Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca2+-activated K+ channels

Article abstract of DOI:10.1016/j.ejmech.2013.02.029

Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca ²⁺-activated K⁺ ion channels (SK_Ca). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SK_Ca channel-blocking activity of 29 analogues of UCL 1848 in which the central CH₂ of UCL 1848 is replaced by other groups X or Y = O, S, CF₂, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO₂, NH₂, CF ₃, F, Cl, CH₃, OCH₃, OCF₃, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SK _Ca channel. One of the new compounds (39, R⁷ = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.

Full text of DOI:10.1016/j.ejmech.2013.02.029

European Journal of Medicinal Chemistry 63 (2013) 907e923
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Further studies on bis-charged tetraazacyclophanes as potent
inhibitors of small conductance Ca2þ-activated Kþ channels
,
b
Donglai Yang a, Lejla Arifhodzic a, C. Robin Ganellin a , Donald H. Jenkinson
*
a Department of Chemistry, University College London, Gower Street, London WC1E 6BT, UK
b Division of Biosciences, University College London, Gower Street, London WC1E 6BT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to
be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane
system) with respect to activity as potent non-peptidic blockers of the small conductance Ca2þ-activated
Kþ ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in
UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in
which the central CH2 of UCL 1848 is replaced by other groups X or Y ¼ O, S, CF2, C]O, CHOH, C^C, CH]
CH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still
further. The possibility of improving potency by introducing ring substituents has also been explored by
synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF3, F, Cl,
CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work,
each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic
neurons, an action mediated by the SK3 subtype of the SKCa channel. One of the new compounds (39,
R7 ¼ Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.
Ó 2013 Elsevier Masson SAS. All rights reserved.
Received 5 January 2013
Received in revised form
21 February 2013
Accepted 22 February 2013
Available online 6 March 2013
Keywords:
Ca2þ-activated Kþ channels
Channel blockers
Cyclophanes
SK3 SKCa subtype
UCL 1684
UCL 1848
1. Introduction
inexcitable cells as diverse as microglia, hepatocytes, chol-
angiocytes, T lymphocytes, chondrocytes and endotheliocytes as
Kþ channels are the most diverse and ubiquitous of the ion
channel families. The present work concerns the subtype which
opens in response to an increase in intracellular Ca2þ and which has
a smaller electrical conductance than other Ca2þ-activated Kþ
channels e hence its designation as SKCa. Cloning and sequencing
studies have shown it to exist in three variants, KCa2.1 (SK1), KCa2.2
(SK2) and KCa2.3 (SK3) the distribution and role of which have been
widely studied [1e3]. SKCa channels are found in many muscle and
nerve cells in which they influence the time course and discharge
pattern of action potentials. They are also present in electrically
well as in some cell lines derived from tumors (e.g. hepatoma,
melanoma). Accordingly, agents that block or activate these chan-
nels are of therapeutic interest. Several diseases of the central
nervous system, including ataxia, Parkinsonism and schizophrenia,
have been identified as potential targets [3,4]. A possible role for Kþ
channel modulators in the treatment of tumor progression has also
been suggested [5]. For example, inhibition of the SK3 subtype of
SKCa, could conceivably reduce metastasis in melanoma since this
channel, which promotes cellular motility, is expressed in mela-
noma cell lines but not normal melanocytes [6]. SKCa channels may
also be important for the genesis and possible treatment of atrial
[7] and incipient ventricular fibrillation [8]. Apart from their ther-
apeutic interest, stable non-peptidic SKCa blockers are valuable
pharmacological and physiological tools.
Two main classes of SKCa modulator have been developed in
response to these needs. The first and as yet the most extensively
studied act at the extracellular vestibule of the channel [2,9]. The
novel compounds described in the present work are of this kind.
Recently, activators and inhibitors acting at the channel’s inner face
have been discovered, an important advance not least because
some of the new compounds show considerable selectivity be-
tween SKCa subtypes [10].
Abbreviations: AHP, afterhyperpolarization; APCI, atmospheric-pressure chem-
ical ionization; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; EI, electron
impact; EMR, equi-effective molar concentration; ESP, electrospray positive; HMQC,
heteronuclear multiple-quantum correlation; HPLC, reversed phase high perfor-
mance liquid chromatography; FAB, fast atom bombardment; MS, mass spectrum;
rt, room temperature; SCG, superior cervical ganglion; SKCa, small conductance
calcium-activated potassium ion channel; SK3, subtype of SKCa; TFA, trifluoroacetic
acid.
* Corresponding author. Department of Chemistry, Christopher Ingold Labora-
tories, University College London, 20 Gordon Street, London WC1H 0AJ, UK.
Tel.: þ44 (0) 20 7679 4624; fax: þ44 (0) 20 7679 7463.
E-mail address: c.r.ganellin@ucl.ac.uk (C.R. Ganellin).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.02.029

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D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
The starting point for many studies of SKCa function and phar-
Further work led to UCL 1684 (Chart 1) [18,19] which has an IC50
of 4.1 nM, making it almost as active as apamin (IC50 2.3 nM under
the same conditions [20]). It possesses two xylyl bridges and these
appear to be critically important with respect to potency. The
combination of p-xylyl-diamino with m-xylyl as in UCL 1684 pro-
vided the optimum structure. Interchanging them, or combining
two p-xylyl or two m-xylyl groups, reduced potency by as much as
40-fold. These groups also impose a partial rigidity upon the
structure that has provided the opportunity for conformational
analysis [19,21,22].
The p-xylyl and m-xylyl groups can be considered to provide
6- and 5-carbon linking chains respectively between the ami-
noquinoline rings and it was of interest to replace them by
carbon chains consisting of a corresponding number of methy-
lene (CH2) groups. Each methylene chain was found to be at an
optimum for activity with 5 carbon atoms, as in UCL 1848 (Chart
1) which has two bridges each containing 5-methylene groups
[21,23]. Extending the chain up to 10 methylenes or contracting
it to 3 methylene groups reduced activity. UCL 1848 has been
reported in preliminary communications [23,24] and is used in
studies of the physiological role of SKCa channels [20,25]. Ac-
tivity was found to be remarkably sensitive to the number of
methylene groups in the bridging chains and this finding led us
to seek to optimize this structure. We have now examined
whether introducing subtle effects on conformation, by isosteric
replacement of CH2 with O or S in various combinations, might
improve potency still further (Table 1). As part of the same
study we have taken the opportunity to introduce additional
rigidity with groups such as C^C, cis CH]CH or 1,4-cyclohexyl,
to alter polarity with C]O, CHOH, or (CF2)3 groups, and to
insert a potential site for branching CH(CH3) (Tables 1 and 2).
We have also investigated analogues of UCL 1848 where the NH
group has been replaced by NMe (16), NCH2Ph (17) or S (18)
(Table 1).
macology, including our own, was the discovery [11] of the potent-
blocking action of apamin, a neurotoxic peptide found in bee
venom. The neurotoxicity had previously been shown to be asso-
ciated with the presence of two adjacent arginine moieties with
positively charged side chains projecting outwards from the bulk of
the molecule. This prompted us to test first the SKCa-blocking action
of the alkaloid tubocurarine, which has two positively charged N
atoms held in a rigid structure, and then, on finding tubocurarine
active [12], the simpler bis-aminoquinolinium dequalinium (Chart
1) [13]. This was more potent than tubocurarine though still
almost 1000 times less active than apamin.
These observations led to a detailed study of the relationship
between the structure and the activity of SKCa blockers related in
the first instance to the bis-aminoquinolinium structure. We had
three main aims. The first was to develop stable non-peptidic
compounds that could be used in the study of the physiological
roles of SKCa channels and which in the longer term might serve as
starting points for therapeutic agents. A second was to further
characterise the binding sites on the target channels by establishing
the structural and electronic properties required for high ligand
affinity. The third aim was to search for, and differentiate phar-
macologically, subtypes of the channels (now identified by mo-
lecular biological techniques, as outlined above).
In the course of the work we have examined the requirement for
a positive charge, the influence of charge number and delocaliza-
tion, and the consequences of varying the length and composition
of the chains linking the charge centers [14e19]. Perhaps the most
important advance was the finding that the introduction of a sec-
ond linker between the exocyclic N atoms, to form a tetraazacy-
clophane, could greatly increase potency. An early compound was
UCL 1530 (Chart 1) (8,19-diaza-3(1,4),5(1,4)-dibenza-1(1,4),7(1,4)-
diquinolinacyclononadecanephanedium) which was found to have
some channel subtype selectivity [16].
Chart 1. Some previous SKCa channel blockers relevant to the present work.

