Antiproliferative and structure activity relationships of amaryllidaceae alkaloids

Article abstract of DOI:10.3390/molecules200813854

The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr) was determined. The best antiproliferative activities were achieved with alkaloids derived

Full text of DOI:10.3390/molecules200813854

Molecules 2015, 20, 13854-13863; doi:10.3390/molecules200813854
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Antiproliferative and Structure Activity Relationships of
Amaryllidaceae Alkaloids
Juan C. Cedrón 1,2, Ángel G. Ravelo 1,3, Leticia G. León , José M. Padrón 1
1
and Ana Estévez-Braun 1,3,
*
1
Instituto Universitario de Bio-Orgánica Antonio González (CIBICAN), Universidad de La Laguna,
Av. Astrofísico Francisco Sánchez 2, La Laguna 38206, Spain; E-Mails: jccedron@hotmail.com (J.C.C.);
agravelo@ull.es (A.G.R.); lgleon@ull.edu.es (L.G.L.); jmpadron@ull.es (J.M.P.)
Departamento de Ingeniería Química Industrial, Universidad de Ingeniería & Tecnología (UTEC),
Av. Cascanueces 2221 Santa Anita, Lima 43, Peru
2
3
Departamento de Química Orgánica, Universidad de La Laguna, La Laguna 38206, Spain
*
Author to whom correspondence should be addressed; E-Mail: aestebra@ull.es;
Tel.: +34-922-31-85-76.
Academic Editor: Derek J. McPhee
Received: 19 June 2015 / Accepted: 27 July 2015 / Published: 30 July 2015
Abstract: The antiproliferative activity of a set of seven natural Amaryllidaceae alkaloids
and 32 derivatives against four cancer cell lines (A2780, SW1573, T47-D and WiDr)
was determined. The best antiproliferative activities were achieved with alkaloids derived
from pancracine (2), haemanthamine (6) and haemantidine (7). For each skeleton, some
structure-activity relationships were outlined.
Keywords: Amarylidaceae alkaloids; antiproliferative activity; SAR
1
. Introduction
Cancer is a major health problem all over the world. It is responsible of the death of over 8 million
people every year, and almost 600,000 deaths in the United States, during 2014 [1]. Alkaloids, such as
paclitaxel, vincristine or vinblastine, are known by possessing important antitumor properties and have
been used in the last years for the treatment of cancer [2].

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The Amaryllidaceae alkaloids have gained much interest because of their wide range of biological
activities. For example, acetylcholinesterase [3], analgesic [4], antifungic [5] and antimalarial [6–8]
activities have been reported for these alkaloids. Since the isolation of pancratistatin [9], a narciclasine-type
alkaloid, and the discovery of its important antitumor properties [10], representative alkaloids of this
family have been evaluated as potential cytotoxic agents [11]. More recently, some studies focus on
the potential as anticancer agents of semisynthetic derivatives of lycorine [12], narciclasine [13] and
crinine [14] have also been performed.
As a part of our ongoing research on Pancratium alkaloids, this work reports the antiproliferative
activity of some Amaryllidaceae alkaloids, and semisynthetic derivatives with pancracine, homolycorine
and haemanthamine skeletons, against four human tumor cell lines (A2780 ovary, SW1573 lung, T-47D
breast and WiDr colon). Some structure-activity relationships are also presented.
2
. Results and Discussion
Fresh bulbs from Pancratium canariense were chopped and macerated with MeOH for two weeks
at room temperature. The bulbs were filtered, dried, and powdered for a second extraction, using a
Soxhlet apparatus with MeOH. Both extracts were collected, concentrated and treated as described [15].
Tazettine (1) (3 mg), pancracine (2) (17 mg), hippeastrine (3) (1.35 g), vittatine (4) (8 mg),
11-hydroxyvittatine 5 (123 mg), haemanthamine 6 (2.01 g) and haemanthidine 7 (360 mg) were isolated
(
Figure 1).
Figure 1. Structure of Amaryllidaceae alkaloids from Pancratium canariense.
Several derivatives from the major alkaloids hippeastrine (3), 11-hydroxyvittatine (5), haemanthamine
6) and haemanthidine (7) were prepared with the aim to generate structurally diverse compounds [6–8].
(

