h. Aer completion, as indicated by TLC, the mixture was
cooled to room temperature and poured drop wise while vigorous
stirring into 30 mL of ice cold water. The precipitated solid
was collected by ltration, washed with water, dried in vacuo to
give the quinazolinocarboline or quinazolinoisoquinoline or
benzimidazocarboline.
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