Hill coefficient ± SEM
3.39 ± 0 09
3.89 ± 1 12
3.10 ± 0.02
3.36 ± 0 06
4.56 ± 0 98
3.15 ± 0 01
3.4 ± 0 93
3.42 ± 0.03
4.79 ± 0.77
3.20 ± 0.07
3.40 ± 0.81
4.12 ± 0.03
4.65 ± 0.31
Fig. 1 Cytotoxic efficacy of MDMA and Series 1 (first generation)
b typical concentration-response curves showing cytotoxic perfor-
MDMA analogues versus L3055 Burkitt's lymphoma cells.
mance of MDMA and Series 1 analogues against the L3055 BL cell
a Chemical structure of MDMA with α-carbon (α-C) indicated (and
line. Cells were cultured at 5 x 105/ml with MDMA or indicated
in tabulated right hand panel) MDMA analogues with the first
analogue at concentrations shown for 48 h prior to measuring
iteration of α-C substituents constituting Series 1 compounds 1–6 as
cytotoxicity by PI uptake using flow cytometry. Results are repre-
shown, together with calculated pIC50 ± SEM and Hill coefficients ±
sented as the mean of three independent experiments ± SEM in terms
SEM from response curves as generated in (b) with number of
of the percentage of cells remaining viable with respect to vehicle (no
separate experiments performed with each compound given as ‘n';
the benzene ring possessing all six carbons within one
acceptor and therefore adds to the hydrophobicity of the
plane (sp2-hybridized) by contrast to the cyclohexyl group,
molecule [Metabolic stability is also increased by
where the carbon atoms are sp3-hybridized and therefore
the inclusion of fluorine.
non-planar and conformationally flexible. Compound 8 has
Compounds 16, 17 and 18 have much larger hydrophobic
an α-benzyl group and thus an additional sp3-hybridized
substituents at the α-position of MDMA, and therefore
carbon between the main carbon chain and the aromatic α-
increased lipophilicity. The naphthyl group (compounds 16
substituent. This provides additional flexibility compared to
and 17) is highly rigid as all the carbon atoms are positioned
phenyl substituents, and extends the aromatic ring from the
in one plane, whereas the biphenyl group differs from
main chain, exploring the depth of a putative hydrophobic
compound 6 by the addition of a para-phenyl group and
pocket in the target receptor(s).
therefore both of the benzene rings are able to rotate around
Compounds 9, 10 and 11 are more polar than their parent
the axis of the bond between them.
(6) due to the addition of a methoxy group. The lone pairs
From results presented in Fig. it can be noted that from
of electrons make the methoxy oxygens hydrogen bond
the second generation of MDMA analogues modified at the
acceptors, and also increase the electron density in the
α-carbon, compounds 16–18 were by far the most potent
aromatic ring. Compounds 9–11 differ only in the position
regards cytotoxicity towards L3055 cells; compounds 17
of the methoxy group. Similarly, compounds 13, 14 and 15
and 18 being the most efficacious and equipotent with a
possess ortho-, meta-, and para-methyl groups, respectively,
pIC50=5.18±0.03 and 5.22±0.08; representing a 10-fold
exploring steric tolerance within the binding site(s). The
and 100-fold improvement over compound 6 and MDMA
ortho-substituents in 9 and 13 are also likely to reduce the
respectively. Similar rank potency of these analogues was
range of low energy conformations available to the side
observed when assessed for their capacity to inhibit 3H-
thymidine incorporation into L3055 cells (data not shown).
Compound 12 contains fluorine in the para-position
It should be noted that all compounds tested for
which reduces electron density in the aromatic ring but
concentration-dependent cytotoxicity generated steep
otherwise is very similar to a hydrogen atom (i.e. an
response curves yielding relatively high Hill coefficients
isosteric replacement). Although the fluorine atom has three
(Figs. and ) suggesting deviation from simple mass
lone pairs of electrons, it is a very poor hydrogen bond
interaction ].