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
909
Table 1
Table 2
Structures and SK3-mediated activitiesa of analogues of UCL 1848 in which CH2 or
NH has been modified in one or both methylene linkers that connect the V groups
(via X) and/or quinolinium nitrogen atoms (via Y).
Structures and SK3-mediated activities of analogues of UCL 1848 in which several
methylene groups have been replaced in one or both methylene linkers.
Compound
X
Y
IC50 ꢀ SD (nM)a
EMRb ꢀ SD
UCL 1848
19
20
e(CH2)3e
eC^Ce
e(CF2)3e
e(CH2)3e
e(CH2)3e
e(CH2)3e
2.7 ꢀ 0.8
1
14 ꢀ 4
5.6 ꢀ 0.5
Compound
V
X
Y
IC50 ꢀ SD (nM)b
2.7 ꢀ 0.8d
EMRc ꢀ SD
33 ꢀ 11
13.5 ꢀ 2.3
UCL 1848
NH
CH2
CH2
1
21
22
e(CH2)3e
42 ꢀ 6
13 ꢀ 3
19 ꢀ 4
1
2
3
NH
NH
NH
CH2
5.9 ꢀ 0.8
3.8 ꢀ 0.4
5.2 ꢀ 0.9
2.6 ꢀ 0.5
1.7 ꢀ 0.3
2.3 ꢀ 0.6
e(CH2)3e
e(CH2)3e
6.1 ꢀ 1.5
c
CH2
23
24
m-C6H4
33 ꢀ 5
12 ꢀ 2
38 ꢀ 8
e(CH2)3e
e(CH2)3e
97 ꢀ 15
4
5
6
7
8
9
10
11
12
13
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
CH2
O
S
O
S
CH2
S
CH2
O
O
O
S
S
S
CH2
CH2
CH2
17 ꢀ 4
4.8 ꢀ 0.4
17 ꢀ 2
5 ꢀ 1
1.4 ꢀ 0.2
5.1 ꢀ 0.8
17 ꢀ 2
25
26
394 ꢀ 69
348 ꢀ 59
153 ꢀ 35
136 ꢀ 30
58 ꢀ 5
37 ꢀ 7
11 ꢀ 2
OH
42 ꢀ 9
12 ꢀ 3
e(CH2)3e
e(CH2)3e
4.1 ꢀ 0.5
18 ꢀ 3
1.2 ꢀ 0.2
5.3 ꢀ 0.9
3.6 ꢀ 0.4
0.91 ꢀ 0.11
Ι
C]O
CH(OH)
12 ꢀ 1
3.2 ꢀ 0.3
d
27
28f
29
1,4-C6H10
1,4-C6H10
114 ꢀ 30
1.7 ꢀ 0.4
4.4 ꢀ 1.6
54 ꢀ 15
0.81 ꢀ 0.22
1.8 ꢀ 0.3
d
c
m-C6H4
p-C6H4
e
e(CH2)3e
14
15
NH
NH
CH2
214 ꢀ 29
300 ꢀ 70
60 ꢀ 9
O
O
O
O
a
See Table 1.
b
Against UCL 1848, see Table 1.
.
83 ꢀ 19
O
O
c
16
17
18
NCH3
NCH2Ph
S
CH2
CH2
CH2
CH2
CH2
CH2
124 ꢀ 16
123 ꢀ 19
124 ꢀ 30
(47 ꢀ 14)e
25 ꢀ 5
25 ꢀ 7
d
.
a
Inhibition of the afterhyperpolarization recorded from a rat sympathetic gan-
glion neuron. See text and Ref. [20].
b
The concentration that caused a 50% reduction in the afterhyperpolarization
e
f
.
recorded from a rat sympathetic ganglion neuron.
c
Equi-effective molar ratio: the ratio of the concentrations of the test compound
UCL 2341.
and of UCL 1848 that cause 50% inhibition of the AHP, as determined in the same
experiment. Each compound was tested on 3e5 neurons.
d
Mean ꢀ S.D. of 13 observations.
e
This compound was assayed against dequalinium, giving an EMR of 0.14 ꢀ 0.04
pentamethylene bridge (Table 2, 26) and the p-xylyl bridge by m-
xylyl to accept the iodine label.
(S.D.). The EMR against UCL 1848 was estimated by applying a factor of 0.003, based
on the relative potency of dequalinium and UCL 1848 [23].
As in our previous work, each compound was assessed by
testing its ability to block the afterhyperpolarization (AHP) which
follows the action potential in superior cervical ganglion (SCG)
neurons. This AHP is mediated by the KCa2.3 (SK3) subtype of SKCa
channel [20].
Other workers have developed non-peptidic SKCa outer pore-
blocking inhibitors though from different chemical starting
points: 2-aminothiazoles [26], bis-tetrahydroisoquinolines [27],
bis-2,4-diaminoquinazolines [28], N-methyl laudanosine [29],
quaternary bicuculline salts [30] and quinoline-appended dia-
zepines [31].
We have also explored whether substituents may exert
electronic effects, which might be reflected in activity changes,
when placed in the 4-aminoquinoline rings at positions 5, 6 or 7
in both structural types, UCL 1848 (Table 3) and UCL 1684
(Table 4).
We have previously reported the synthesis of an iodinated
compound, based on the UCL 1684 structure, to provide a potential
125I ligand for labeling studies [19]. We have now explored a
similar ligand, where the m-xylyl bridge has been replaced by a

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D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
Table 3
Table 4
Structures and SK3-mediated activities of analogues of UCL 1848 having sub-
stituents in the non-nitrogen rings.
Structures and SK3-mediated activitiesa of analogues of UCL 1684 having sub-
stituents in the quinolinium non-nitrogen rings.
R5 = R6 = R7 = H unless otherwise indicated.
R5 = R6 = R7 = H unless otherwise indicated.
Compound
R6
IC50 ꢀ SD (nM)a
EMRb ꢀ SD
UCL 1848
H
2.7 ꢀ 0.8
4.1 ꢀ 0.3
2.3 ꢀ 0.4
4.0 ꢀ 0.6
4.1 ꢀ 0.3
3.0 ꢀ 0.5
3.8 ꢀ 0.2
6.8 ꢀ 0.5
3.9 ꢀ 0.3
1
30
31
32c
33
34
35
36
37
NO2
NH2
CF3
F
2.1 ꢀ 0.1
1.04 ꢀ 0.25
1.1 ꢀ 0.2
2.1 ꢀ 0.1
1.1 ꢀ 0.2
2.0 ꢀ 0.1
3.1 ꢀ 0.5
1.8 ꢀ 0.3
Compound
R6
IC50 ꢀ SD (nM)a
EMRb ꢀ SD
UCL 1684
H
4.1 ꢀ 0.2c
5.1 ꢀ 0.4
3.7 ꢀ 0.3
27 ꢀ 5
1.44 ꢀ 0.13
2.6 ꢀ 0.2
1.7 ꢀ 0.2
11.0 ꢀ 2.3
6.9 ꢀ 1.1
8.0 ꢀ 1.7
7.6 ꢀ 1.0
7.4 ꢀ 1.5
5.9 ꢀ 0.8
43
44
45
46
47
48
49
50
NO2
NH2
CF3
F
Cl
CH3
OCH3
OH
R7
17 ꢀ 2
Cl
21 ꢀ 4
CH3
OCH3
OCF3
R7
19 ꢀ 2
15 ꢀ 3
38
CF3
Cl
Cl
8.1 ꢀ 1.1
2.6 ꢀ 0.2
8.3 ꢀ 2.3
3.0 ꢀ 0.4
1.6 ꢀ 0.3
0.53 ꢀ 0.07
3.5 ꢀ 0.6
15 ꢀ 2
39e
40d
41
51
52
53
CF3
Cl
76 ꢀ 10
19 ꢀ 1
31 ꢀ 6
OCH3
1.1 ꢀ 0.2
R5 R7
7.3 ꢀ 0.9
4.1 ꢀ 0.5
OCH3
9.8 ꢀ 0.9
42
Cl Cl
21 ꢀ 3
8.6 ꢀ 1.5
R5 R7
a
See Table 1.
Against UCL 1848, see Table 1.
UCL 2079.
54
Cl Cl
24 ꢀ 4
10 ꢀ 2
b
a
c
d
e
See Table 1.
Against UCL 1848, see Table 1.
From Ref. [20].
þ
þ
+
b
+
In 40 N ðCH Þ N chain is replaced by NCH2
CH2N.
2
5
c
UCL 2053.
2. Chemistry
starting material in place of I. The bis-NCH2Ph analogue (Table 1,
¼ NCH2Ph, 17) was synthesized from 1,5-di(benzylamino)
V
The synthetic route to the compounds of Tables 1 and 2 is out-
lined in Scheme 1. The route can be divided generally into two
steps: the first step involves the reaction of diamine compounds (I)
heated with 4-chloroquinoline in p-cresol, pentanol, or phenol to
give the diquinoline intermediates II, which were generally
collected, washed and dried, but not purified further. The second
step involves the preparation of the cyclophanes by bis-
quaternisation of the quinoline nitrogen atoms, using the requi-
pentane [32] and quinolin-4-yl triflate in bis(2-methoxyethyl)
ether, followed by alkylation with 1,5-diiodopentane in boiling
butan-2-one under reflux for 2 days, analogously to Scheme 1.
The dithia analogue (Table 1, V ¼ S, 18) was synthesized (Scheme
2) from pentane-1,5-di-isothiouronium dibromide [33] and 4-
chloroquinoline with KOH in ethanol, via the intermediate V, fol-
lowed by alkylation with 1,5-diiodopentane in boiling butan-2-one.
The putative iodinated ligand (Table 2, 26) was prepared fromthe
bridged phenol(25) bytreatment withNaI and Chloramine T in DMF.
The latter (phenol 25) being obtained from 2,6-bis(bromomethyl)
anisole VI [19] (see also Table 5) as outlined in Scheme 3.
Compounds having substituents in the quinoline non-nitrogen
ring (Tables 3 and 4) were obtained by heating the appropriate 6-
or 7-substituted 4-chloroquinoline (or 4,5,7-trichloroquinoline)
with 1,5-diaminopentane or p-xylylenediamine in refluxing pen-
tanol, analogously to Scheme 1. The requisite substituted 4-
chloroquinolines VIII (Scheme 6, see Supplementary data) were
either purchased (in the cases where R ¼ 6-Cl, 6-CF3, 7-Cl, 7-CF3),
or prepared by heating the corresponding substituted 4-
hydroxyquinoline VII (Scheme 6) with refluxing POCl3 (where
R ¼ 6-F, 6-OCF3, 5,7-Cl2), or synthesized according to Scheme 6
(where R ¼ 6-Me, 6-OMe, 6-NO2, 7-OMe). Where R ¼ 6-NH2 (31,
44) the compounds were prepared from the corresponding nitro
derivatives (30, 43) by reduction with hydrogen and Pd/C catalyst in
methanol (31) or SnCl2/HCl/AcOH (44).
site a,u-dihalogeno-alkanes III in boiling butan-2-one, DMF, or 4-
methylpentan-2-ol. The final compounds were generally purified
as trifluoroacetates by preparative HPLC. In a few cases they were
purified by crystallization of the salt. In the case of 19 the diamine I
(X ¼ C^C), was treated with the very reactive quinoline-4-triflate
instead of 4-chloroquinoline to give the intermediate II (X ¼ C^C).
The diamine intermediates (I) were prepared (Scheme 4, see
Supplementary data) by the published procedures listed in Table 5
(see Supplementary data), or were obtained commercially. The bis-
diquinoline intermediates (II, where X ¼ C]O or CHOH) (for
compounds 12 and 13 respectively) were synthesized via the cor-
responding 1,3-dioxolane IV as indicated in Scheme
5 (see
Supplementary data). The dioxolane IV, itself, was synthesized via
the route outlined in Scheme 5 starting from diethyl acetone-1,3-
dicarboxylate. The dihalogeno intermediates (III) (R1 ¼ Cl, Br or I)
were prepared by the published procedures also listed in Table 5, or
were obtained commercially.
The bis-NMe analogue (Table 1, V ¼ NMe, 16) was prepared
The compounds have been named as cyclophanes according to
IUPAC Recommendations [17]. To assist readers who are not au fait
according to Scheme 1 using 1,5-di(methylamino)pentane as the

