Lycorine and its derivatives for anticancer drug design.

Abstract

Amaryllidaceae alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, Alzheimer's disease for which galanthamine has already reached the market. Among this chemical family, lycorine displays very promising anti-tumor properties. This review first focuses on the chemical diversity of natural and synthetic analogues of lycorine and their metabolites, and then on mechanisms of action and biological targets through which lycorine and its derivatives display their anti-tumor activity. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

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Mini-Reviews in Medicinal Chemistry, 2010, 10, 41-50
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1389-5575/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Lycorine and its Derivatives for Anticancer Drug Design
D. Lamoral-Theys1, C. Decaestecker2, V. Mathieu2, J. Dubois1, A. Kornienko3, R. Kiss*,2,
A. Evidente4 and L. Pottier2
1Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Appliquée, Institut de Pharmacie, Université Libre
de Bruxelles, Brussels, Belgium
2Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium
3Department of Chemistry, New Mexico Institute of Mining and Technology, NM 87801, USA
4Dipartimento di Scienze del Suolo, della Pianta, dell’Ambiente e delle Produzioni Animali, Università di Napoli Fede-
rico II, Via Università 100, 80055 Portici, Italy
Abstract: Amaryllidaceae alkaloids are extensively studied for their biological activities in several pharmaceutical areas,
including, for example, Alzheimer’s disease for which galanthamine has already reached the market. Among this chemical
family, lycorine displays very promising anti-tumor properties. This review first focuses on the chemical diversity of natu-
ral and synthetic analogues of lycorine and their metabolites, and then on mechanisms of action and biological targets
through which lycorine and its derivatives display their anti-tumor activity. Our analysis of the structure-activity relation-
ships of this family of compounds highlights the existence of various potential leads for the development of novel anti-
cancer agents.
Key Words: Lycorine, Amaryllidaceae, Cancer, Design, Discovery, Structure-Activity relationship.
INTRODUCTION
Cancer is a worldwide disease, which is responsible for
millions of deaths every year. The standard cancer treatment
protocols include surgery, radiotherapy and chemotherapy.
Unfortunately, chemotherapy is not effective in treating can-
cers associated with either natural (innate) resistance to
apoptosis (e.g. gliomas [1], melanomas [2], esophageal can-
cers [3], pancreatic cancers [4], non-small-cell-lung cancers
[5], and above all metastatic cancers [6, 7]), and/or acquired
resistance to drugs during treatment [8-10]. In this connec-
tion, three major points must be emphasized: (i) > 80% of
the drugs currently used to combat cancers are pro-apoptotic,
(ii) pro-apoptotic drugs are inefficient against naturally
apoptosis-resistant cancers (see above) and/or effluxed by
various types of pumps during the process of acquired resis-
tance [11, 12], and (iii) > 90% of cancer patients die from
their metastases. Discovery of new cellular and/or molecular
pathways enabling innate or acquired resistance of cancers to
current chemotherapeutics to be overcome is therefore of
crucial importance if one wants to efficiently combat those
cancers associated with dismal prognoses as those mentioned
above. Within the oncology area, natural products and their
derivatives accounted for up to 60% of approved drugs dur-
ing the period from 1983 to 1994 [13]. In the current review,
we will report on the toxicity versus pharmacological proper-
ties of compounds isolated from Amaryllidaceae plants,