Hill coefficient ± SEM
4.10 ± 0.04
6.56 ± 0.43
4.16 ± 0 03
5.92 ± 0 58
4.04 ± 0.04
4.82 ± 0.38
4.10 ± 0.01
6.05 ± 0.16
4.16 ± 0.02
5.60 ± 0.73
4.20 ± 0.02
5.89 ± 1.12
4.20 ± 0.05
6.68 ± 073
4.29 ± 0.05
5.05 ± 0.17
4.37 ± 0.03
5.69 ± 0.27
4.90 ± 0.02
4.04 ± 0.74
5.18 ± 0.03
4.38 ± 0.73
5.22 ± 0.08
5.05 ± 0.97
Fig. 2 Cytotoxic efficacy of Series 2 (second generation) analogues versus L3055 Burkitt's lymphoma cells. As in Fig. but here with Series 2compounds 7–18; MDMA again included for comparison
Cytotoxic efficacy of selected α-substituted MDMA
(primarily detecting active caspase-3) and propidium iodide
analogues towards B-cell lines of different malignant
(plasma membrane permeability) staining, L3055 BL cells
transfected with empty vector showed classic progressionfrom early to late apoptosis over the course of the 6 h
The constituent cells of B-cell lines from a diverse
monitored (Fig. ). While at the fixed concentration of the
range of malignancies were treated with MDMA and six
analogues used L3055-Bcl-2 cells again showed a degree of
of the α-substituted MDMA analogues (selected accord-
resistance to their cytotoxic actions, nevertheless the death
ing to their activity versus sensitive L3055 cells and
that occurred failed to register an ‘early apoptosis' stage at
applied at a concentration at or close to their maximal
any time point as indicated by cells staining as PhiPhiLux+/
cytotoxic performance against this cell line) then
PI-. While no PhiPhiLux positivity was developed with
analysed for remaining viability (Fig. Given the
compound 6, compound 18 progressively moved a portion
resistance often afforded to therapeutic regimens by
of cells to what is conventionally considered a ‘late
dysregulated/overexpressed BCL2 in B-cell lymphoma,
apoptotic' stage: PhiPhiLux+/PI+. However, assessing
cells were simultaneously assessed for Bcl-2 protein
engagement of the apoptotic machinery by alternative more
content (vs calnexin standard) by Western blotting. The
direct methods gave no evidence for compound 18
origin of cells spanned patients additional to those
provoking this pathway in L3055-Bcl-2 cells. Thus the
diagnosed with BL (L3055 series; KHM2B): precursor
specific detection of active caspase-3 by antibody revealed
acute lymphoblastic leukemia (LILA), pro-lymphocytic leu-
its appearance in response to compounds 6 and 18 in
kemia (JVM2), mantle cell lymphoma (Rec-1; NCEB-1),
L3055-VC but not in L3055-Bcl-2 cells (Fig. Like-
primary mediastinal B-cell lymphoma (K1106), diffuse large
wise, the cleavage of poly (ADP-ribose) polymerase
B-cell lymphoma (K422; DoHH2), multiple myeloma
(PARP) ], as shown occurring in L3055-VC cells with
(KMS11; H929). Immortalized B-cell lines generated from
the well characterized apoptosis-inducing agent anti-IgM,
the peripheral blood of three donors by transformation with
was also seen on application of MDMA and here more
Epstein-Barr virus (EBV) were also included (HCD1; AT-AY;
potently with compounds 16, 17, and 18 whereas L3055-
ViWo)—EBV being invariably linked to endemic BL, PTLD
Bcl-2 cells revealed little if any PARP cleavage in response
(post-transplant lymphoproliferative disease) and a high
to any of the agents applied (Fig. JC-1 staining to
proportion of HIV-associated lymphoma.
indicate collapse of mitochondrial potential similarly
MDMA and its analogues were set at concentrations
supported the different routes to cell death by analogs
displaying maximal/near-maximal impact on L3055 cell
depending on the expression of Bcl-2 in L3055 BL cells
viability to serve as a reference. At these concentrations
(data not shown).