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
911
X
CH2
CH2
Cl
HN
NH
HN
N
NH
X
II
R'
Y
R'
N
+
+
H2N
X=
X
I
NH2
a
N
b
N
N
III
CH2
Y
CH2
CH2SCH2
CH2OCH2
CH2SCH2
CH2OCH2
CH2CH2CH2
CH2CHCH2
Y=
CH2CH2CH2
CH2CHCH2
CH3
CH3
(CF2)3
C
C
H
O
O
C
C
H
H
O
O
CH2 CH2
H
CH2 CH2
OMe
aReagents and conditions: (a) p-cresol, 130-150 °C, 3-24 h, or phenol, 100 °C, or 1-pentanol,
reflux, 10 – 72 h, (34 – 76%); (b) butan-2-one/DMF (10:1), reflux 5 d, or butan-2-one, reflux
3 - 6 d, or DMF, 110 °C, 2 d, or 4-methyl-pentan-2-ol, reflux, 2 d, purify by hplc
a
Scheme 1. General synthesis for compounds in Tables 1 and 2 involving intermediates I, II and III (compounds 1e17, 19e23, 27e29).
with the cyclophane numbering system, the structures in Tables 1
and 4 have been numbered to indicate how the compounds have
been named in the Experimental section. The quinolone rings are
regarded as “superatoms” and one of them is numbered 1. The
linking chain is then numbered sequentially so that the second
quinolone superatom (as in Table 1) is given the lowest possible
number which is 7; this determines that Y is at position 4 and X is at
11, leaving V at positions 8 and 14. In Table 4, the benzene rings are
also superatoms. Starting again from quinolone as 1, sequential
numbering of the chain such that the lowest numbers obtain for the
Cl
S
S
H2N
S
NH2
S
N
+
+
a
NH2
N
NH2
N
V
I
I
S
b
S
+
+
N
N
18
aReagents and conditions: (a) KOH, EtOH, reflux, 3 h, (100%); (b) butan-2-one, reflux, 4 d,
prep hplc, (3%).
a
Scheme 2. Synthesis of intermediate V and compound 18.

912
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
benzene rings which are 3 and 8 respectively, and quinolone as 5.
The amino groups are accordingly numbered 6 and 10. The qui-
nolone rings are linked into the cyclophane system at their 1,4
positions, and the benzene rings are linked in respectively at the 1,3
and 1,4 positions.
Molecular formulae and molecular weights of the compounds
from Tables 1e4 are given in Tables 6e10 along with the crystalli-
zation solvents and mp’s, and are located in the Supplementary data.
3. Biology
Each compound was assayed for its ability to reduce the SK3
(KCa2.3)-mediated afterhyperpolarization that follows the action
potential in cultured rat superior cervical ganglion (SCG) neurons,
as previously described [16,20]. The neurons were isolated from 17-
day-old SpragueeDawley rats using procedures in accordance with
European Directive 2010/63/Eu. See Section 6.2 for more
aReagents and conditions: (a) K Phthal, DMF, 50 °C, 48 h, (53%) ; (b) NH2NH2H2O, MeOH,
reflux, 2.5 h. (85%); (c) HCl, reflux 2 h, (85%) ; (d) pentanol, reflux, 2 d, (57%); (e) BBr 3,
CH2Cl2 ,0°C, 30 min, NaOH, (86%) ; (f) I(CH2)5I, butan-2-one/DMF (4 :1), reflux, 5 d, prep
hplc; (7%) ; (g) NaI/DMF, RT, Chloramine T, HCl, prep hplc, (63%) ; (h) I(CH2)5I, butan-2-
one/DMF (4 :1), reflux, 5 d, prep hplc, (22%).
a
Scheme 3. Synthesis of compounds 24e26.

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
913
information on the electrophysiological methods. A reference SK3
blocker was included in each assay in order to allow for small and as
yet unanalyzed variations in the sensitivity of individual neurons.
In the early part of the present work, as in our past studies [14e
16,19] dequalinium was used for this purpose. However, once the
great potency of UCL 1848 had been established [23], it was thought
preferable to employ it as a reference rather than the 330-fold less
active dequalinium.
IC50s and equi-effective molar concentration ratios (EMRs),
relative to either dequalinium or UCL 1848, were estimated by
simultaneous least squares fitting of the data with the test and
reference agents. Further details and an example are included in
the Supplementary data. Both the IC50s and the EMRs, ꢀstandard
deviations, are listed in the Tables. The EMR values were used for
comparisons between compounds.
IC50 ¼ 16 ꢀ 4 nM. Here, stereochemical differences are probably
causing the change in potency.
UCL 1848 was developed from a study where benzene rings
were replaced by several methylenes in the bridging groups in the
structures of UCL 1684 and analogues. Some mixed structures were
investigated in which the corresponding p- or m-xylyl linking
groups were combined with an alkylene linker [21]. In the present
paper, the p- or m-xylyl linking groups are interchanged and
combined with a pentamethylene linker to see whether such
combinations might offer a potency advantage (compounds 23, 29,
Table 2). It is of interest to find that, in both cases, the compounds
23 and 29 are more potent blockers than the corresponding alter-
nate isomers, as follows.
Thus, 23, an analogue of UCL 1848 which has the NHealkylenee
NH chain replaced by NHem-xylyleneeNH, is more potent
(IC50 ¼ 33 ꢀ 5 nM) than the corresponding NHep-xylyleneeNH
compound (3b in Ref. [21]) (IC50 ¼ 60 ꢀ 3 nM). Furthermore, 29,
an analogue of UCL 1848 which has the NþealkyleneeNþ chain
replaced by Nþep-xylyleneeNþ, is much more potent
(IC50 ¼ 4.4 ꢀ 1.6 nM) than the corresponding Nþem-xylyleneeNþ
compound (4b in Ref. [21]) (IC50 ¼ 31 ꢀ 1 nM). Whence, although
the m- and p-xylylene combinations were optimal for UCL 1684,
when combined with an alkylene group in the structure the
preferred (m- or p-) xylylene linker is switched.
The importance of the NH group in the quinoline 4 position is
apparent from compounds 16e18 (Table 1). Replacing the hydrogen
atom of 16 by methyl reduces potency at least 30-fold; the effect
does not appear to be due to steric hindrance since the benzyl
compound, 17, is similarly less active, as is 18 where the NH link is
replaced by S. The S compound 18 may be less active, however, due
to an electronic influence, as was revealed with dequalinium ana-
logues [14]. Even so, it appears likely that the NH is acting as a
hydrogen donor for a hydrogen bond.
4. Results and discussion
An oxygen or sulfur atom is accommodated in the bridging
chain Y joining the two quinolinium nitrogen atoms (5, 10) without
altering potency (Table 1), but they reduce potency by a factor of 5
when they are in the chain X joining the two amino nitrogen atoms
V (4, 11). An oxygen atom in both chains (6) similarly reduces po-
tency by a factor of 5. Thus the oxygen in chain Y is still accom-
modated. This additivity does not appear to hold when there is a
sulfur atom in one of the chains. Thus, with sulfur in chain Y, the
addition of an oxygen atom (8) into chain X reduces potency by a
factor of approximately 10-fold (6.5e13). Similarly, non-additivity
is seen with a sulfur atom in chain X and oxygen in chain Y (7),
or with a sulfur atom in both chains (9).
The differences between O and S linkages in this context are
interesting but are not sufficiently revealing to inform on what
properties may be critical. Oxygen is much more polar and ready to
accept hydrogen bonds, the CeO bond is shorter than CeC and
hence it shortens the bridging chain and make it more rigid. In
contrast, the CeS bond is longer than CeC, it lengthens the bridging
chain and makes it more flexible.
Rigidifying and shortening bridging chain X by using cis-ethene
or ethyne as in 19 or 22 (Table 2) reduces potency by a factor of 5- to
7-fold, results similar to those with O or S. However, cis-ethene in
bridging chain Y reduces potency by 19 ꢀ 4-fold; this is in distinct
contrast from the effects of O or S. Furthermore there is no indi-
cation from these results that increasing electron density is ad-
vantageous; similarly a carbonyl group in chain X, (12), a hydrogen
bond acceptor having high electron density, reduces potency.
Increasing electron density and increasing lipophilicity with fluo-
rine atoms (20) also reduces potency.
Very bulky groups such as 1,3-dioxolane (14,15) (Table 1) are not
tolerated. It is of interest, however, to find that a methyl group can
be accommodated in either bridging chain (1, 2), or both chains (3)
with only a relatively small drop (2- to 3-fold) in potency. A hy-
droxyl group can be accommodated in chain X (13) without
affecting potency. Thus branching with lipophilic (CH3) or hydro-
philic (OH) groups has no strong influence.
Wishing to obtain a compound that could be labeled with 125I,
and so provide a non-peptidic radioligand, we synthesized 26
(Table 2), a congener of UCL 1848 (Chart 1) in which a p-iodophenol
moiety was incorporated in the linker between the amino nitro-
gens. The corresponding phenolic compound (25) was also pre-
pared. However, just as in a similar earlier attempt [19] based on
the UCL 1684 structure, the outcome was a more than 100-fold
reduction in potency, so ruling out the iodo-compound as a po-
tential radioligand. Possible explanations for the deleterious effects
of these substitutions have been discussed previously [19].
We have also explored the influence of substituents in the non-
nitrogen-containing rings of both types of structure, as analogues of
UCL 1848 (Table 3) and UCL 1684 (Table 4) respectively. Generally,
they did not improve potency or show any trend between elec-
tronic properties, hydrogen-bonding properties, polarity and
channel-blocking activity. It was apparent, however, that the sub-
stituents had a more obvious deleterious effect on the activity of
analogues of UCL 1684 than on analogues of UCL 1848, especially
for the 7-substituted compounds. This suggests that the quinoline
rings are accommodated more readily into the architecture of the
channel-binding site for the methylene-bridged structures.
One compound, however, 39 (Table 3), with a 7-chloro substit-
uent, was approximately twice as potent (EMR ¼ 0.53 ꢀ 0.07) as UCL
1848 (EMR ¼ 1.00 as reference) and, indeed, is the most potent
channel-blocking compound that we have synthesized and tested.
The isomeric 6-chloro-substituted compound, 34, was only equi-
active (EMR ¼ 1.1 ꢀ 0.2). The 5,7-dichloro-substituted compound,
42, was much less active (EMR ¼ 8.6 ꢀ 1.5). In contrast, the 7-chloro-
substituted analogue 52 of UCL 1684 did not show improved po-
tency (EMR ¼ 7.3 ꢀ 0.9) and did not show any significant difference
from the 6-chloro isomer, 47, (EMR ¼ 8.0 ꢀ 1.7). Compound 29
(Table 2), with p-xylyl in the Nþ$Nþ bridging chain of UCL 1848 was
Replacing the p-phenyl linking group in UCL 1684 by 1,4-
cyclohexyl provides a compound, 28, (Table 2) which has retained
(or even increased a little) the potency. This result is very inter-
esting because it again suggests that the benzene ring is not
strongly involved in a
p-electron interaction with the channel-
binding site, in agreement with our previous observations [23].
In another cyclohexyl compound, 27, the NHealkyleneeNH
chain in UCL 1848 is replaced by the formal equivalent of six
methylene groups; thus, this compound (IC50 ¼ 114 ꢀ 30 nM)
should be compared with the homologue of UCL 1848, the com-
pound 2d in Ref. [21] where n ¼ 5 and m ¼ 6, which had

