Design, synthesis and cytotoxic activities of novel β-amino alcohol derivatives

Article abstract of DOI:10.1016/j.bmcl.2011.02.087

Three series of novel β-amino alcohols possessing an N-anthranyl group have been obtained using tryptophan as the major starting material. These compounds were screened for cytotoxic activity against five human cancer cell lines in vitro by MTT assay, and

Full text of DOI:10.1016/j.bmcl.2011.02.087

Bioorganic & Medicinal Chemistry Letters 21 (2011) 2302–2304
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and cytotoxic activities of novel b-amino alcohol derivatives
Bing Bai a,c, Xing-Yao Li a,c, Yan Li a, , Hua-Jie Zhu a,b,
⇑
⇑
a Organic Synthesis and Natural Product Laboratory, State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany,
Chinese Academic of Sciences (CAS), Kunming 650204, PR China
b College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, PR China
c Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three series of novel b-amino alcohols possessing an N-anthranyl group have been obtained using
tryptophan as the major starting material. These compounds were screened for cytotoxic activity against
five human cancer cell lines in vitro by MTT assay, and some of them exhibited potential ability to be
anticancer agents. Structure–activity relationship was carefully investigated. Only the compounds
possessing small substituents (H or CH3) at C-6 position showed the same activity as cisplatin (DDP) did.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 30 January 2011
Revised 21 February 2011
Accepted 23 February 2011
Available online 26 February 2011
Keywords:
b-Amino alcohol
Cytotoxic activity
Structure–activity relationship
MTT
b-Amino alcohol is a big class of compounds with a wide range
of bioactivities, such as antiplasmodial,1 antileishmanial,2 antipro-
liferative,3 antimicrobial.4 In recent decades, plenty of compounds,
which were synthesized and used in the treatment of cancers, have
an indole moiety.5–8 Some compounds had tryptophan moiety,
such as b-carboline,9,10 tetrahydro-b-carboline,11,12 which showed
strong cytotoxic activity. In our previous work, chiral secondary
and tertiary b-amino alcohols derived from tryptophan or abrine
(N-methyl tryptophan) have been synthesized and used as cata-
lysts in enantioselective additions of diethylzinc to aldehydes.
However, their bioactivities were not investigated.13–16 We won-
der if such kinds of b-amino alcohols derived from tryptophan have
whether any potential ability to be anticancer agents or not. In-
deed, simple structures with strong cytotoxic activity as the same
as cisplatin (DDP) will be of much more attraction in pharmaceu-
tical industry.
alcohols 5a–5e, 6a–6j and 7a–7d were synthesized via additions
of methyl esters 2–4 with different Grignard reagents, respectively
(Scheme 1). All compounds were characterized by 1H NMR, 13C
NMR and MS.
The typical procedure for synthesis of 5 was introduced. To the
solution of 2 (100 mg, 0.25 mmol) in a dried THF was added meth-
ylmagnesium bromide (4.0 equiv) by syringe under nitrogen pro-
tection cooled with an external ice-bath. The solution was then
warmed to room temperature for 10 h (checked with TLC), and
then quenched with saturated NH4Cl under ice-bath. The mixture
was extracted with ethyl acetate and the combined organic layers
were dried over anhydrous Na2SO4, and then evaporated under
reduced pressure. The residue was purified by chromatography
(silica gel) eluting with petroleum ether/EtOAc (3:1) to give a pale
yellow powder 5b (85 mg, 85% yield). The specific data are listed in
Ref. 18. Other experimental procedures are summarized in
Supplementary data.
Total 19 synthesized amino alcohols 5a–5e, 6a–6j, 7a–7d were
screened in vitro for study of cytotoxic activity against five human
cancer cell lines, HL-60, SMMC-7721, A-549, MCF-7 and SW480, in
order to study the structure–activity relationship (SAR). The MTT
assay was used in antitumor activity study. The cell lines were
cultured in DMEM medium supplemented with 10% fetal bovine
serum at 37 °C in humidified air containing 5% CO2. The cytotoxic
activity results are summarized in Table 1.
Herein, we report the synthesis of series of b-amino alcohols
derived from tryptophan (Scheme 1). The N-anthoranyl group
was employed as a substituent of amino group in view of that the
flat rigid structure may be of benefit to a high cytotoxic activity.