each of the analogues tested displayed (albeit a varyingdegree of) cytotoxicity against the spectrum of malignan-
Mechanisms and pathways to lymphoma cell killing
cies included. The best compound (18) showed a consis-
by selected α-substituted MDMA analogues
tently substantive impact against each of the subtypes. Asreported previously Bcl-2 content showed some degree
Depending upon cell type and system studied, MDMA has
of correlation with a cell's ability to resist killing from
been purported to provoke toxicity via a diverse array of
MDMA. With each of the analogues, however, there wasscant correlation between Bcl-2 protein level and extent of
Fig. 3 Cytotoxic performance of MDMA and selected analogues b
against B-cell lines of different malignant derivation and relation-
cytotoxicity observed (Fig. ). To assess the influence of
ship to Bcl-2 expression. a Cells from lines as shown plated at 5 x
Bcl-2 directly, a detailed concentration-dependent response
105/ml and cultured for 24 h with compounds indicated prior to
was established for the cytotoxic efficacy of the analogues
assessing (absolute) % viability of population as in Fig.
against L3055 cells transfected with empty vector versus
Concentration of drug applied as follows: MDMA, 2000 μM;compound 6, 500 μM; compound 12, 250 μM; compound 15,
cells expressing the BCL2 transgene. The latter were only
125 μM; compound 16, 31.25 μM; compound 17, 31.25 μM;
marginally more resistant (approximately a single log2
compound 18, 31.25 μM. Below is shown representative western
difference) to each of the analogues than cells negative for
blot analysis of Bcl-2 protein levels amongst the lines together with
Bcl-2 expression (Fig. ). This was consistent for cells
calnexin blotting control. Next are shown regression plots with Rvalues generated from remaining % viability in response to
plated at relatively low or high starting density.
compound versus relative Bcl-2 content amongst the lines tested; bconcentration-response curves to compounds of L3055 cells carrying
Mode of cell death induced by selected first and second
empty vector (L3055-VC) or a Bcl-2 transgene (L3055-Bcl2). Cells were
generation α-substituted MDMA analogues
plated at two different starting densities, 105 cells/ml and 5x105 cells/mlas indicated, and incubated with compound for 24 h prior toassessing viability/cytotoxicity as in Fig. Results represent the
When assessing cell integrity in response to compound 6 at
mean of three independent experiments ± SEM given as % viability
500 μM and compound 18 at 31.25 μM by dual PhiPhiLux
relative to vehicle control
compound 6
compound 18
f respo
o
% o
time of incubation [hours]
compound 6
compound 18
100 101 102 103 104
100 101 102 103 104
100 101 102 103 104
Fig. 4 Mode of cell death in L3055-VC and L3055/Bcl2 cells in
generate an estimate of lipophilicity where the output value
response to MDMA analogues 6 and 18. a Cells from L3055 variant
is known as "average log P" [In brief, the average log
lines indicated were cultured with compound 6 (500 μM) or
P value is the simple average of log P estimates determined
compound 18 (31.25 μM) for 6 h before dual staining with PhiPhiLux(PPL) and PI (upper graph; dot plots) revealing four subpopulations of
using eight different models. A plot of average log P versus
cells: PIlo/PPLlo = viable (bottom left quadrant), PIlo/PPLhi = early
the pIC50 value of cytotoxic performance (including SEM
apoptotic (bottom right), PIhi/PPLhi=late apoptotic (top right), and
values for both variables) was constructed and a curve was
PIhi/PPLhi=necrotic (top left). The lower set of graphs illustrate similar
fitted by weighted linear regression as detailed in Fig.
analyses arising from exposing cells to the compounds over 1-6 h withthe data represented as the % of cells arising in each quadrant at the
When operating at pH values that favour ionisation of the
different times of harvest: viable marked in white, early apoptotic
compounds under consideration, as in this case (pH=7.4),
marked light grey, late apoptotic marked dark grey, necrotic marked
log P values should be corrected using the pKa to account
black. Data are the mean of three independent experiments (n=3) ±
for the increase in aqueous solubility of the ionised form.