914
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
of sufficient interest (EMR ¼ 1.8 ꢀ 0.3) to merit the introduction of a
7-chloro substituent, affording 40 (Table 3). In this case, however,
channel-blocking potency was decreased (EMR ¼ 3.5 ꢀ 0.6).
Turning to the biological implications of the work, one of our
initial aims was to develop potent non-peptidic blockers as tools for
the study of the roles of SKCa channels. UCL 1684 has already been
found useful in situations, e.g. superfusion [34] and micropressure
application [35] in vivo, where the biodegradation of apamin could
pose a problem. It is also preferable to apamin for micro-
ionophoretic application [36]. A further advantage is that these
blockers are rapidly reversible in action. Of the 54 compounds
assayed in the present work, only two (39 and 44) had an offset
slower than the time required (5e10 min) for the drug-containing
solution to clear from the dish holding the isolated neurons.
Seven of the new compounds (10, 13, 28, 31, 32 (UCL 2079, [37]),
34, 41) are similar to UCL 1848 inpotency, with one (39) being almost
twice as active. Taken as a group, their potency is such that con-
centrations in the nanomolar range can be used in functional studies.
10 and 100 nM should suffice for greater than 95% block of the SK2
and SK3 subtypes respectively. Higher concentrations may evince
additional actions such as the recently described Ca2þ and voltage-
dependent inhibition of ryanodine receptors by UCL 1684 [38].
The new compounds should also be of help in understanding
the mechanism of action of SKCa channels. The most potent of our
tetraazacyclophanes are relatively compact molecules, certainly in
relation to apamin, and they are also more rigid. This has allowed
conformational analysis [21,22] which has revealed that a charge
center separation of 5.6e5.8 Å is optimal for potency [21]. Though
this may be thought to provide a potential molecular caliper for the
putative corresponding negative charge carriers on the channel, the
binding of a doubly charged and relatively rigid ligand such as UCL
1684 can be expected to influence the tertiary structure of the
subunits, certainly in the binding region and probably beyond it.
The interaction between the channel subunits could also be
affected. Hence the spatial arrangement of the outer pore region
may differ appreciably between liganded and unliganded channel
subunit assemblies. In keeping with this, it has recently been sug-
gested [2,39] that apamin acts through an allosteric mechanism not
involving direct pore block. The same may hold for our compounds
though their smaller size, and relatively simple chemical structure,
implies that their interactions with the channel are less extensive
than for apamin and may be different in character.
Other evidence supports such a difference. The binding of apa-
min to the SKCa channel is strongly dependent on the experimental
conditions. When studied directly, using labeled apamin applied to
intact cells under physiological conditions of ionic strength, tem-
perature and pH, the observed equilibrium dissociation constant
(Kd) is in good accord with estimates based on the concentrations
needed to block the functional response [40,41]. However, if apa-
min binding is examined, as it often is, using cell membrane
preparations suspended at 0 ꢁC in a slightly alkaline solution (pH
7.5e8.5) of low ionic strength, Kd is now found to be 3e8 pM, 40e
1000 times lower than the values from functional measurements
[42,43]. Subtype selectivity is also lost [43]. In contrast, when the
binding of UCL 1684 is estimated from its ability to displace labeled
apamin under the same experimental conditions, there is no such
discrepancy: the Ki for UCL 1684 is similar to that estimated from
physiological measurements [42]. Other evidence that the actions
of UCL 1684 and apamin are not always identical comes from recent
physiological and pharmacological studies. Mouse pancreatic islet
apamin is only weakly active [45,7]. Finally, it has now been shown
that the blocking actions of UCL 1684 and apamin are affected quite
differently by point mutations (S245T and Y246L) in the S3eS4
extracellular loop of rat SK2 subunits [46].
A fuller understanding of the molecular action of outer pore SKCa
blockers could be key to the most immediate challenge in the
medicinal chemistry of SKCa channels. This is the development of
non-peptidic agents with high selectivity for one or other of the
SK1, SK2 and SK3 subtypes. The differential sensitivity of the sub-
types to apamin, though modest, suggests that this should be
achievable. Recent evidence [47] for the occurrence of SKCa het-
eromeric complexes with distinct tissue distributions and suscep-
tibility to blockers points in the same direction. Though only a few
of our most active previous compounds (UCL 1684, UCL 1848, UCL
2079 [37]) have been examined for selectivity, the evidence so far
available [20,37,48,49] suggests that they show the same general
pattern as apamin. Whether the same holds for the range of new
and comparably potent compounds that we describe here remains
for future study.
5. Conclusions
The tetraazacyclophane UCL 1848 contains two bridges, each of
5-methylene groups, and its SKCa channel-blocking activity is
extraordinarily sensitive to changes in chemical structure. To
investigate this further, the sensitivity of the linking alkane chain to
conformational effects has been thoroughly explored by
substituting O or S in place of the central CH2, or by introducing
acetylenic, ethene or CF2 groups. The results suggest that the alkane
structure of UCL 1848 has been optimized with respect to SK3
channel-blocking potency. Quinoline has previously been shown to
be the best heterocycle for SK3 activity in this structural type but
the possibility of improving potency by introducing substituents
had not previously been explored in detail. We have now demon-
strated that the incorporation of substituents into the benzenoid
rings of the quinolinium groups of UCL 1684 and UCL 1848, while
generally compatible with high activity, does little to further in-
crease it. In general it is clear that compounds having substituents
in the 1848 structure are more potent than the correspondingly
substituted 1684 structures; this is especially apparent with 7-
substituted compounds. Seven of the new compounds are, how-
ever, comparable in potency with UCL 1848, and one compound
(39, R7 ¼ Cl, UCL 2053) is twice as potent as UCL 1848. The avail-
ability of these new compounds should be useful for future studies
of SKCa function and subtype selectivity.
6. Experimental protocols
6.1. Chemistry
6.1.1. General methods
Starting materials and solvents were obtained from Aldrich
Chemical Company, Lancaster Synthesis, BDH or Merck. Tetrahy-
drofuran was distilled with sodium and benzophenone under an
atmosphere of nitrogen immediately prior to use. Butan-2-one and
pentan-1-ol were dried over molecular sieves. All other solvents
and reagents were used as received unless stated otherwise.
Melting points were determined on an Electrothermal (open
capillary) melting point apparatus and are uncorrected. Mass spectra
were recorded on either a VGmicromass 305 electron impact (EI) or
VG-ZAB SE fast atom bombardment (FAB) mass spectrometer with a
Finnigan Incos II data system at University College London. 1H NMR
spectra were recorded at 200, 300 or 400 MHz onVarian XL-200,
Bruker 300, or Varian VXR-400 instruments.13C NMR spectra were
recorded at 100 MHz on a Varian VXR-400 or Bruker 300 instrument.
b-cells have been reported to possess an SK channel that is blocked
by UCL 1684 but not by apamin [44]. More recently, atrial cells from
several species including man have been found to express a func-
tional SKCa channel, inhibition of which by outer pore blockers
(among them UCL 1684) has an antifibrillatory action, whereas

