Synthesis and cytotoxic activity of 3-phenyl-4-substituted-β- carbolines

Article abstract of DOI:10.1016/j.cclet.2012.09.010

A new class of 3-phenyl-4-substituted-β-carbolines via iodine-mediated electrophilic cyclization as key step were synthesized and their inhibitory activity against three tumor cell lines was evaluated in vitro. It was found that some of the tested compoun

Full text of DOI:10.1016/j.cclet.2012.09.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1230–1232
www.elsevier.com/locate/cclet
Synthesis and cytotoxic activity of 3-phenyl-4-
substituted-b-carbolines
Liu Liu a, Ying Ying Xu b, Ze Qi Yang a, Jian Nan Xiang b, Guang Yu Xu a,
*
a Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical
Engineering, Hunan Normal University, Changsha 410081, China
b College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
Received 11 July 2012
Available online 23 October 2012
Abstract
A new class of 3-phenyl-4-substituted-b-carbolines via iodine-mediated electrophilic cyclization as key step were synthesized
and their inhibitory activity against three tumor cell lines was evaluated in vitro. It was found that some of the tested compounds
showed better cytotoxicity against HeLa and MCF-7 cells than harmine.
# 2012 Guang Yu Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: b-Carboline; Synthesis; Iodine-mediated cyclization; Cytotoxicity; Harmine
b-Carbolines ring is an important structure motif present in many biologically natural alkaloids [1–3]. A number of
b-carboline derivatives display interesting biological activities [4]. For example, the b-carboline alkaloid harmine 1
(Fig. 1) showed significant activity against several tumor cell lines [5]. Among the variety of strategies available for the
formation of b-carboline ring system, the most extensively used are the traditional Pictet–Spengler and Bischler–
Napieralski condensations [6–8]. More recently, intense efforts are directed toward to synthesize b-carboline core
using different methods [9–12]. Yamamoto reported the synthesis of substituted isoquinolines from 2-alkynyl-1-
methylene azide aromatics via iodine-mediated eletrophilic cyclization [13]. However, an analogous transformation
via iodine-mediated cyclization of 2-alkynyl-1-methylene azide indoles to synthesize b-carboline derivatives has not
been developed. In this regard, we envisioned that iodine-mediated electrophilic cyclization is an attractive option for
the synthesis of 4-substituted b-carboline derivatives 2 which was rarely reported in the literature. In this paper, we will
report the synthesis of 4-substituted 3-phenyl-b-carboline derivatives via iodine-mediated cyclization reaction as key
step. After structure characterization, these target compounds were evaluated for their inhibitory activity against
HeLa, MCF-7 and A549 cells proliferation.
The synthesis route of target compounds was illustrated in Scheme 1. The commercially available 2-methylindole 3
was treated with KOH in DMF followed by the addition of iodine to afford 3-iodoindole-2-methylindole in good yield.
This compound was not stable at room temperature and, therefore, immediately converted to N-sulfonly-3-iodine-2-
methylindone 5 with NaOH followed by addition of benzenesulfonyl chloride. Subsequent coupling of 5 with
* Corresponding author.
E-mail address: gyxu@hunnu.edu.cn (G.Y. Xu).
1001-8417/$ – see front matter # 2012 Guang Yu Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.09.010

L. Liu et al. / Chinese Chemical Letters 23 (2012) 1230–1232
1231
R
N
N
N
H
N
O
N
H
N
H
harmine 1
β
-carbolines
2
Fig. 1. The structure of b-carboline, harmine and the target compounds.
I
I
a
b
c
N
N
SO2Ph
N
H
N
H
SO2Ph
6
5
4
3
I
f
e
d
g
N
N
SO2Ph
N
SO2Ph
N
SO2Ph
CH2N3
CH2Br
9
8
7
R
R
h
N
N
N
H
N
SO2Ph
2
10
Scheme 1. Reagents and conditions: (a) I2, KOH, DMF, r.t., 4 h, yield: 94.3%; (b) PhSO2Cl, benzene, aq. NaOH, Bu4N+HSO4À, r.t., 12 h, yield:
71.7%; (c) PhCBB CH, PdCl2(PPh3)2, CuI, Et3N, N2, 35 8C, yield: 82.3%; (d) NBS, AIBN, CCl4, reflux, yield: 90.0%; (e) NaN3, petroleum/water,
Bu4N+HSO4À, reflux, 12 h, yield: 81.0%; (f) I2, CH3NO2, 105 8C, 20 h, yield:43.9%; (g) R-B(OH)2, Pd(PPh3)2Cl2, K3PO4, toluene, 45À60 8C, 20 h,
yield: 42.8À84.3%; and (h) 40% NaOH, dioxane, 80 8C, 3 h, 76.8À90.0%.
phenylacetylene in the presence of Pd(PPh3)2Cl2 and Et3N in DMF led to 2-methyl-3-(phenylethynyl)-1-
(phenylsulfonyl)indole 6, which was heated in refluxing CCl4 and then treated with NBS and AIBN to give 7.
Treatment of 7 with NaN3 in mixed solvent of water and petroleum at 90 8C to yield azide 8, which reacted with iodine
in CH3NO2 at 105 8C in basic conditions to give 4-iodine-3-phenyl-1-(phenylsulfonyl)-b-carbonline 8. The compound
8 was coupled with phenylboric acid or cyclopropylboronic acid using Pd(PPh3)2Cl2 as catalyst in toluene to give 3-
phenyl-4-substituted-1-(phenylsulfonyl)-b-carbonline 9. It should be mentioned that the coupling of linear alkylboric
acid with 8 was also attempted, but no desired product was obtained. Finally the target compounds were obtained by
hydrolysis of 9 with NaOH in aq. dioxane. The chemical structures of target compounds were identified by 1H NMR,
13C NMR and MS spectra. The spectral data of selected compounds were outlined in Ref. [14].
Table 1
Structures and cytotoxic activity to HeLa, MCF-7 and A549 cell lines of 3-phenyl-4-substituted-b-carbolines.
Compd.
R
IC50 (mmol/L)
HeLa
MCF-7
A549
1a
1b
Phenyl
>100
58.9
33.6
20.8
51.1
>100
>100
45.1
75.2
47.9
47.4
73.7
47.3
35.6
35.3
48.4
49.8
51.3
54.0
>100
47.4
72.7
82.6
26.4
28.9
8.2
4-Methylphenyl
4-Methoxyphenyl
2-Methoxyphenyl
Cyclopropyl
1c
1d
1e
14.1
36.5
32.1
18.8
17.8
20.3
4.2
1f
1g
3-Nitrophenyl
3-Formylphenyl
4-Fluorophenyl
4-Acetylphenyl
2-Bromophenyl
1h
1i
1j
Harmine