SEM with the values shown obtained after subtracting vehicle control;b L3055-VC and L3055-Bcl2 cells at 5x105/ml treated for 2 h with
However, uncorrected log P values were used here as the
compound 6 at 500 μM and compound 18 at 31.25 μM (black line) or
pKa values (dictated by the shared amino group), and
vehicle control (shaded) then stained with antibody to active caspase-3
therefore the correction factors, were expected to be very
with intensity of staining analysed by FACS. A representative example
similar for all compounds, thus, not affecting the rank order
of two independent experiments is shown. c Western blot analysis ofPARP cleavage in L3055-VC and L3055-Bcl2 cells plated at 106/ml
obtained. Furthermore, the use of uncorrected log P
and treated for 6 h with MDMA at 2000 μM or compounds 16, 17 or
predictions to estimate lipophilicity has been shown to be
18 at 31.25 μM; upper 117 kDa band = intact PARP, lower 97 kDa
more reliable, as it avoids the introduction of a second
band = cleaved PARP; anti-IgM (25 μg/ml) is a positive control
source of error associated with the calculation of pK
treatment known to signal PARP cleavage in L3055-VC cells via cell
surface BCR. This experiment was performed twice with a represen-
Bearing these considerations in mind, a persuasive correla-
tative example shown
tion emerges with r2=0.88 as seen in Fig.
not necessarily mutually exclusive pathways as reviewedfor example in ]. Here, the possible involvement of
monoamine transporters in delivering MDMA and itsanalogues to engage intracellular pathways for lymphoma
Analogues of MDMA with modified α-substituents were
B-cell killing was first investigated. For this, L3055-VC cells
iteratively designed and synthesised, and found to be up to
were pre-treated with a range of monoamine transporter
10-fold (first generation) and 100-fold (second generation)
(MAT) inhibitors targeting: SERT (fluoxetine), SERTand NET
more potent than the parent amphetamine derivative at
(clomipramine and imipramine) or DAT (GBR12909); and
promoting lymphoma cell death: the goal and driver to this
also with cocaine, which blocks all three MATs. From results
study. Impressively, forced over-expression or high consti-
detailed in Fig. a it can be seen that none of the MAT
tutive levels of anti-apoptotic Bcl-2 failed to protect, to any
inhibitors afforded protection against lymphoma cell toxicity
significant degree, the anti-lymphoma actions of the
induced by MDMA or two of its more potent analogues
analogues; this despite their ability to promote apoptotic
indicating that they are unlikely to be serving as conduits to
cell death in Bcl-2-deplete cells. Thus, in the face of high-
the compounds' actions in this regard.
level Bcl-2, death still occurred but in a caspase-3-, PARP-
Since MDMA has been widely reported to mediate
independent fashion that was similarly independent from a
toxicity via direct or indirect production of reactive oxygen
collapse in mitochondrial membrane potential. It should be
species (ROS), L3055-WT and -VC cells were pre-treated
noted, however, that while analogues of MDMA efficiently
with enzymes that either degrade superoxide (O •–
generated active caspase-3 within 4–6 h of exposure in the
oxide dismutase, SOD) or H2O2 (catalase). However,
bulk of native L3055 BL cells, a majority of their Bcl-2-
neither SOD (data not detailed) nor catalase were seen to
overexpressing counterparts were still alive at 6 h. Thus, at
protect tumor B cells from the detrimental effect of the
least for BL, if translated to an in vivo therapeutic, these
MDMA analogues studied, whereas catalase efficiently
compounds show potential to reduce tumor burden through
reversed cell killing provoked by H2O2 (Fig. ). Cells
efficient apoptotic clearance without the attendant inflam-
pre-treated with these enzymes but now conjugated to
matory side effects of necrotic death.
polyethylene glycol (PEG) to facilitate cell uptake ,
Importantly, improved cytotoxic performance against
similarly failed to protect (Fig. and data not detailed).
lymphoma cells does not simply reflect a generally
Finally, we examined the possibility that increased
enhanced, non-specific toxicity profile of the compounds.