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Scheme 1 shows the preparation of montanine-type derivatives 2a and 2b by thionyl chloride
mediated rearrangement of 6 and 7, respectively [16].
Scheme 1. Preparation of montanine-type derivatives 2a and 2b.
Scheme 2 summarizes the modifications achieved on the structure of the homolycorine-type
alkaloid hippeastrine 3 [7]. Derivatives were obtained by modifying the methylendioxy group (3a),
the lactone moiety (3b), the aminomethyl group (3c), the hydroxyl group at C-2 (3d–3g), and the double
bond at C3–C4 (3h,3i). Compounds 3j and 3k were also obtained under treatment with SOCl .
2
H
N
Me
H
H
N
N
Me
H
Me
O
O
H
O
OH
H
O
HO
HO
H
O
O
O
OH
NH
OH
H
O
H
3
b (95%)
O
3
a (55%)
3
c (33%)
CH3CO2NH4
H
N
Me
12
1
1
4
H
H
N
Me
H
N
Me
O
O
OR
3
4
a
H
H
H
1
0
10b
O
O
O
9
CrO3
O
RCl
O
O
2
OH
H
O
1
H
O
O
O
8
6a
6
3
3
3
d: R=Ac (100%)
e: R=COC H N (100%)
7
O
5
4
f: R=p-BrC H CO (100%)
3
3g (55%)
6
4
Br2
H
H
H
H
Cl
N
N
N
Me
Me
Me
H
O
H
Br
H
O
H
N
O
O
Me
Br
OH
O
O
O
+
OH
H
O
H
O
H
O
H
O
O
O
O
O
H
O
3
h (25%)
3j (43%)
3k (47%)
3
i (20%)
Scheme 2. Preparation of homolycorine-type derivatives 3a–3k.
The haemanthamine-type derivatives are shown in Schemes 3–5 [6]. These compounds have been
prepared from the alkaloids 11-hydroxyvittatine 5 (compounds 5a–5c, Scheme 3), haemanthamine 6

Molecules 2015, 20
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(
derivatives 6a–6k, Scheme 4) and haemanthidine 7 (compounds 7a–7e, Scheme 5). Similarly, the
transformations carried out with compound 3 were performed with these alkaloids.
Scheme 3. Preparation of derivatives 5a–5c from 11-hydroxyvittatine (5).
Scheme 4. Preparation of derivatives 6a–6k from haemanthamine (6).
Scheme 5. Preparation of derivatives 7a–7e from haemanthidine (7).