The experimental conditions that were reported for
N-akylation were modified slightly in our N-akylation experiments
to give N-anthryl-L
-tryptophan methyl ester (2).17 Intermediates 3a
and 3b were obtained through indole N-alkylation using sodium
hydride as a reduction reagent, and 4a, 4b through N-acetylation
in presence of triethylamine as a base. Then a series of amino
For 5a–5e, compounds 5b, 5c and 5d, which featured methyl,
ethyl and n-propyl, respectively, exhibited quite strong activities
against all of the five cancer cell lines. Among the three
compounds, 5b had the smallest group (methyl) at C-6 position
⇑
Corresponding authors. Tel./fax: +86 871 5216179.
E-mail address: hjzhu@mail.kib.ac.cn (H.-J. Zhu).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.087

B. Bai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2302–2304
2303
R1
O
R1
6a: R = CH3 R1 = H
OMe
OH
NH
6b: R = CH3 R1 = Me
6c: R = CH3 R1 = Et
NH
(iv)
N
R
N
R
6d: R = CH3 R1 = n-Pr
6e: R = CH3 R1 = n-Bu
6f: R = CH3CH2 R1 = H
6g: R = CH3CH2 R1 = Me
6h; R = CH3CH2 R1 = Et
6i; R = CH3CH2 R1 = n-Pr
6j: R = CH3CH2 R1 = n-Bu
3a: R = CH3
6a-6j
3b: R = CH3CH2
(ii)
O
R1
R1
O
OH
OMe
5a: R1 = H
OMe
NH
N
NH
(iv)
(i)
N
H
N
H
H
5b:
5c:
5d:
R
1 = Me
NH2
R
R
1 = Et
1
1 = n-Pr
5e: R1 = n-Bu
2
5a-5e
R1
(iii)
O
R1
OH
O
OMe
O
N
N
(iv)
7a: R = CH3 R1 = H
7b: R = CH3 R1 = Me
7c: R = Ph R1 = H
7d: R = Ph R1 = Me
N
N
H
H
R
R
4a: R = CH3
4b: R = Ph
7a-7d
Scheme 1. Reagents and conditions: (i) anthraldehyde, CH2Cl2, molecular sieve, rt, a week. then NaBH4, CH3OH, rt, 10 min; (ii) CH3I or CH3CH2Br, K2CO3, DMF, rt, 12 h; (iii)
CH3COCl or PhCOCl, Et3N, CH2Cl2, rt. (iv) Grignard reagents, THF, rt, 6–10 h; for R1 = H, LiAlH4, THF, rt, 1 h.
against the five cancer cell lines than the 6c–6e and 6h–6j did (Ta-
ble 1). A small R1 substituent such as H or methyl had more activity
than bulky group did when R is either methyl or ethyl. Subse-
quently, the SAR of the amino was investigated by introducing acyl
groups. Substitution on amino with an acetyl and benzoyl group
resulted in no any loss in cytotoxic activity against all the cell lines
for compounds 7a–7c except for 7d. It exhibited that this position
is not the sensitive point.
The overall cytotoxic activity studies of these compounds indi-
cated that the compound with H or methyl group (e.g., 5b, 6a, 6b,
6f, 6g, 7a–7c) possess a better activity than with a more bulky
group. In addition, indole and substituent on amino nitrogen do
not have apparent effect on the antitumor activity except for 5a
and 7d.
Table 1
Inhibition activity against five human cancer cell lines by MTT assay
Compound HL-60
SMMC-7721 A-549
MCF-7
SW480
IC50
(
l
M) IC50
(lM)
IC50
(l
M) IC50
(l
M) IC50
(lM)
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
6f
>40
9.55
>40
>40
>40
>40
11.71
>40
>40
>40
13.49
15.13
>40
>40
>40
17.42
17.56
>40
>40
>40
17.30
17.24
30.66
>40
13.39
12.97
17.32
>40
11.04
11.58
10.86
>40
12.50
24.26
23.86
>40
16.63
15.24
>40
>40
>40
14.94
13.90
>40
>40
>40
16.07
15.60
17.38
>40
12.16
13.18
>40
4.48
4.78
>40
>40
>40
6.18
5.44
>40
>40
>40
3.64
6.49
7.03
>40
14.99
15.48
>40
16.51
11.77
>40
>40
>40
>40
>40
17.05
13.61
>40
16.51
14.99
>40
6g
6h
6i
More experimental procedures can be found in Supplementary
data including all of the molecular information, for example, 1H,
13C NMR data.