lipophilicity may be associated with the enhanced anti-
A companion study shows that the most active compound
lymphoma performance of the more potent analogues in
versus lymphoma cells from Series 1 (compound 6) and
this study. To explore this, we used the online program,
two of the even more active ones from Series 2 (compounds
ALOGPs 2.1, which accepts a structural formula to
16 and 17) are in fact less toxic than MDMA to SH-SY5Y:
compound 15
compound 16
at 10µMa
catalase at 1500U/ml
catalase at 1000U/ml
PEG-catalase
at 100U/ml
catalase at 500U/ml
ability %
at 62.5µ
Fig. 5 Investigation of potential pathways through which MDMA
H2O2 or compounds indicated (compound 6, 500 μM; compound 12,
analogues elicit cytotoxicity in L3055 cells. a Impact of monoamine
250 μM; compound 15, 125 μM; compounds 16, 17 and 18,
transporter (MAT) inhibitors. L3055 cells at 105/ml were pre-incubated
31.25 μM) and then culturing for 20 h prior to assessing viability as
with MAT inhibitors for 1 h before adding MDMA or compounds 15
above; c Influence of scavenging intracellular ROS with PEG-
and 16 at 125 μM and 31.25 μM respectively then culturing for 20 h
catalase. L3055-VC cells at 105/ml were pre-treated with PEG-
prior to assessing cell viability as in Fig. b Influence of scavenging
catalase for 1.5 h before adding H2O2, MDMA, or compound 6 at
extracellular ROS with catalase. L3055 cells at 105/ml were pre-
concentrations indicated and then culturing for 24 h prior to assessing
treated with catalase at concentrations shown for 1 h before adding
a catecholaminergic neuroblastoma cell line that is used to
The literature around MDMA and the mechanisms
model MDMA neurotoxicity. The same study also shows
underlying its toxicity is large, varied and occasionally
compound 6 having diminished psychoactivity when
contradictory –the cell system, cellular origin,
compared with MDMA in the prepulse inhibition of the
animal species, drug concentration and other elements all
acoustic startle reflex test in Wistar rats []. Further-
contributing confounding factors. Here we scrutinized
more, in the present study, while constituent cells of
several of the major candidate pathways proposed for
derived lines from all B-cell malignancies proved suscep-
MDMA for their potential contribution to the toxic action
tible to one or more of the analogues tested, the relative
of the analogues versus B-lymphoma cells. The current
level of sensitivity to a given compound could be quite
study was predicated on the discovery that B lymphoma
different depending upon the cell line targeted indicating a
cells express both SERT and DAT, the transporters for
degree of selectivity in the compounds' actions against
serotonin and dopamine, respectively, and to which MDMA
lymphoma cell subtypes.
binds in the human with high affinity as it also does to NET,
MDMA and its analogues in this respect. Similar failure ofPEGylated SOD and catalase to inhibit death deliveredfrom the compounds under study equally argued againstintracellular ROS formation contributing to the lymphomacell killing observed.
If not through ROS generation or from entering via
monoamine transporters, how are MDMA and its rede-signed analogues attacking the lymphoma cells? Screeningagainst the sensitive L3055 cell line revealed no significantdifference in the cells' response to compounds containing
α-subsituents with either different steric (13–15, 16–17) orstereoelectronic (9–12) properties. Instead, the addition offurther aromatic rings, thereby increasing the size ofsubstituents at the α-carbon of MDMA, appeared aunifying factor to increasing potency: i.e. compound 6 inSeries 1 with a single aromatic ring and compounds 18, 17and 16 in Series 2 with two aromatic rings being the mostpotent from each iteration. That said, the non-aromaticcyclohexyl substituent confers equipotency to phenyl. Size
Fig. 6 Calculated liphophilicities of MDMA and analogues versus
of the α-subsituent and overall lipophilicity of the com-
cytotoxic performance. Relationship between average log P ± SEM
pound may therefore be primary determinants of potency. In
and pIC50 ± SEM for MDMA (□), alkyl α-substituted analogues 1–5
an earlier study we noted from a seemingly otherwise
(◊), monocyclic aromatic α-substituted analogues 6–15 (Δ) and
disparate set of compounds capable of killing lymphoma
polycyclic aromatic α-substituted analogues 16–18 (○). The curvewas fitted to all data points shown using weighted linear regression
cells the shared feature of being cationic amphiphiles
that gave an r2 value of 0.88
This class of compounds has the capacity to disrupt cellularmembranes, as do amphiphilic molecules generally. Greater
the norepinephrine transporter [Against serotoner-
lipophilicity also enhances entry into cells, thereby increasing
gic JAR cells for example, MDMA's cytotoxicity is
the effective intracellular concentration, and entropically
delivered via SERT: being inhibited by imipramine, a
favours complex formation (the hydrophobic effect) and thus,
monoamine transporter blocker with highest affinity for
potentially, affinity of drug for intracellular receptors/targets.