Molecules 2015, 20
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All compounds were tested for their antiproliferative activity against the human solid tumor cell lines
A2780 (ovary), SW1573 (lung), T-47D (breast) and WiDr (colon) [17]. The data on antiproliferative
activity shown in Table 1 allows a classification of the compounds in three groups.
Table 1. In vitro antiproliferative activity against human solid tumor cells a.
Compound
A2780
≥100
SW1573
≥100
4.3 ± 0.7
3.9 ± 0.7
≥100
12.5 ± 7.0
90.3 ± 11.0
17.3 ± 9.0
≥100
T47-D
≥100
6.5 ± 2.0
8.8 ± 1.0
≥100
52.9 ± 14.0
≥ 100
26.7 ± 10.0
≥100
WiDr
≥100
9.1 ± 1.0
7.5 ± 2.0
≥100
39.1 ± 20.0
≥100
29.1 ± 11.0
≥100
1
2
8.3 ± 0.5
3.4 ± 1.0
75.2 ± 25.0
16.5 ± 10.0
41.1 ± 3.0
16.8 ± 7.0
≥100
2
a
2
b
3
3
a
3
b
3
c
3
3
d
e
58.7 ± 7.0
≥100
91.5 ± 10.0
≥100
≥100
≥100
≥100
≥100
3
f
≥100
≥100
≥100
≥100
3
g
14.6 ± 8.0
≥100
25.0 ± 6.0
≥100
≥100
≥100
≥100
≥100
3
h
3
i
67.2 ± 13.0
≥100
≥100
≥100
≥100
≥100
≥100
≥100
3
j
3
4
k
54.9 ± 24.0
≥100
≥100
≥100
≥100
≥100
≥100
≥100
5
21.0 ± 2.0
≥100
16.9 ± 4.0
≥100
12.5 ± 9.0
≥100
21.1 ± 6.0
≥100
5
a
5
5
b
c
35.9 ± 5.0
100
34.8 ± 4.0
100
51.1 ± 3.0
100
53.8 ± 3.0
100
6
0.68 ± 0.2
≥100
2.1 ± 2.0
≥100
0.87 ± 0.4
≥100
1.2 ± 0.5
≥100
6
a
6
6
6
b
c
d
27.2 ± 10.0
19.1 ± 1.0
≥100
29.5 ± 12.0
21.9 ± 4.0
≥100
72.3 ± 24.0
46.1 ± 30.0
≥100
63.3 ± 35.0
32.8 ± 22.0
≥100
6
e
≥100
≥100
≥100
≥100
6
f
≥100
≥100
≥100
≥100
6
g
1.5 ± 0.1
33.2 ± 2.0
31.4 ± 7.0
≥100
2.7 ± 0.1
39.1 ± 20.0
29.8 ± 3.0
≥100
4.4 ± 1.5
78.6 ± 24.0
≥100
3.5 ± 2.0
67.4 ± 34.0
58.9 ± 12.0
≥100
6
h
6
6
i
j
≥100
6
7
7
k
27.2 ± 5.0
1.5 ± 0.1
≥100
22.0 ± 20.0
2.0 ± 1.0
≥100
≥100
1.8 ± 1.0
≥100
≥100
2.7 ± 2.0
≥100
a
7
7
b
c
6.9 ± 1.0
≥100
4.5 ± 0.7
≥100
8.2 ± 1.2
≥100
10.1 ± 0.5
≥100
7
d
≥100
≥100
≥100
≥100
7
e
≥100
≥100
≥100
≥100
a
Values representing GI50 are given in µM and are means of two to three experiments.
A first group is formed with the inactive compounds (GI50 values ≥ 100 µM). Tazettine (1) and
vittatine (4) belong to this group. The second group includes compounds with GI50 values in the range
of 10–100 µM, indicating a moderate activity. Alkaloids hippeastrine (3) and 11-hydroxyvittatine (5)
are found in this group. The last and smallest group is composed of those products with GI50 ≤ 10 µM,

Molecules 2015, 20
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being the most active alkaloids, haemanthamine (6) and haemanthidine (7), together with the
montanine-type alkaloid pancracine (2).
Some physicochemical descriptors (MW, LogP, H-bond donors, H-bond acceptors, Rotable bonds
and TPSA) of all tested compounds were calculated using Molinspiration Cheminformatics software
(
2014) and the corresponding values are included in Table 2.
Table 2. Physicochemical descriptors a,b.
Compound MW
LogP
1.53
0.54
2.39
2.55
1.23
0.37
0.59
−2.91
1.93
2.37
4.47
1.04
1.41
2.29
2.12
2.60
1.59
0.67
2.08
2.38
7.15
1.29
1.99
2.14
4.52
3.46
−0.19
1.74
1.10
1.55
1.29
2.22
1.25
0.83
2.23
1.68
7.30
5.17
−0.65
H-Bond Donors
H-Bond Acceptors Rotable Bonds TPSA
1
2
331
287
319
349
315
303
314
314
357
420
498
313
317
475
297
333
271
287
371
497
653
301
343
406
484
383
275
299
299
314
301
461
317
317
401
422
683
481
291
1
6
5
4
5
6
6
6
6
7
8
7
6
6
6
5
5
4
5
7
9
7
5
6
7
6
6
5
5
5
6
5
5
6
6
8
8
8
8
6
1
1
1
2
0
0
0
0
2
3
3
0
0
0
0
0
0
0
4
6
6
1
3
4
4
4
0
1
1
1
1
1
1
1
5
4
7
7
0
60.40
62.16
30.94
40.17
68.24
90.23
71.03
68.01
74.32
87.21
74.32
65.08
68.24
68.24
48.01
48.01
41.93
62.16
74.32
100.10
74.32
51.17
57.25
70.14
57.25
57.25
84.15
43.47
48.01
63.53
51.17
51.17
65.00
71.40
83.55
90.37
83.55
83.55
104.38
2
0
0
1
3
2
1
0
0
0
0
1
1
0
0
1
2
0
0
0
1
0
0
0
0
4
0
0
1
1
1
1
2
0
1
0
0
5
2
a
2
b
3
3
a
3
b
3
c
3
d
3
e
3
f
3
g
3
h
3
i
3
j
3
k
4
5
5
a
5
b
5
c
6
6
a
6
b
6
c
6
d
6
e
6
f
6
g
6
h
6
i
6
j
6
k
7
7
a
7
b
7
c
7
d
7
e
a
Values were calculated using Molinspiration Cheminformatics software (Molinspiration, Slovensky Grob,
Slovak Republic, 2015, http://www.molinspiration.com); b Optimal range MW < 500, LogP < 5, H-bond
donors < 5, H-bond acceptors < 10, Rotable bonds < 5, TPSA < 140.