*Address correspondence to these authors at the Laboratoire de
Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels,
Belgium; Tel: +32 477 622083; Fax: +322 3325335;
E-mail: rkiss@ulb.ac.be
known for their medicinal properties over millenaries. In-
deed, the useful anticancer properties of oil extracted from
the daffodil Narcissus poeticus L. were already known to
Hippocrates of Cos, who used it to treat uterine tumors in the
fourth century B.C. [14]. Pliny the elder also reported the
topical anticancer use of different Amaryllidaceae in the first
century A.D. [14]. Recently, an important breakthrough was
achieved with alkaloid galanthamine that has reached the
market for the treatment
(RazadyneTM formerly Reminyl ®; [15]).
of Alzheimer’s disease
CHEMICAL DIVERSITY
Amaryllidaceae provide a great diversity of alkaloids
which have been extensively studied due to their challenging
chemistry and promising activities [14, 16-21]. Biosyntheti-
cally, these natural products have been shown to arise from a
common intermediate, norbelladine (Fig. 1). This intermedi-
ate undergoes different cyclizations, possibly followed by
rearrangements and/or elimination of two carbons, ring
opening, and/or recyclization to provide a variety of skele-
tons [14, 22-27]. As detailed below, the tetracyclic alkaloid
lycorine [1] and related phenanthridines display very inter-
esting anti-tumor properties among all the various skeletons
available [28-37]. This lycorine family of compounds com-
prises analogues possessing a double bond in the C-ring as
found in lycorine itself, 1-O-acetylnorpluviine 2 [38], pseu-
dolycorine 3 [35], galanthine 4 [35], sternbergine 5 [35, 39],
diacetyllycorine 6 [36], 2-O-acetylpseudolycorine 7 [35],
diacetyllycorinone 8 [37], 1-O-acetyllycorine 9 [29], ly-
corine-2-one 10 [29], N-methyllycorine iodide 11 [29], nor-
pluviine 12 [29], amarbellisine 13 [29, 40], and lycorene 14
[29]. The C-ring can be totally saturated as in 1,2-di-O-

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42 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 Lamoral-Theys et al.
acetyl-?-dihydrolycorine 15 [29, 41] and compounds 16-18
[41]. Other compounds have a fully aromatized C-ring and
an olefin in the D-ring as found in crisiaticidine A 19 [42]
and pratorimine 20 [42, 43]. In addition, some analogues
have an aromatic B-ring but no double bond in the ring D as
found in anhydrolycorinium chloride 21 [37, 44, 45], com-
pounds 22-23 [46], anhydrolycorinone 24 [38], the nitro-
functionalized compound 25 [41] and ungeremine (lycobe-
taine) 26 [44, 47-49]. Among the aromatic lycorine ana-
logues, some are neutral, some bear a positive charge and
one is zwitterionic. And finally, among all these compounds,
other differences occur, such as an amide function in lieu of
the amine, dioxole ring versus no dioxole ring, variations of
the stereochemistry of the asymmetric carbons, and last but
not least, the number of free hydroxyl residues (see Fig. 1
and Table 1).
DIVERSITY IN BIOLOGICAL MECHANISMS OF
ACTION
Various biological mechanisms have been invoked to ex-
plain the antitumor activities of lycorine and its congeners. It
was first postulated that lycorine inhibits protein biosynthe-
sis [50]. However, some experiments showed that it is not an
initiation inhibitor [51] and others showed that it could not
inhibit the peptide bond formation though it did link to ribo-
some under certain conditions [52]. Lycorine interferes with
vitamin C biosynthesis [53]. While some studies report pro-
apoptotic effects for lycorine [30, 33, 54], others point to
anti-apoptotic activity in cells challenged with polymor-
phonuclear leukocyte-derived calprotectin [55]. Several
groups observed cell cycle arrest after treatment with ly-
corine [33, 55] or with ungeremine [54]. In this last case, the
effect was attributed to ungeremine’s ability to inhibit spe-
cifically topoisomerase II? [49]. Besides this biomolecular
target, caspases 3, 7 and 9 (proapoptotic proteins) have been
shown to be up-regulated by lycorine while Mcl-1 and Bcl-xl
(antiapoptotic proteins) were down regulated [30]. Finally,
lycorine also proved to be able to interact with DNA [56].
STRUCTURE-ACTIVITY
ANALYSES WITH RESPECT TO ANTI-TUMOR AC-
TIVITY
RELATIONSHIP (SAR)
To the best of our knowledge, there is only one literature
report offering a rationalization of the differences in antican-
Lycorine
NH
N
Crinine
N
Galanthamine
Narciclasine
AB
C
D
H
N
HO
HO
HO
NorBelladine
para-ortho coupling
o-p
O
O
p-p
p-p and then
elimination of
two Carbons
O
O
OH
N
O
O
OH
HO
OH
OH
OH
OH
O
O
O
O
N
O
O
O
OH
Tazzetine
O
O
O
N
OH
Lycorenine
O
O
N
O
OH
Montanine
p-p and then
ring-opening
and recyclisation
p-p and then
rearrangement

Fig. (1). Different phenol oxidizing coupling patterns for norbelladine.