SERT [The capacity of serotonin to drive apoptosis in
Numerous studies indicate a selectivity of lipophilic com-
BL cells is reversed by SERT blockade with e.g. the
pounds for impacting rapidly proliferating cancer cells over
selective serotonin reuptake inhibitor, fluoxetine []. How-
normal cells ] and others show, amongst related series
ever, adopting the approach of pharmacological transporter
of compounds, a clear correlation between anti-proliferative
blockade in this work, neither MDMA nor two of its more
activity/cytotoxicity and degree of lipophilicity
potent redesigned analogues were seen to be delivering
When this relationship was examined for the newly
their toxic hit to lymphoma cells via any of the three
synthesized analogues of MDMA, a strong correlation was
monoamine transporters probed. Moreover, Montgomery
indeed observed with anti-lymphoma potency closely track-
and colleagues [examining the action of MDMA and
ing calculated lipophilicity, at least for those compounds with
several MDMA analogues on 5-HT and NA uptake in cells
aromatic α-substituents. We are currently exploring pre-
transfected with SERT or NET reported a Hill coefficient for
cisely how this physiochemical property of the compounds
inhibition by MBDB (our compound 3) of 1 for both
translates mechanistically to improved lymphoma killing
HEK-SERT and PC12-NET compared to that generated
in order to assist further rational design of MDMA
from its anti-lymphoma action in this study of >3. Others
analogues as anti-neoplastics.
have shown that MDMA is capable of promoting cell death
Irrespective of relative anti-lymphoma potency all com-
independently of SERT expression or activity [A
pounds including MDMA generated steep inhibition curves
second major mechanism for MDMA's cellular toxicity in
with Hill coefficients >3 indicating a high degree of
other systems was similarly ruled out here for both the lead
cooperativity in their action. Similar behaviour has been
compound and the more (anti-lymphoma) potent synthe-
observed from SSRIs and tricyclic antidepressants (Sera-
sized analogues: namely the, direct or indirect, production
feim Blood 2003; Meredith FASEB J 2005) and at least
of reactive oxygen species. Inhibitors of extracellular ROS
with the former class of compound we know that cell death
which have previously been shown to reverse the anti-
is preceded by the stimulation of Ca2+ entry. Preliminary
lymphoma actions of dopamine ] did not protect against
data (unpublished) indicate similarly altered Ca2+ flux in
L3055 BL cells on exposure to MDMA and analogues
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Source: http://www.celentyx.co.uk/Wasik%20et%20al.%202011%20Investigational%20New%20Drugs.pdf
Toxicology 192 (2003) 249–261 Reducing acute poisoning in developing countries—options for restricting the availability of pesticides Flemming Konradsen , Wim van der Hoek , Donald C. Cole , Gerard Hutchinson , Hubert Daisley , Surjit Singh , Michael Eddleston a Department of International Health, Institute of Public Health, University of Copenhagen, Panum, Blegdamsvej 3,
North Manchester CCG Board Meeting – 11 February 2015 Dr Martin Whiting Paper prepared by: Dr Martin Whiting Dr Martin Whiting Sub-Committee consideration Chief Clinical Officer's Report Background papers and links to priorities/objectives: To provide an update to the board on strategic Purpose of the paper: developments within Greater Manchester.