Molecules 2015, 20
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With respect to the antiproliferative activity of tazzetine (1), haemanthamine (6), and haemanthidine (7),
our results are consistent with those obtained by Evidente et al. [16] for their antiproliferative activity
against six different cancer cell lines (A549, OE21, Hs683, U373, SKMEL and B16F10). Thus tazzetine
also turned out to be inactive, and haemanthamine (6) and haemanthidine (7) had IC50 values ranging
from 3.1 to 8.5 µM.
From the results of antiproliferative activity some structure-activity relationships can be outlined.
The replacement of the hydroxyl groups in the E ring of pancracine (2) by a chlorine and a methoxy
group (2a), respectively, produced a similar result but the introduction of a methoxy group at C-6 (2b)
reduced the antiproliferative activity. Since 2a and 2b have similar Log P values, the steric hindrance
at C-6 seems an important factor for the activity of this series of compounds.
Regarding to the alkaloids of the hippeastrine series, all modifications made at the hydroxyl group of
hippeastrine (3) (derivatives 3d–3g) produced a significant loss of the activity, indicating the importance
of a hydrogen-bond-donor (HBD) at C-2. The role of the C3-C4 double bond was evident since inactive
derivatives 3h and 3i were obtained under hydrogenation or bromination. Another important group is the
methylendioxy because when this group was converted into the corresponding aromatic diol 3a, the
activity decreased drastically. On the other hand, the presence of the lactone ring is not essential for the
activity, thus when the lactone moiety was transformed into the lactam (derivative 3b), similar activities
were obtained.
Comparison of the antiproliferative activities of the natural alkaloids vittatine (4), 11-hydroxyvittatine
(
5), haemanthamine (6) and haemanthidine (7) indicate how important are for the activity the presence
of a methoxy group at C-3 together an hydroxyl group at C-11.
These facts were confirmed with the preparation of derivatives 6a–f. Furthermore compounds 5, 6
and 7 have lower LogP than the inactive compound 4. The obtention of the inactive derivatives 6i and
6
j shows the importance of the double bond at C1-C2 for the activity. Removal of the methylendioxy
group also led to a less active compound (6k), indicating that this group is also important for the
haemanthamine series. Haemanthidine 7, which possesses a hydroxyl group at C-6, can be considered
as active as haemanthamine 6. The acylation of the hydroxyl groups at C-6 and C-11 produces a loss of
antiproliferative activity (7a, 7c, 7d) but compound 7b having a free hydroxyl at C-11 and a nicotinoyl
group at C-6.
Since most of the alkaloids evaluated for antiproliferative activity were also previously evaluated
for antimalarial activity [6,7], a comparative antiproliferative vs. antimalarial SAR study is included.
For antimalarial activity the natural alkaloids tazzettine (1) and vittatine (4) were active against
Plasmodium falciparum, while they were inactive for antiproliferative activity. With respect to the
compounds related to pancracine (2), we obtained identical SAR for both activities. Regarding the
derivatives 3a–3k, similar SAR were determined for the modifications on the hydroxyl group at C-2,
and on the double bond C-3–C-4. The aromatic diol 3a obtained from the transformation of the
methylendioxy group resulted inactive for antiproliferative activity, but it showed good antimalarial
activity. The same behavior was detected for compound 6e. In the derivatives obtained from the diol 5
all diesterified compounds resulted inactive for antiproliferative activity but compound 5b, with two
nicotinoyl groups, which showed high antimalarial activity. For the derivatives obtained from 6, all
modifications carried out on the hydroxyl group at C-11 led to a loss of antimalarial and antiproliferative
activity, while the hydrogenation of the double bond produced opposite results; compound 6i resulted