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L. Liu et al. / Chinese Chemical Letters 23 (2012) 1230–1232
The in vitro antitumor activities of the prepared compounds were tested against HeLa, MCF-7 and A549 cells with
harmine as positive controls. The results were summarized in Table 1. It showed that some of the compounds displayed
enhanced anti-tumor potency over harmine against HeLa and MCF-7 cell lines. However, the compounds with electro-
withdrawing substituents in phenyl group at C4-position displayed lower anti-tumor activity against HeLa and MCF-7
cells. A general trend is that compounds with an electro-donating group in phenyl group at C4-position have better
activity against these three cell lines than electro-withdrawing group. In addition, all target compounds showed anti-
tumor activity against A549 cell line.
In summary, we have synthesized a series of novel 4-substituted 3-phenyl-b-carbolines by several steps. Some of
the compounds showed better in vitro inhibitory activity against HeLa and MCF-7 than reference harmine. The further
synthesis and biological study for the similar novel carboline analogs are underway in our laboratory.
Acknowledgments
This work was supported by NSFC (No. 20602010), Scientific Research Fund of Hunan Provincial Education
Department (No. 10B061) and Program for Science and Technology Innovative Research Team in Higher Educational
Institutions of Hunan Province.
References
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[3] T. Ohmoto, K. Koike, in: A. Brossi (Ed.), The Alkaloids, vol. 36, Academic Press, San Diego, 1989, p. 135.
[4] R. Cao, W. Peng, Z. Wang, Curr. Med. Chem. 14 (2007) 479.
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[14] Selected data of title compounds: 1a: off-white solid, mp 202.5–204 8C; 1H NMR (500 MHz, CDCl3): d 6.94 (t, 1H, J = 7.50 Hz, ArH), 7.02 (d,
1H, J = 8.00 Hz, ArH), 7.08 (d, 1H, J = 8.00 Hz, ArH), 7.20–7.24 (m, 3H, ArH), 7.33–7.44 (m, 8H, ArH), 9.19 (s, 1H, ArH), 10.00 (s, 1H, NH);
13C NMR (CDCl3): d 111.62, 119.55, 121.64, 123.44, 126.71, 127.58, 127.68, 127.98, 128.53, 130.05, 130.25, 130.36, 132.07, 135.30, 138.06,
140.74, 141.32, 147.30; MS (EI) 320 (M++1), 319 (100), 277, 169, 69, 57; Anal. Calcd. for C23H16N2: C, 86.22; H, 5.03; N, 8.74. Found: C,
86.40; H, 4.90; N, 8.70. 1e: off-white solid, mp: 198–199.5 8C; 1H NMR (500 MHz, CDCl3): d 0.34–0.37 (m, 2H, CH2), 1.03–1.07 (m, 2H,
CH2), 2.47–2.52 (m, 1H, CH), 7.27 (s, 1H, ArH), 7.31 (t, 1H, J = 7.50 Hz, ArH), 7.39 (t, 1H, J = 7.25 Hz, ArH), 7.46 (t, 2H, J = 7.50 Hz, ArH),
7.52 (t, 1H, J = 7.50 Hz, ArH), 7.76 (d, 2H, J = 7.50 Hz, ArH), 8.57 (d, 1H, J = 8.00 Hz, ArH), 8.96 (s, 1H, ArH), 9.44 (s, 1H, NH); 13C NMR
(CDCl3): d 10.58, 14.18, 21.06, 111.44, 119.68, 121.94, 125.20, 126.96, 127.78, 129.47, 129.97, 130.77, 131.06, 135.05, 141.07, 141.94,
149.96, 171.20; MS (EI) 285 (M++1): 269, 256, 159, 127, 121, 97, 83, 71, 57 (100), 43; Anal. Calcd. for C20H16N2: C, 84.48; H, 5.67; N, 9.85.
Found: C, 84.30; H, 5.89; N, 9.45.