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Lycorine and its Derivatives for Anticancer Drug Design
Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 43
cer activities in this chemical series [46]. This study com-
pares in vivo activities of ungeremine 26, compounds 21 and
22, and other analogues lacking the D-ring of lycorine, or
those having one more carbon in this ring, for their activity
against mouse leukemia cells [46]. Four conclusions resulted
from the SAR analyses in the above-mentioned study:
1. The presence of a positive charge on the nitrogen is
important for the antineoplastic activity.
2. The planarity of molecules is important, may be be-
cause of the DNA-interaction possibility.
3. The quaternized nitrogen should not be sterically
hindered.
4. The presence of alkoxy functions at proper posi-
tions is important for the activity, may be because
of metabolism-related issues [46].
Among approximately three hundred molecules sharing
the ABCD tetracycle of lycorine (natural, synthetic or hemi-
synthetic compounds), only twenty-six have been tested for
their activity against different cancer cell lines. Among these
twenty-six compounds, twenty were found active against at
least one cell line and six were found inactive against every
cell lines tested. We detail in Table 1 all the reported data
with the corresponding references. The importance of some
structural features cannot be evaluated since the reported
compounds show no diversity for those structural elements.
For example the stereochemistry of the asymmetric carbons
is the same for all the tested compounds or is not determined.
With the exception of ungeremine 26 Fig. (2), which dis-
plays nanomolar activity against one cell line [49], the active
compounds usually display IC50 in vitro growth inhibitory
activity ranging between 0.1 and 50 ?M (Table 1). When
considering these mean growth inhibitory activities within
the various compound categories, we failed to identify clear
SAR trends. Therefore, we instead focused our analyses on
nine structural elements as detailed below. Furthermore, we
carried out statistical analyses to determine whether each of
these structural elements (parameters) provides a significant
contribution to the SAR data. To this end, the exact Fisher
test was used to evaluate the difference in proportions of
active compounds between those characterized by the pres-
ence vs. the absence of a specific structural element. A p-
value < 0.05 is considered as indicative of a significant con-
tribution. However, it should be kept in mind that the ob-
tained p-values depend on the number of compounds avail-
able for computing the proportions.
N
O
O
O