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
915
In all cases the residual protic solvent was the internal standard.
2H, NCH2CH2CH2). 13C NMR: 155.1, 146.2, 137.0, 134.0, 126.7, 123.8,
Spectra were recorded in the solvent specified, with chemical shifts
118.5, 117.5, 97.5, 50.8, 42.5, 34.8, 26.8, 24.7, 22.9, 17.8. HPLC: (A/
(d) expressed in parts per million relative to the internal standard.
B ¼ 65/35) Rt ¼ 5.0 min,purity 100%. Anal. Calcd. for [C29H36N4]2þ
2
Microanalyses (CHN) were carried out by the Microanalytical Section
of the Chemistry Department at University College London and were
generally within 0.4% of the calculated value; the results are pre-
sented in four Tables in the Supplementary data.
[CF3CO2]ꢃ, 0.5CF3CO2H, 0.5H2O.
6.1.4. 4,11-Dimethyl-8,14-diaza-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate hemihydrate (3)
Analytical high performance liquid chromatography (HPLC) was
carried out on a Gilson or Shimadzu HPLC apparatus using a Kro-
masil C18 5 mm reversed phase column, a flow rate of l mL/min and
UV detection at 254 nm. Preparative HPLC was carried out on a
Gilson apparatus using a Kromasil C18 10 mm 250 ꢂ 22 mm
reversed phase column, a flow rate of 18 mL/min and UV detection
at 254 nm. In both cases the mobile phase compositions are indi-
cated in the appropriate section. In most cases, solvent mixtures of
water (A) þ 0.1%trifluoroacetic acid (TFA) and MeOH (B) þ 0.1% TFA
were used with a flow of l8 mL/min. In some cases (B2) MeCN was
used instead of MeOH. Some excess TFA and H2O were retained in
the salts after HPLC as indicated by the CHN analysis results.
Flash column chromatography was carried out using silica ge1
N,N0-di(quinolin-4-yl)-1,5-diamino-3-methylpentane (0.25 g,
0.68 mmol) was treated with 1,5-dibromo-3-methylpentane
(0.25 g, 1.04 mmol) as described for (1) to yield 30 mg (7%) of
the product, mp: 198e203 ꢁC. MS (ESPþ): 453 [MH]þ, 227 [M]2þ
.
1H NMR (DMSO-d6)
d: 9.22 (br s, 2H, NH), 9.17 (br s, 2H, NH), 8.40
(d, 2H, quinoline H-5, J ¼ 8.2 Hz), 8.35 (d, 2H, quinoline H-5,
J ¼ 8.2 Hz), 8.20 (d, 2H, quinoline H-2, J ¼ 6.9 Hz), 7.99 (m, 4H,
quinoline H-8), 7.94 (d, 2H, quinoline H-2), 7.87 (m, 4H, quinoline
H-7), 7.63 (m, 4H, quinoline H-6), 6.62 (d, 2H, quinoline H-3,
J ¼ 6.9 Hz), 6.44 (d, 2H, quinoline H-3), 4.63 (m, 4H, NCH2), 4.42
(m, 4H, NCH2), 3.58 (m, 4H, NHCH2), 3.39 (m, 4H, NHCH2), 1.85
(m, 4H, NCH2CH2), 1.60 (m, 14H, NCH2CH2, NHCH2CH2,
NHCH2CH2CH), 1.09 (m, 12H, CH3), 0.62 (br s, 1H, NCH2CH2CH),
0.36 (br s, 1H, NCH2CH2CH). 13C NMR: 154.7, 154.6, 146.0, 145.9,
135.9, 136.6, 133.8e2 C’s, 126.6e2 C’s, 123.6, 123.55, 118.3, 118.2,
117.4e2 C’s, 97.7, 97.2, 50.7, 50.6, 41.1, 35.1, 33.9, 33.8, 32.1, 28.0,
26.0, 25.0, 23.8, 19.4, 19.3, 18.1, 17.8. HPLC: (A/B ¼ 65/35)
(BDH, particle size 40e63 mm). Analytical thin layer chromatography
was performed on pre-coated aluminium-backed plates (Merck
Kieselgel60 F254) and visualised using UV light (254 nm), perman-
ganate developer solution [KMnO4 (3 g), K2CO3 (20 g), 5% aq. NaOH
(5 mL) and water (300 mL)] or vanillin developer solution [vanillin
(15 g) in ethanol (250 mL) and conc. H2SO4 (2.5 mL)] as appropriate.
Rt ¼ 6.9 min, purity 100%. Anal. Calcd. for [C30H38N4]2þ
2
[CF3CO2]ꢃ, 0.5CF3CO2H, 0.5H2O.
6.1.2. 11-Methyl-8,l4-diaza-1,7(1,4)-diquinolinacyclotetradecapha-
nium di-trifluoroacetate hemihydrate (1)
6.1.5. 8,14-Diaza-11-oxa-l,7(1,4)-diquinolinacyclotetradecaphanium
diiodide (4)
N,N0-di(quinolin-4-yl)-1,5-diamino-3-methylpentane (0.21 g,
0.57 mmol) in 2-butanone (20 mL), DMF(3 mL), and 1,5-
diiodopentane (0.21 g, 0.65 mmol) were heated under reflux
and N2 for 5 days. After cooling, a small amount of Et2O was added
and the precipitate obtained was filtered off, washed with Et2O,
and purified by preparative HPLC using eluents A/B ¼ 65/35. The
compound was dissolved in iPrOH, filtered, and evaporated to
dryness to yield 40 mg (12%) of the product, mp: 206e209 ꢁC. MS
Bis[2-(4-quinolinyl)aminoethyl]ether (0.36 g, 1.0 mmol) in DMF
(150 mL) and 1,5-diiodopentane (0.32 g, 1.0 mmol) were heated
under reflux for 96 h and then evaporated. The residue was crys-
tallized from MeOH and recrystallized from DMF to give a white
solid (102 mg, 14% yield), mp: 311 ꢁC. MS (FAB): 427 (M ꢃ 1)þ. HPLC
l
(A/B ¼ 75/25): 95.2% purity, Rt ¼ 10.8 min. H NMR (DMSO-d6)
d:
9.21 (br t, 2H, NH), 8.41 (d, 2H, quinoline H-5, J ¼ 8.4 Hz), 8.26 (d,
2H, quinoline H2, J ¼ 7.4 Hz), 8.05 (d, 2H, quinoline H-8, J ¼ 8.8 Hz),
7.90 (t, 2H, quinoline H-7, J ¼ 7.6 Hz), 7.65 (t, 2H, quinoline H-6,
J ¼ 7.8 Hz), 6.79 (d, 2H, quinoline H-3, J ¼ 7.4 Hz), 4.55 (m, 4H,
NCH2), 3.78 (m, 8H, NHCH2 and OCH2), 1.76e1.72 (m, 4H), 0.77 (m,
2H). Anal. Calcd. for [C27H32N4O]2þ 2Iꢃ, 0.4HI.
(ESPþ): 439 [M ꢃ H]þ, 220 [MH]2þ. 1H NMR (DMSO-d6)
d: 9.13 (br
t, 2H, NH, J ¼ 5.2 Hz), 8.39 (d, 2H, quinoline H-5, J ¼ 8.3 Hz), 8.17 (d,
2H, quinoline H-2, J ¼ 7.4 Hz), 7.99 (d, 2H, quinoline H-8,
J ¼ 8.8 Hz), 7.88 (t, 2H, quinoline H-7, J ¼ 7.7 Hz), 7.63 (t, 2H,
quinoline H-6, J ¼ 7.7 Hz), 6.61 (d, 2H, quinoline H-3, J ¼ 7.4 Hz),
4.60 (m, 2H, NCH2), 4.47 (m, 2H, NCH2), 3.62 (m, 2H, NHCH2), 3.50
(m, 2H, NHCH2), 1.78e1.62 (m, 9H, NCH2CH2, NHCH2CH2,
NHCH2CH2CH), 1.08 (d, 3H, CH3, J ¼ 6.2 Hz), 0.87 (m, 1H,
NCH2CH2CH2), 0.55 (m, 1H, NCH2CH2CH2). 13C NMR: 154.8, 146.4,
136.9, 133.9, 126.7, 123.7, 118.4, 117.4, 97.3, 52.7, (33.1 and 26.8,
HMQC shows three types of C’s here), 22.0, 19.3 and one type of C
under DMSO shown by HMQC. HPLC: (A/B ¼ 65/35), Rt ¼ 7.4 min.
6.1.6. 8,14-Diaza-4-oxa-1,7(1,4)-diquinolinacyclotetradecaphanium
dibromide (5)
N,N0-bis(4-quinolinyl)pentane-l,5-diamine,15e (0.36 g,1.0 mmol)
in DMF (150 mL) with bis(2-bromoethyl)ether (Table 5) (0.23 g,
1.0 mmol) were heated at 100 ꢁC for 48 h, then to reflux for 72 h, and
then evaporated. The residue was crystallized from iPrOH, then
recrystallized from MeOH to give an off white solid (106 mg, 17%
yield), mp: 305 ꢁC decomp. MS (FAB): 427 (M ꢃ 1)þ; HPLC: (A/B ¼ 70/
purity
0.4CF3CO2H, 0.5H2O.
¼
99.8%. Anal. Calcd. for [C29H36N4]2þ 2[CF3CO2]ꢃ,
30), 99.7% purity, Rt ¼ 9.3 min. lH NMR (DMSO-d6)
d: 9.39 (br t, 2H,
NH), 8.53 (d, 2H, quinoline H-2, J ¼ 8.4 Hz), 8.29 (d, 2H, quinoline H-5,
J ¼ 7.6 Hz), 8.09 (d, 2H, quinoline H-8, J ¼ 8.8 Hz), 7.91 (t, 2H, quin-
oline H-7, J ¼ 8.0 Hz), 7.66 (t, 2H, quinoline H-6, J ¼ 7.6 Hz), 6.84 (d,
2H, quinoline H-3), 4.73 (m, 4H, NCH2), 3.80 (m, 4H, OCH2), 3.61 (m,
4H, NHCH2),1.70 (m, 4H),1.50 (m, 2H). Anal. Calcd. for [C27H32N4O]2þ
2Brꢃ, 2H2O.
6.1.3. 4-Methyl-8,14-diaza-1,7(1,4)-diquinolinacyclotetradecaphan-
ium di-trifluoroacetate hemihydrate(2)
N,N0-di(quinolin-4-yl)-l,5-diaminopentane (0.15 g, 0.42 mmol)
and l,5-dibromo-3-methylpentane (0.15 g, 0.78 mmol) (Table 5)
similarly to (1) yielded 16 mg (6% yield) of the product; mp: 203e
205 ꢁC. MS (ESPþ): 439 [M ꢃ H]þ, 220 [M]2þ. 1H NMR (DMSO-d6)
d:
9.21 (br s, 2H, NH), 8.38 (d, 2H, quinoline H-5, J ¼ 8.4 Hz), 8.12 (d,
2H, quinoline H-2, J ¼ 7.5 Hz),8.00 (d, 2H, quinoline H-8, J ¼ 8.9 Hz),
7.88 (dd,2H, quinoline H-7, J1 ¼ 7.3 Hz, J2 ¼ 8.0 Hz), 7.62 (dd, 2H,
quinoline H-6, J1 ¼ 7.4 Hz, J2 ¼ 7.8 Hz), 6.59 (d, 2H, quinoline H-3,
J ¼ 7.5 Hz), 4.70 (m, 2H, NCH2), 4.41 (m, 2H, NCH2), 3.68 (m,2H,
NHCH2), 3.44 (m, 2H, NHCH2), 1.74e1.40 (m, 10H, NCH2CH2,
NHCH2CH2, NHCH2CH2CH2), 1.12 (d, 3H, CH3, J ¼ 6.3 Hz), 0.55 (br s,
6.1.7. 8,14-Diaza-4,11-dioxa-l,7(1,4)-diquinolinacyclotetradeca-
phanium dibromide dihydrate (6)
Bis[2-(4-quinolinyl)-aminoethyl]ether (0.36 g, 1.0 mmol) in
DMF (150 mL) and bis(2-bromoethyl)ether (0.23 g, 1.0 mmol) were
heated under reflux for 60 h and then evaporated. The residue was
crystallized from MeOH to give an offþwhite solid (85 mg,13% yield),
mp: 324 ꢁC. MS (FAB): 429 (M ꢃ 1) . HPLC (A/B ¼ 70/30): 98.8%