>40
>40
6j
>40
>40
7a
7b
7c
7d
DDP
14.05
11.96
20.68
>40
15.23
14.51
13.18
>40
In summary, three series of novel b-amino alcohols are derived
from tryptophan, and some of them exhibited relatively strong
cytotoxicity as the same as DDP did against the five tumor cell
lines. It is interesting to develop derivatives from amino acids for
treatment of the corresponding tumors. To design more efficient
derivatives from amino acids based on the current study may suc-
cessfully lead to development of a potent anticancer agent. Further
developments involving cyclization to afford a six-membered het-
erocycle via the Pictet–Spengler reaction, preparation of analogs
with a N-phenanthyl or N-naphthyl group, and replacement with
other amino acids are in progress.
1.04
14.99
6.81
24.70
24.34
and inhibited the cancer growth rate by 50% or more at a concen-
tration of 10 M, which displayed the greatest activity equivalent
to DDP except for HL-60 cancer. In contrast, proton or more bulky
group (e.g., n-butyl) resulted in lower activity against all of the can-
cer cell lines.
l
Further investigation of influence of indole group on anticancer
activity was carried out using the same methods in cytotoxic activ-
ity investigation for 6a–6j, which had indole N-methyl or N-ethyl,
respectively. Compounds6a, 6b, 6f and 6g possessed the same sub-
stituent R as 6c–6e, 6h–6j did, but different R1. It is found that the
former compounds 6a, 6b, 6f, 6g had higher inhibitory activity
Acknowledgments
The work was supported by the NSFC (30873141), 973 Program
(2009CB522300), program of recruited science and technology
talents (2009C1120), the State Key Laboratory of Phytochemistry
and Plant Resources in West China, and Hebei University.

2304
B. Bai et al. / Bioorg. Med. Chem. Lett. 21 (2011) 2302–2304
13. Dai, W. M.; Zhu, H. J.; Hao, X. J. Tetrahedron: Asymmetry 2000, 11, 2315.
Supplementary data
14. Zhu, H. J.; Zhao, B. T.; Dai, W. M.; Zhou, Jun; Hao, X. J. Tetrahedron: Asymmetry
1998, 9, 2879.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.02.087.
[15]. Zhu, H. J.; Zhao, B. T.; Zuo, G. Y.; Pittman, C. U., Jr.; Dai, W. M.; Hao, X. J.
Tetrahedron: Asymmetry 2001, 11, 2613.
16. Zhu, H. J.; Jiang, J. X.; Saebo, S.; Pittman, C. U., Jr. J. Org. Chem. 2005,
70, 261.
17. Ip, Nancy, Zhu, H. J., Ip, Fanny, U.S. Patent 61/021,608, PCT Int. Appl. 2009, WO
2009092324.
References and notes
18. For compound 5b (85% yield). A pale yellow powder. ESI-MS m/z: 409 [M+H]+.
1H NMR (500 MHz, CDCl3) d: 1.24 (s, 3 H), 1.54 (s, 3H), 2.65 (m, 2H), 3.26 (m,
3H), 4.30 (d, 1H, J = 12.0 Hz, ArCHNH), 4.49 (d, 1H, J = 12.0 Hz, ArCHNH), 6.98
(s, 1H), 7.20 (t, 1H, J = 7.4 Hz), 7.27–7.38 (m, 5H), 7.47 (d, 1H, J = 8.0 Hz), 7.62
(d, 2H, J = 8.8 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.90 (d, 2H, J = 8.5 Hz), 8.27 (s, 1H).