Fig. (2). Ungeremine 26, the most active compound in the series.
The presence of at least one charge: Among the mole-
cules that do have a charge, three are active out of four,
whereas among neutral products, seventeen are active out of
twenty-two (p > 0.05). Thus, in contrast to what is empha-
sized in ref. [46], the presence of at least one charge does not
contribute to the SAR data significantly. This feature could
be explained, at least partly, by the fact that neutral com-
pounds may be transformed into charged active metabolites
(e.g. protonation of uncharged alkaloids or oxidation to imin-
ium or N-oxide forms). So if there is really a difference, the
metabolism would provide a large bias, thus preventing us
from observing a statistically relevant discrimination. Two
possibilities may therefore explain the difference between
our current analysis and the conclusions drawn in ref. [46],
namely, (i) this study has been carried out on murine leuke-
mia cell lines, which can differ from human cancer cell lines
in terms of activity and/or metabolism, and (ii) it includes
compounds lacking the D-ring of lycorine as well as those
having one more carbon in this ring.
The presence of an additional olefin in the ring D.
Among the molecules that have an additional double bond,
two are active out of two, whereas among compounds with
the saturated ring D, eighteen are active out of twenty four (p
> 0.05). This parameter seems to be not discriminative, but
the very biased repartition should lead to cautious interpreta-
tion. It will be possible to conclude about this structural
variation only when more compounds having a double bond
in the ring D will have been tested for their antitumor activ-
ity.
Planarity. Among the planar molecules, five are active
out of eight while among the non-planar compounds, fifteen
are active out of eighteen (p > 0.05). Again, in contrast to
what is emphasized in ref. [46] this parameter seems to be
not discriminative in this series of compounds, but this is
probably due to the same reason(s) as the ones we advocated
for the presence of a charge.
The presence of the dioxole ring. Among the molecules
that have the dioxole ring, eleven out of sixteen are active,
whereas among those that do not, nine are active out of ten
(p > 0.05). The statistical analysis thus reveals that this pa-
rameter does not provide discriminent SAR information. The
fact remains that when the dioxole ring is open, it may un-
mask a phenol function or even two. As the presence of at
least one hydroxyl function is one of the most significant
parameters (see below), there is a strong bias in the interpre-
tation of the importance of this structural variation. The cau-
tion that we emphasized here is supported by the fact that
compounds 21 and 22, differing only by the presence or ab-
sence of the dioxole ring (no unmasking of a phenol), have
in fact a significant difference in activity. Compound 21 with
a dioxole is active, while compound 22 without a dioxole is
not. Only studies with a larger selection of compounds hav-
ing no dioxole (but no phenol) on the A-ring will allow one
to draw definitive conclusions as whether this structural ele-
ment is an important SAR contributor.
The presence of at least two hydroxyl functions (either
alcohol or phenol). Among the molecules that have at least
two hydroxyl groups, seven are active out of seven, whereas
among molecules without hydroxyl functions, thirteen are
active out of nineteen (p > 0.05). Thus, this parameter should
not be considered as being discriminent.

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44 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 Lamoral-Theys et al.
Table 1. In vitro and in vivo Antitumor Activities of Lycorine Analogues.
Structure
IC50 in vitro Growth Inhibitory Concentration
*T/C index (%) to Characterize in vivo
Antitumor Activity
N
O
O
OH
HO
Lycorine 1

0.5 < IC50 < 10 ?M on various types of leukemia and lym-
phoma cell lines [30]

3 < IC50 < 10 ?M on various types of carcinoma [32], multiple
myeloma [33] and melanoma [38] cell lines
T/C = 134% in HL-60 leukemia-bearing mice
treated with 10 mg/kg [31]
N
O
HO
AcO
1-O-Acetylnorpluviine 2
6 ?M on BL-6 mouse melanoma cells [38]






























N
HO
O
OH
HO
Pseudolycorine 3


2 ?M on MOLT-4 (acute lymphoblastic leukemia) to 35 ?M
on HEPG2 (hepatocellular carcinoma) cells [35]
N
O
O
O
HO
Galanthine 4

12 ?M on MOLT-4 (acute lymphoblastic leukemia) to > 150
?M on HEPG2 (hepatocellular carcinoma) cells [35]
N
O
HO
OH
AcO
Sternbergine 5

39 ?M on MOLT-4 (acute lymphoblastic leukemia) to > 150
?M on HEPG2 (hepatocellular carcinoma) cells [35, 39]
N
O
O
OAc
AcO
Diacetyl-lycorine 6

24 ?M on BL-6 mouse melanoma cells [36]

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Lycorine and its Derivatives for Anticancer Drug Design
Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 45
Structure
IC50 in vitro Growth Inhibitory Concentration
*T/C index (%) to Characterize in vivo
Antitumor Activity
N
HO
O
OAc
HO
2-O-acetylpseudolycorine 7

2 ?M on MOLT-4 (acute lymphoblastic leukemia) to 79 ?M
on HEPG2 (hepatocellular carcinoma) cells [35]









diacetyl-lycorinone 8
N
O
O
OAc
AcO
O

Inactive on 50 cancer cell lines [41]









1-O-acetyl-lycorine 9
N
O
O
OH
AcO

<5 ?M on HeLa (adenocarcinoma) cells [29]









N
O
O
O
HO
Lycorine-2-one 10

5 < IC50 <25 ?M on HeLa (adenocarcinoma) cells [29]