916
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
purity, Rt ¼ 8.3 min. 1H NMR (DMSO-d6)
d
: 9.32 (br t, 2H, NH), 8.48
6.1.12. 8,14-Diaza-1,7(1,4)-diquinolina-11-thiacyclotetradecaphan-
ium diiodide (11)
(d, 2H, quinoline H-5, J ¼ 8.0 Hz), 8.27 (d, 2H, quinoline H-2,
J ¼ 7.6 Hz), 8.08 (d, 2H, quinoline H-8, J ¼ 8.8 Hz), 7.91 (t, 2H,
quinoline H-7, J ¼ 7.6 Hz), 7.66 (t, 2H, quinoline H-6, J ¼ 7.6 Hz), 6.85
(d, 2H, quinoline H-3, J ¼ 7.6 Hz), 4.70 (m, 4H, NCH2), 3.70 (m, 12H,
NHCH2 and OCH2). Anal. Calcd. for [C26H30N4O2]2þ 2Brꢃ, H2O.
Bis[2-(4-quinolinyl)-aminoethyl]sulfide (0.37 g, 1.0 mmol) in 4-
methyl-2-pentanol (150 mL) and l,5-diiodopentane (0.32 g,
1.0 mmol) were heated at reflux for 7 days, then cooled, and the
precipitate was collected. Repeated crystallization from DMF/
MeOH gave a white solid (yield 105 mg, 14.5%), mp: 290 ꢁC decomp.
MS (FAB): 443 (M ꢃ 1)þ; HPLC (A/B ¼ 65/35): 98.4% purity,
6.1.8. 8,14-Diaza-1,7(1,4)-diquinolina-4-oxa-11-thiacyclotetradeca-
phanium dibromide sesquihydrate (7)
Rt ¼ 6.1 min. lH NMR (DMSO-d6)
d: 9.28 (br t, 2H, NH), 8.45 (d, 2H,
Bis[2-(4-quinolinyl)-aminoethyl]-sulphide (0.75 g, 2.0 mmol) in
DMF (150 mL) and bis(2-bromoethyl)ether (0.46 g, 2.0 mmol) were
treated as for (6) to give an off white solid (0.22 g, 17% yield), mp:
307 ꢁC decomp. MS (FAB): 445 (M ꢃ 1)þ. HPLC (A/B ¼ 70/30): 98.1%
quinoline H-2, J ¼ 8.4 Hz), 8.39 (d, 2H, quinoline H-5, J ¼ 9.4 Hz),
8.01 (d, 2H, quinoline H-7, J ¼ 9.4 Hz), 7.69 (t, 2H, quinoline H-8,
J ¼ 8.6 Hz), 7.65 (t, 2H, quinoline H-6, J ¼ 7.6 Hz), 6.77 (d, 2H,
quinoline H-3, J ¼ 7.2 Hz), 4.61 (m, 4H, NCH2), 3.80 (m, 4H, NHCH2),
2.92 (m, 4H, SCH2), 1.78 (m, 4H, CH2), 0.85 (m, 2H, CH2). Anal. Calcd.
for [C27H32N4S]2þ 2Iꢃ, 0.2HI.
purity, Rt ¼ 8.1 min. lH NMR (DMSO-d6)
d: 9.38 (br t, 2H, NH), 8.50
(d, 2H, quinoline H-5, J ¼ 8.4 Hz), 8.41 (d, 2H, quinoline H-2,
J ¼ 6.8 Hz), 8.12 (d, 2H, quinoline H-8, J ¼ 8.8 Hz), 7.96 (t, 2H,
quinoline H-7, J ¼ 7.8 Hz), 7.72 (t, 2H, quinoline H-6, J ¼ 7.8 Hz), 6.87
(d, 2H, quinoline H-3, J ¼ 7.6 Hz), 4.75 (m, 4H, NCH2), 3.78e3.74 (m,
8H, NHCH2 and OCH2), 3.06 (m, 4H, SCH2). Anal. Calcd. for
[C26H30N4OS]2þ 2Brꢃ, 1.5H2O.
6.1.13. 8,14-Diaza-11-oxo-l,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate monohydrate (12)
N,N0-bis(4-quinolinyl)-pentan-3-one-l,5-diamine
(0.2
g,
0.54 mmol) in 2-butanone (60 mL) and 1,5-diiodopentane (0.2 g,
0.62 mmol) were heated under reflux for 24 h. The mixture was
cooled, the resulting precipitate was purified by preparative HPLC
to give a white solid, which was recrystallized from MeOH/Et2O
(yield 35 mg, 9% yield), mp: 186 ꢁC decomp. MS (FAB): 439
(M ꢃ 1)þ; HPLC (A/B ¼ 70/30): 100% purity, Rt ¼ 10.4 min. lH NMR
6.1.9. 4-Diaza-11-oxa-1,7(1,4)-diquinolina-4-thiacyclotetradeca-
phanium di-trifluoroacetate (8)
Bis[2-(4-quinolinyl)aminoethyl]ether (0.36 g, 1.0 mmol) in DMF
(150 mL) with bis(2-bromoethyl)sulfide, (Table 5) (0.25 g,
1.0 mmol), were treated as for (1) to give a pale yellow solid which
was crystallized from MeOH, (yield 35 mg, 4.8%), mp: 225 ꢁC
decomp. MS (FAB): 445 (M ꢃ 1)þ; HPLC (A/B ¼ 75/25): 99.6% purity,
(DMSO-d6) d: 9.13 (br t, 2H, NH), 8.28 (m, 4H, quinoline H-2,5), 8.04
(d, 2H, quinoline H-8), 7.89 (t, 2H, quinoline H-7), 7.56 (t, 2H,
quinoline H-6), 6.93 (d, 2H, quinoline H-3), 4.55 (m, 4H, NCH2), 3.80
(m, 4H, NHCH2), 2.87 (t, 4H, CH2C]O), 1.74 (m, 4H, CH2), 0.81 (m,
2H, CH2). Anal. Calcd. for [C28H32N4O]2þ 2[CF3CO2]ꢃ, 0.2CF3CO2H,
H2O.
Rt ¼ 13.7 min. lH NMR (DMSO-d6)
d: 9.43 (br t, 2H, NH), 8.51 (d, 2H,
quinoline H-5, J ¼ 8.2 Hz), 8.05 (d, 2H, quinoline H-2, J ¼ 7.4 Hz),
7.91 (t, 2H, quinoline H-8, J ¼ 8.6 Hz), 7.89 (d, 2H, quinoline H-7,
J ¼ 7.8 Hz), 7.65 (t, 2H, quinoline H-6, J ¼ 7.8 Hz), 6.71 (d, 2H,
quinoline H-3, J ¼ 7.4 Hz), 4.64 (m, 4H, NCH2), 3.80e3.70 (m, 8H,
NHCH2 and OCH2), 2.92 (m, 4H, SCH2). Anal. Calcd. for
[C26H30N4OS]2þ 2[CF3CO]ꢃ, 0.5CF3CO2H.
6.1.14. 8,14-Diaza-11-hydroxy-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate dihydrate (13)
N,N0-bis(4-quinolinyl)-pentan-3-one-1,5-diamine, (0.34 g,
0.92 mmol) in 20 mL of MeOH and 0.06 g of NaBH4 was stirred at
room temperature for 1 h. After evaporation of solvent, the residue
was purified by chromatography (silica gel) to give a white solid
(0.34 g, 99% yield), N,N0-bis(4-quinolinyl)-pentan-3-ol-1,5-diamine,
6.1.10. 8,14-Diaza-1,7(1,4)-diquinolina-4,11-dithiacyclotetradeca-
phanium di-trifluoroacetate (9)
Bis[2-(4-quinolinyl)aminoethyl]sulfide (0.74 g, 2.0 mmol) and
bis(2-bromoethyl)sulfide, (0.50 g, 2.0 mmol) were treated as for
(1) to give a pale yellow solid which was crystallized from MeOH/
Et2O, (yield 19 mg, 1.3%), mp: 212 ꢁC decomp. MS (FAB): 461
(M ꢃ 1)þ; HPLC (A/B ¼ 75/25): 96.9% purity, Rt ¼ 15.0 min. lH NMR
MS (FAB): 373 (M þ 1)þ; lH NMR (DMSO-d6)
d: 8.32 (d, 2H,
quinoline H-2), 8.2 (d, 2H, quinoline H-5), 7.75 (d, 2H, quinoline H-
8), 7.6 (t, 2H, quinoline H-7), 7.35 (t, 2H, quinoline H-6), 7.2 (br t,
2H, NH), 6.45 (d, 2H, quinoline H-3), 4.9 (br s, 1H, OH), 3.8 (m, 1H,
CHOH), 3.3 (m, 4H, NCH2), 1.7e0.9 (m, 4H, CH2). The latter (0.33 g,
0.88 mmol) in 2-butanone (100 mL) and l,5-diiodopentane (0.6 g,
1.8 mmol) were heated under reflux for 12 h. The mixture was
cooled, the resulting precipitate was purified by preparative HPLC
to give a white solid, which was crystallized from MeOH/Et2O
(yield 45 mg, 7%), mp: 204 ꢁC decomp. MS (FAB): 441 (M ꢃ 1)þ;
HPLC (A/B ¼ 70/30): 99.95% purity, Rt ¼ 10.4 min. lH NMR (DMSO-
(DMSO-d6) d: 9.45 (br t, 2H, NH), 8.49 (d, 2H, quinoline H-5,
J ¼ 8.8 Hz), 8.24 (d, 2H, quinoline H-2, J ¼ 7.6 Hz), 8.14 (d, 2H,
quinoline H-6, J ¼ 8.8 Hz), 7.98 (t, 2H, quinoline H-7, J ¼ 7.6 Hz),
7.74 (t, 2H, quinoline H-8, J ¼ 7.6 Hz), 6.67 (d, 2H, quinoline H-3,
J ¼ 7.6 Hz), 4.79 (m, 4H, NCH2), 3.78 (m, 4H, NHCH2), 3.11 (m, 4H,
CH2), 2.98 (m, 4H, CH2). Anal. Calcd. for [C26H30N4S2]2þ
[CF3CO2]ꢃ, 0.5CF3CO2H.
2
d6) d: 9.33 (br t, 2H, NH), 8.42 (m, 4H, quinoline H-2,5), 8.04 (d, 2H,
6.1.11. 8,14-Diaza-1,7(1,4)-diquinolina-4-thiacyclotetradeca-
phanium di-trifluoroacetate hemihydrate (10)
quinoline H-8, J ¼ 8.8 Hz), 7.91 (t, 2H, quinoline H-7, J ¼ 7.5 Hz),
7.58 (t, 2H, quinoline H-6, J ¼ 7.5 Hz), 6.87 (d, 2H, quinoline H-3,
J ¼ 7.4 Hz), 5.01 (m, 1H, OH), 4.78 (m, 2H, NCH2), 4.34 (m, 2H,
NCH2), 3.89 (m, 2H, NHCH2), 3.67 (m, 3H, NHCH2 and CHOH), 1.72
(m, 6H). Anal. Calcd. for [C28H34N4O]2þ 2[CF3CO2]ꢃ, 0.1CF3CO2H,
2H2O.
N,N0-bis(4-quinolinyl)pentane-1,5-diamine, (0.50 g, 1.4 mmol)
and bis(2-bromoethyl)sulfide, (Table 5), (0.35 g, 1.4 mmol) were
treated as for (1) to give a pale yellow solid which was crystallized
from MeOH, (yield 60 mg, 6%), mp: 203 ꢁC decomp. MS (FAB): 443
(M ꢃ 1)þ; HPLC (A/B ¼ 65/35), 100% purity, Rt ¼ 5.7 min. H NMR
l
(DMSO-d6)
d: 9.32 (br t, 2H, NH), 8.46 (d, 2H, quinoline H-5,
6.1.15. 8,16-Diaza-9(4,1),15(1,4)-diquinolina-1,4-dioxaspiro[4.13]
octadeca-cyclophanium di-trifluoroacetate (14)
J ¼ 8.2 Hz), 8.09 (d, 2H, quinoline H-6, J ¼ 8.8 Hz), 8.07 (d, 2H,
quinoline H2, J ¼ 7.2 Hz), 7.96 (t, 2H, quinoline H-7, J ¼ 7.6 Hz), 7.70
(t, 2H, quinoline H-8, J ¼ 7.6 Hz), 6.59 (d, 2H, quinoline H-3,
J ¼ 7.2 Hz), 4.74 (m, 4H, NCH2), 3.57 (m, 4H, NHCH2), 3.09 (m, 4H,
SCH2), 1.7 (m, 4H, CH2), 1.5 (m, 2H, CH2). Anal. Calcd. for
[C27H32N4S]2þ 2[CF3CO2]ꢃ, 0.5H2O, 0.5CF3CO2H.
2,2-bis[2-(4-quinolinyl)-aminoethyl]-1,3-dioxolane, (0.2 g,
0.48 mmol) in 2-butanone (50 mL) and 1,5-diiodoopentane (0.2 g,
0.62 mmol) were heated under reflux for 3 days, then cooled, and
the resulting precipitate was purified by preparative HPLC to give a
white solid which was crystallized from MeOH/AcOEt, (yield 15 mg,