Molecules 2015, 20
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inactive for antiproliferative activity and had antiplasmodial activity. Finally, similar SAR for
antiproliferative and antimalarial activities were obtained for the derivatives 7a–7d.
3. Experimental Section
3
.1. Natural and Semisynthetic Amaryllidaceae Alkaloids
The natural alkaloids Tazettine (1) (3 mg), pancracine (2) (17 mg), hippeastrine 3 (1.35 g), vittatine 4
(
8 mg), 11-hydroxyvittatine 5 (123 mg), haemanthamine 6 (2.01 g) and haemanthidine 7 (360 mg)
were isolated from Pancratium canariense as describe in reference [15]. Derivatives 2a and 2b were
prepared according to the procedure described in reference [17]. Homolycorine-type derivatives 3a–3k
were synthesized following the reference [7] while the haemathamine-type derivatives were obtained
as describe in reference [6].
3
.2. Antiproliferative Assay
Growth inhibition and cytotoxicity against the human solid tumor lines A2780 (ovary), SW1573 (lung),
T-47D (breast) and WiDr (colon) was screened using the sulforhodamine B (SRB) assay described in
reference [18]. Cells were inoculated at densities of 7000 (A2780), 6000 (SW1573), 15,000 (T-47D)
and 10,000 (WiDr) cells per well, based on their doubling times. Pure compounds were initially
dissolved in DMSO at 400 times the desired final maximum test concentration (100 µM). Control cells
were exposed to an equivalent concentration of DMSO. Each agent was tested in duplicate at five
different tenfold dilutions. Drug incubation times were 48 h, after which cells were precipitated with
2
5 µL ice-cold 50% (w/v) trichloroacetic acid and fixed for 60 min at 4 °C. Then the SRB assay was
performed. The optical density (OD) of each cell was measured at 490 nm using a Bio-Tek’s Elx800
NB 96-well plate reader. The percentage growth was calculated at each of the drug concentration
levels based on the difference in OD at the start and end of drug exposure. Values were corrected for
background OD from wells only containing medium. The resulting biological activities are expressed
as GI50, the concentration of compound responsible of a 50% growth inhibition, and are shown in Table 1.
4
. Conclusions
In conclusion, a set of diverse Amaryllidaceae alkaloids with different skeletons has been tested for
antiproliferative activity. The compounds belonging to the pancracine and haemantine series were the
most active. From the obtained result the key structural requirements for each series were outlined. The
best antiproliferative activities were achieved with the natural alkaloids 6 and 7 and also with the
derivatives 6g and 7b. The physicochemical descriptors (Table 2) of these compounds do not violate
the optimal requirements for druggability, which suggests that these alkaloids are promising lead
compounds for further research.
Acknowledgments
We gratefully acknowledge the financial support from Spanish MINECO (SAF2012-37344-C03-C01)
and Instituto de Salud Carlos III (PI11/00840). These projects are also co-founded by the European

Molecules 2015, 20
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Regional Development Fund (ERDF). We also thank EU Research Potential (FP7-REGPOT-2012-
1367-IMBRAIN).
6
Author Contributions
Isolation, preparation of the derivatives and structural determination (JCC, AGR, AEB).
Antiproliferative activity (JMP, LGL).
Conflicts of Interest
The authors declare no conflict of interest.
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