N
O
O
OH
HO
N-methyl-lycorine
iodide 11
I

25 ?M on HeLa (adenocarcinoma) cells [29]

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46 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 Lamoral-Theys et al.
Structure
IC50 in vitro Growth Inhibitory Concentration
*T/C index (%) to Characterize in vivo
Antitumor Activity
N
O
HO
HO
Norpluviine 12

> 25 ?M on HeLa (adenocarcinoma) cells [29]































N
O
O
O
HO
Amarbellisine 13

5 ?M on HeLa (adenocarcinoma) cells [29, 40]

N
O
O
Lycorene 14

Inactive on HeLa (adenocarcinoma) cells [29]

1,2-di-O-acetyl-?-
dihydrolycorine 15
N
O
O
OAc
AcO

> 25 ?M on HeLa (adenocarcinoma) cells [29]
N
O
O
O
O
HO
O
16

Inactive on 48 cancer cell lines [41]







N
O
O
O
O
O
17

Inactive on 48 cancer cell lines [41]

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Lycorine and its Derivatives for Anticancer Drug Design
Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 47
Structure
IC50 in vitro Growth Inhibitory Concentration
*T/C index (%) to Characterize in vivo
Antitumor Activity
N
O
O
O
HOBr
Br
18

Inactive on 57 cancer cell lines [41]








N
HO
HO
O
Crisiaticidine A 19

13 ?M on Meth-A (mouse sarcoma) to
17 ?M on LLC (mouse lung carcinoma) cells [42]








N
HO
O
O
Pratorimine 20

16 ?M on Meth-A (mouse sarcoma) cells [42]
Low activity on MOLT-4
(acute lymphoblastic leukemia) cells (no IC50 is provided) [43]








N
O
O
anhydrolycorinium 21







T/C = 153% in P388 lymphocytic leukemia-
bearing mice treated with 25 mg/kg [46]
N
O
O
22






Inactive (T/C < 125%) in P388 lymphocytic leu-
kemia-bearing mice treated with 25 mg/kg [46]
N
O
O
O
O
23

Inactive on 39 cancer cell lines [41]

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48 Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 Lamoral-Theys et al.
Structure
IC50 in vitro Growth Inhibitory Concentration
*T/C index (%) to Characterize in vivo
Antitumor Activity
N
O
O
O
Anhydrolycorinone 24

12 ?M on BL-6 mouse melanoma cells [38]







N
O
O
NO2
O
25









Inactive (T/C < 125%) in P388 lymphocytic leu-
kemia-bearing mice treated with 25 mg/kg [41]
N
O
O
NO2
O
25

5 ?M on P388 mouse lymphocytic leukemia cells [37]
4.5 ?M on P388 (mouse lymphocytic leukemia).
0.1 < IC50 < 3 ?M on various types of carcinoma cells [48, 49,
44, 47] and IC50 = 2 nM on GXF251 [49]
T/C = 152% in P388 lymphocytic leukemia-
bearing mice treated with 25 mg/kg [46]
Numbers in parentheses refer to references.
*the potential survival gain obtained using lycorine derivatives was evaluated by means of the %T/C index, which is the ratio of the median survival time of the
treated animal group (T) and that of the control group (C). Toxic effects are indicated by %T/C indices < 75%. The benefits of chemotherapy are considered to
be significant when associated with %T/C indices > 130%.