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
917
4%), mp: 200 ꢁC. MS (FAB): 483 (M ꢃ 1)þ; HPLC (A/B ¼ 70/30): 98.4%
and KOH (0.8 g, 14.0 mmol) in absolute EtOH were heated under
reflux for 3 h. The solvent was then evaporated and the residue was
dispersed in water, and extracted with CH2Cl2. The combined ex-
tracts were dried (K2CO3) and evaporated to give 1,5-bis(quinolin-4-
purity, Rt ¼ 11.1 min. lH NMR (CD3OD)
d: 8.33 (d, 2H, quinoline H-2),
8.18 (d, 2H, quinoline H-5), 8.02 (d, 2H, quinoline H-8), 7.86 (t, 2H,
quinoline H-7), 7.68 (t, 2H, quinoline H-6), 6.51 (d, 2H, quinoline H-
3), 4.63 (m, 4H, NCH2), 4.12 (s, 4H, OCH2CH2O), 3.67 (m, 4H,
NHCH2), 2.08 (t, 2H, CH2C), 1.92 (m, 4H, CH2), 0.89 (m, 2H, CH2).
Anal. Calcd. for [C30H36N4O2]2þ 2[CF3CO2]ꢃ, 0.6CF3CO2H, 1.5H2O.
yl-thio)-pentane, as an off white solid (1.35 g, 100% yield), mp:
l
107 ꢁC. H NMR (CDCl3)
d: 8.72 (d, 2H, quinoline H-2), 8.1 (d, 2H,
quinoline H-5), 8.05 (d, 2H, quinoline H-8), 7.65 (t, 2H, quinoline H-
7), 7.5 (t, 2H, quinoline H-6), 7.1 (d, 2H, quinoline H-3), 3.1 (t, 4H,
NCH2), 1.9 (m, 4H, CH2), 1.8 (m, 2H, CH2). The latter (0.7 g, 1.8 mmol)
and 1,5-diiodopentane (0.87 g, 2.6 mmol) were treated as for (14) to
give a pale yellow solid which was crystallized from MeOH/Et2O,
(yield 42 mg, 3.2%), mp: 182 ꢁC. MS (FAB): 461 Mþ; base peak
(100%): 573 (M þ 113)þ; HPLC (A/B ¼ 50/50): 98.9% purity,
6.1.16. 9,19-Diaza-8(1,4),20(4,1)-diquinolina-1,4,13,16-tetraoxadi-
spiro[4.6.4.6]-docosacyclophanium di-trifluoroacetate monoethyl
acetate (15)
2,2-bis[2-(4-quinolinyl)-aminoethyl]-1,3-dioxolane
(0.2
g,
0.48 mmol) in 2-butanone (50 mL) and 2,2-bis(2-bromoethyl)-1,3-
dioxolane, (Table 5), (0.48 g, 1.5 mmol) added were heated under
reflux for 3 days, then cooled, and the resulting precipitate was
purified by preparative HPLC to give a white solid that was crystal-
lized from MeOH/AcOEt, (yield 10 mg, 2.3%), mp: 174 ꢁC. MS (FAB):
541 (M ꢃ 1)þ; HPLC (A/B ¼ 70/30): 95.0% purity, Rt ¼ 13.2 min. 1H
Rt ¼ 5.7 min. lH NMR (DMSO-d6)
d: 8.84 (d, 2H, quinoline H-2), 8.42
(d, 2H, quinoline H-5), 8.35 (d, 2H, quinoline H-8), 8.09 (t, 2H,
quinoline H-7), 7.92 (t, 2H, quinoline H-6), 7.80 (d, 2H, quinoline H-
3), 4.89 (m, 4H, NCH2), 3.45 (m, 4H, NHCH2), 1.82 (m, 8H, CH2), 1.67
(m, 2H), 1.03 (m, 2H). Anal. Calcd. for [C28H32N2S2]2þ 2[CF3CO2]ꢃ,
0.3CF3CO2H.
NMR (CD3OD) d: 8.28 (d, 2H, quinoline H-2), 8.04 (m, 4H, quinoline
H-5,8), 7.6e7.7 (m, 4H, quinoline H-6,7), 6.54 (d, 2H, quinoline H-3),
4.56 (m, 4H, NCH2), 4.12 (s, 4H, OCH2CH2O), 3.67 (m, 4H, NHCH2),
3.45 (s, 4H, OCH2CH2O), 2.21 (m, 4H, CH2), 2.11 (m, 4H, CH2). Anal.
Calcd. for [C32H38N4O4]2þ 2[CF3CO2]ꢃ, 0.2CF3CO2H, 0.1AcOEt.
6.1.20. 8,13-Diaza-1,7(1,4)diquinolina-10-ynecyclotridecaphanium
di-trifluoroacetate (19)
Bis(4-quinolinyl)but-2-yne-1,4-diamine, (0.28 g, 0.83 mmol)
and l,5-diiodopentane (0.28 g, 0.86 mmol) were treated as for (1) to
give a white solid which was crystallized from MeOH/Et2O, (yield
6.1.17. 8,14-Diaza-8,14-dimethyl-1(1,4),7(4,1)-diquinolinacyclo-
tetradecaphanedium di-trifluoroacetate trihydrate (16)
91 mg, 16.5%), mp: 226 ꢁC decomp. MS (FAB): 407 (M ꢃ 1)þ; HPLC
l
N,N0-bis(4-quinolinyl)-N,N0-dimethylpentane-1,5-diamine was
heated with 1,5-diiodopentane in 2-butanone (200 mL) under
reflux for 7 days. The mixture was then cooled and the precipitated
product was filtered off, washed with AcOEt, chromatographed on a
silica gel column with CH2Cl2/MeOH/TFA (17:4:0.01) and crystal-
lized from MeOH. The resulting product was further washed with
AcOEt to give 0.18 g of a white solid (6% yield), which was purified
further by preparative HPLC and had mp: 125e127 ꢁC. MS (FAB):
453 (M ꢃ 1)þ; base peak (100%): 567 (M þ 113)þ; HPLC (A/B ¼ 65/
(A/B ¼ 70/30): 98.2% purity, Rt ¼ 14.8 min. H NMR (DMSO-d6)
d:
9.78 (br t, 2H, NH), 8.56 (d, 2H, quinoline H-2), 8.43 (d, 2H, quin-
oline H-5), 8.12 (d, 2H, quinoline H-8), 7.96 (t, 2H, quinoline H-7),
7.67 (t, 2H, quinoline H-6), 6.78 (d, 2H, quinoline H-3), 4.64 (m, 4H,
NCH2), 4.38 (m, 4H, NHCH2),1.7e1.8 (m, 4H, CH2), 0.78 (m, 2H, CH2).
Anal. Calcd. for [C27H28N4]2þ 2[CF3CO2]ꢃ, 0.2CF3CO2H.
6.1.21. 8,14-Diaza-10,10,11,11,12,12-hexafluoro-1,7(1,4)-diquinolina-
cyclotetradecaphanium di-trifluoroacetate sesquihydrate (20)
N,N0-bis(quinolin-4-yl)-2,2,3,3,4,4-hexafluoropentane-1,5-
diamine (0.3 g, 0.64 mmol) and 1,5-diiodopentane (0.3 g,
0.93 mmol) were treated as for (1) and (19þ) to yield 90 mg (17%),
mp: 238 ꢁC decomp. MS (FAB): 533 (M ꢃ 1) ; HPLC (A/B ¼ 60/40):
35): 100% purity, Rt ¼ 12.5 min. 1H NMR (DMSO-d6)
d: 8.34 (d, 2H,
quinoline H2, J ¼ 8.0 Hz), 8.18 (d, 2H, quinoline H-5, J ¼ 8.4 Hz), 8.09
(d, 2H, quinoline H-8, J ¼ 9.2 Hz), 7.94 (t, 2H, quinoline H-7,
J ¼ 7.0 Hz), 7.62 (t, 2H, quinoline H-6, J ¼ 7.6 Hz), 6.76 (d, 2H,
quinoline H-3, J ¼ 8.0 Hz), 4.57 (m, 4H, NþCH2), 3.90 (m, 4H, NCH2),
3.37 (s, 6H, NCH3), 1.82 (m, 4H, NþCH2CH2), 1.68 (m, 4H, NCH2CH2),
100% purity, Rt ¼ 6.85min. lH NMR (DMSO-d6)
d: 9.37 (br t, 2H, NH),
8.56 (d, 2H, quinoline H-2), 8.47 (d, 2H, quinoline H-5), 8.11 (d, 2H,
quinoline H-8), 7.96 (t, 2H, quinoline H-7), 7.67 (t, 2H, quinoline H-
0.86 (m, 4H, CH2CH2CH2CH2CH2). Anal. Calcd. for [C30H38N4]2þ
[CF3CO2]ꢃ, 0.8CF3CO2H, 3H2O.
2
6), 7.04 (d, 2H, quinoline H-3), 5e4 (very br, 4e6H),1.78 (m, 4H). 13
C
NMR (CD3OD): 157.9, 148.0, 139.0, 135.7, 128.7, 124.7, 120.0, 119.5,
99.9, 56.2, 28.7, 24.9. Multiple peaks (weak) at 43 ppm (CF2) and
117 (CF2CF2CF2). Anal. Calcd. for [C28H28F6N4]2þ 2[CF3CO2]ꢃ,
0.3CF3CO2H, 1.5H2O.
6.1.18. 8,14-Diaza-8,14-dibenzyl-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate monohydrate (17)
N,N0-bis(4-quinolinyl)-N,N0-dibenzylpentane-l,5-diamine (0.6 g,
1.1 mmol) in 2-butanone (100 mL) and l,5-diiodopentane (0.50 g,
1.5 mmol) and were heated under reflux for 48 h. After removing
half of the solvent, the mixture was heated at reflux for a further
24 h. It was cooled, the resulting precipitate was purified by pre-
parative HPLC to give a pale yellow solid which was crystallized
from MeOH/Et2O, (yield 42 mg, 3.2%), mp: 110 ꢁC. MS (FAB): 605
6.1.22. 7,13-Diaza-l,6(1,4)-diquinolinacyclotridecaphanium-3-ene
di-trifluoroacetate hydrate methanolate (21)
N,N0-di(quinolin-4-yl)-1,5-diaminopentane (0.15 g, 0.42 mmol)
in 2-butanone (30 mL), and cis-1,4-dichlorobut-2-ene (0.10 g,
0.8 mmol) (Table 5) were heated under reflux and N2 for 5 days.
After cooling, a small amount of Et2O was added and the crude
product was filtered off and washed with Et2O to give 150 mg (31%
yield) of crude product which was purified by preparative HPLC.
The resulting compound was dissolved in iPrOH, filtered, and
evaporated to dryness to afford 15 mg (4.4% yield) of the pure
product, mp: 214e216 ꢁC. MS (ESPþ): 409 [M ꢃ H]þ. 1H NMR
(M þ 1)þ; base peak (100%): 719 (M þ 113)þ; HPLC (A/B ¼ 45/55):
l
99.9% purity, Rt ¼ 7.6 min. H NMR (DMSO-d6)
d: 8.40 (d, 2H,
quinoline H-2), 8.25 (d, 2H, quinoline H-5), 8.15 (d, 2H, quinoline H-
8), 8.04 (t, 2H, quinoline H-7), 7.56 (t, 2H, quinoline H-6), 7.4e7.2 (m,
10H, phenyl), 6.85 (d, 2H, quinoline H-3), 5.03 (s, 4H, CH2ePh), 4.65
(m, 4H, NCH2), 3.82 (m, 4H, NHCH2), 1.78 (m, 4H), 1.6 (m, 4H), 1.02
(m, 4H). Anal. Calcd. for [C42H46N4]2þ 2[CF3CO]ꢃ, 1.8CF3CO2H, H2O.
(DMSO-d6)
d: 9.43 (br s, 2H, NH), 8.48 (d, 2H, quinoline H-5,
J ¼ 8.3 Hz), 8.29 (d, 2H, quinoline H-8, J ¼ 8.8 Hz), 8.06 (t, 2H,
quinoline H-7, J ¼ 7.7 Hz), 7.76 (m, 4H, quinoline H-6,2), 6.67 (m, 2H,
NHCH2CH]), 6.60 (d, 2H, quinoline H-3, J ¼ 7.4 Hz), 5.33 (br s, 4H,
NCH2), 4.11 (br s, 1H, CH3OH), 3.55 (br s, 4H, NHCH2), 3.15 (s, 3H,
CH3OH), 1.62 (br s, 4H, NHCH2CH2), 1.32 (br s, 2H, NHCH2CH2CH2).
6.1.19. 1,7(1,4)-Diquinolina-8,14-dithiacyclotetradecaphanium di-
trifluoroacetate (18)
A mixture of S,S0-(pentan-1,5-yl)-diisothiuronium dibromide,
(Table 5), (1.32 g, 3.45 mmol), 4-chloroquinoline (1.13 g, 6.9 mmol)