13C NMR (125 MHz, CDCl3) d 24.2, 27.9, 28.1, 47.3, 67.5, 72.2, 111.5, 113.4,
118.9, 119.7, 122.4, 122.8, 123.9, 124.7, 125.8, 127.2, 127.4, 128.9, 129.9, 131.3,
131.4, 136.7. For 6b. ESI-MS m/z: 423 [M+H]+. 1H NMR (500 MHz, CDCl3) d: 1.25
(s, 3H), 1.55 (s, 3H), 2.60 (m, 2H), 3.26 (m, 3H), 3.70 (s, 3H, NCH3), 4.30 (d, 1H,
J = 12.0 Hz, ArCHNH), 4.49 (d, 1H, J = 12.0 Hz, ArCHNH), 6.83 (1H, s), 7.18 (t, 1H,
J = 7.7 Hz), 7.27–7.40 (m, 6H), 7.64 (d, 2H, J = 8.9 Hz), 7.70 (d, 1H, J = 8.0 Hz),
7.90 (d, 2H, J = 8.0 Hz), 8.28 (s, 1H). 13C NMR (125 MHz, CDCl3) d: 24.3, 27.8,
28.2, 47.4, 67.6, 72.1, 109.5, 111.8, 119.0, 119.1, 122.0, 124.0, 124.7, 125.8,
127.1, 127.5, 127.8, 128.9, 129.3, 129.7, 131.3, 137.4. For 7b: ESI-MS m/z: 473
[M+Na]+. 1H NMR (500 MHz, CDCl3) d: 0.22 (s, 3H), 0.78 (s, 3H), 2.71 (s, 3H,
COCH3), 3.07 (dd, 1H, J = 15.2, 2.3 Hz), 3.26 (dd, 1H, J = 10.8, 2.3 Hz), 3.54 (m,
1H), 4.69 (d, 1H, J = 14.7 Hz, ArCHNH), 5.10 (d, 1H, J = 14.6 Hz, ArCHNH), 6.87
(s, 1H), 7.11 (t, 1H, J = 7.7 Hz), 7.21 (t, 1H, J = 7.5 Hz), 7.27 (d, 1H, J = 7.8 Hz),
7.30 (d, 1H, J = 7.9 Hz), 7.39 (m, 4H), 7.46 (d, 2H, J = 8.8 Hz), 7.90 (d, 2H,
J = 8.4 Hz), 8.32 (s, 1H). 13C NMR (125 MHz, CDCl3) d: 21.2, 24.5, 28.5, 48.1,
69.8, 71.1, 111.3, 113.6, 118.9, 119.5, 122.1, 122.8, 123.4, 124.8, 125.3, 126.6,
127.6, 129.2, 129.4, 130.9, 131.4, 136.2, 172.5. See Supplementary data for
more details about other new compounds’ data.
1. Hans, R. H.; Gut, J.; Rosenthal, P. J.; Chibale, Kelly. Bioorg. Med. Chem. Lett. 2010,
20, 2234.
2. Coimbra, E. S.; De Almeida, M. V.; Júnior, C. O. R.; Taveira, A. F.; Da Costa, C. F.;
De Almeida, A. C.; Reis, E. F. C.; Da Silva, A. D. Chem. Biol. Drug Des. 2010, 75,
233.
3. Córdova, I.; León, L. G.; León, F.; San Andrés, L.; Luis, J. G.; Padrón, J. M. Eur. J.
Med. Chem. 2006, 41, 1327.
4. Prasad, A. K.; Kumar, P.; Dhawan, A.; Chhillar, A. K.; Sharma, D.; Yadav, V.;
Kumar, M.; Jha, H. N.; Olsen, C. E.; Sharma, G. L.; Parmar, V. S. Bioorg. Med. Chem.
Lett. 2008, 18, 2156.
5. Islam, M. N.; Iskander, M. N. Mini-Rev. Med. Chem. 2004, 4, 1077.
6. Bhattacharyya, B.; Panda, D.; Gupta, S.; Banerjee, M. Med. Res. Rev. 2008, 28,
155.
7. Zefirova, O. N.; Diikov, A. G.; Zyk, N. V.; Zefirov, N. S. Russ. Chem. Bull. Int. Ed.
2007, 56, 680.
8. Singh, P.; Kaur, M.; Verma, P. Bioorg. Med. Chem. Lett. 2009, 19, 3054.
9. Guan, H. J.; Chen, H. S.; Peng, W. L.; Ma, Y.; Cao, R. H.; Liu, X. D.; Xu, A. L. Eur. J.
Med. Chem. 2006, 41, 1167.
10. Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro, J.; Hibino, S. J. Org. Chem. 2001,
66, 8793.
11. Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.; Huemmer, S.;
Mayer, T. U.; Surrey, T.; Giannis, A. Bioorg. Med. Chem. 2005, 13, 6094.
12. Ruan, X. Q.; You, Q. D.; Yang, L.; Wu, W. T. Acta Pharm. Sin. 2008, 43, 828.