The presence of at least one phenolic function. Among
the molecules that have at least one phenolic function, eight
are active out of eight, whereas among molecules without a
phenol, twelve are active out of eighteen (p = 0.08). Al-
though this parameter cannot strictly be considered as dis-
criminative in terms of SAR analysis, a slight tendency for
phenolic compounds as being better candidates for antican-
cer activity seems nevertheless to emerge.
The insaturation pattern of the C-ring. This structural
element has three possible variants: fully saturated, one dou-
ble bond or aromatic. There are only four examples of mole-
cules with a fully saturated C-ring. We thus first compared
only compounds containing an aromatic ring or a single ole-
fin moiety. Among the molecules that do have a double
bond, thirteen are active out of fourteen, whereas among
molecules with an aromatic ring C, five are active out of
eight (p > 0.05). This parameter cannot be considered as sig-
nificant. But once again, this should not be surprising be-
cause of a possible metabolic transformation of compounds
with one double bond into aromatic products. Indeed, keep-
ing this possible metabolism in mind, it would not have been
logical to find a strong discrimination for this parameter.
Then we wanted to check the significance of each value ver-
sus the two others. When considering the aromatic com-
pounds versus all the others, the result is the same as when
considering the saturated compounds versus all the others.
The p-value is 0.25 in both cases, thus pointing at non sig-
nificant repartitions. But if one considers the compounds
bearing a double bond in the C-ring (thirteen active out of
fourteen) versus all the others (seven active out of twelve),
then the p value is 0.052. While this value is just above 5%,
we can nevertheless consider that it reflects an actual ten-
dency in terms of SAR analysis due to the small number of
compounds that have been taken into consideration. The
presence of one double bond and only one in the C-ring
gives better chances to have an active compound against at
least one cancer cell line. We believe this feature to be also
associated with metabolic transformations. A compound
with no double bound at all might be metabolized too slowly
while a compound already aromatic might not reach its target
as easily. Therefore, only one double bond would be just the
good compromise. In order to prove such a hypothesis, it
would be necessary to know for sure the activities of all the
final metabolites in this series.
The presence of at least one hydroxyl function (either
alcohol or phenol). Among the molecules that have at least
one hydroxyl group, fifteen are active out of sixteen,
whereas among molecules with no hydroxyl at all, five are

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Lycorine and its Derivatives for Anticancer Drug Design
Mini-Reviews in Medicinal Chemistry, 2010, Vol. 10, No. 1 49
active out of ten (p = 0.02). This parameter thus allows a
statistically significant discrimination, emphasizing that the
research for novel lycorine derivatives should lead to the
generation of molecules with at least one hydroxyl group.
When comparing this discrimination to the one obtained with
“at least two hydroxyls”, which cannot be considered sig-
nificant, it is interesting to notice that the first hydroxyl im-
proves the value of the candidates much more pronouncedly
than do the additional hydroxyls. As secondary and tertiary
alcohols are commonly linked to a stereogenic center, this
observation is highly significant for the synthesis of com-
pounds bearing only one asymmetric carbon compared to
compounds bearing two or more asymmetric carbons. And
because the hydroxyls may be phenolic, one might design
only symmetrical compounds for efficient synthesis, facile
purification, and for easier eventual scale-up.
The presence of a basic amine (versus a non-basic am-
ide). Only twenty two molecules were taken into account
here because the iminium ions and the ammonium salts (or at
maximum ions) are not suitable for this comparison. Among
the compounds that have a basic amine, fourteen are active
out of fourteen, whereas among compounds with an amide
function, three are active out of eight (p = 0.002). This
parameter thus contributes to actual statistical significance in
terms of SAR analysis. In other words, the amide function is
highly detrimental for anticancer activity. Synthetic chemists
should therefore focus on amine entities instead of amides in
order to generate novel lycorine derivatives with improved
anti-tumor activities.
CONCLUSION
Although only twenty-six out of more than three hundred
lycorine analogues have been evaluated for antitumoral ac-
tivity, the reported results are already highly encouraging
and attest to a high potential of this family of compounds to
provide excellent leads for anticancer drug discovery. The
current review offers chemists some rational guidelines for
the design and synthesis of compounds. In this series, im-
proved anticancer activities might be reached by focusing on
the importance of phenol and alcohol functions, the insatura-
tion pattern, and the presence of an amine.
ACKNOWLEDGEMENTS
Grant support: Fonds Yvonne Boël (Brussels, Bel-
gium). R. Kiss is a director of research, C. Decaestecker is a
senior research associate and V. Mathieu is a senior research
assistant with the Fonds National de la Recherche Scienti-
fique (FNRS, Belgium).
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Received: August 20, 2009

Revised: November 20, 2009 Accepted: November 21, 2009