918
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
HPLC: (A/B ¼ 75/25) Rt ¼ 11.3 min, purity ¼ 99.2%. Anal. Calcd. For
7.76 (d, 2H, quinoline H-8 or 5, J ¼ 8.2 Hz), 7.62 (t, 2H, quinoline H-6
or 7, J ¼ 7.5 Hz), 7.45 (t, 2H, quinoline H-6 or 7, J ¼ 7.5 Hz), 7.00 (d,
2H, phenol H-4 and 6, J ¼ 7.5 Hz), 6.66 (t,1H, phenol H-5, J ¼ 7.5 Hz),
6.40 (d, 2H, quinoline H-3, J ¼ 5.4 Hz), 4.54 (s, 2H, NHCH2) HPLC: (A/
B ¼ 55/45), Rt ¼ 9.83 min. Purity ¼ 98.8%. The latter (0.4 g,
0.99 mmol) (l0 mL) with 1,5-diiodopentane (0.4 g, 1.23 mmol) was
treated as for (1) to give 570 mg of solid, 120 mg of which was then
purified by preparative HPLC to give 11 mg (7%þyield) of the prod-
uct, mp: 230e235 ꢁC; MS (ESPþ): 475 [M ꢃ H] ; 1H NMR (DMSO-
[C27H30N4]2þ 2[CF3CO2]ꢃ, 1.2CF3CO2H, H2O, CH3OH.
6.1.23. 2,7-Diaza-1,8(1,4)-diquinolinacyclotridecaphanium-4-ene
di-trifluoroacetate hemihydrate (22)
N,N0-di(quinolin-4-yl)-1,4-diamino-cis-but-2-ene (0.2 g, 0.59
mmol) and 1,5-diiodopentane (0.2 g, 0.62 mmol) were treated as for
(1) to give the product (20 mg, 4.5% yield), mp: 207e210 ꢁC; MS
(ESPþ): 409 [M ꢃ H]þ; 1H NMR
d: 9.36 (br s, 2H, NH), 8.47 (d, 2H,
quinoline H-5, J ¼ 7.6 Hz), 8.15 (d, 2H, quinoline H-2, J ¼ 7.4 Hz), 8.05
(d, 2H, quinoline H-8, J ¼ 8.8 Hz), 7.91 (t, 2H, quinoline H-7, J ¼ 7.4 Hz),
7.67 (t, 2H, quinoline H-6, J ¼ 7.6 Hz), 6.83 (d, 2H, quinoline H-3,
J ¼ 7.4 Hz), 6.07 (t, 2H, NHCH2CH, J ¼ 4.5 Hz), 4.55 (t, 4H, NCH2), 4.38
(d, 4H, NHCH2, J ¼ 4.2 Hz), 1.77 (br s, 4H, NCH2CH2), 0.65 (quint, 2H,
NCH2CH2CH2); HPLC: (A/B ¼ 70/30), Rt ¼ 7.5 min, purity ¼ 99.5%.
Anal. Calcd. For [C27H30N4]2þ 2[CF3CO2]ꢃ, CF3CO2H, 0.5H2O.
d6)
d
: 8.49 (d, 2H, quinoline H-5, J ¼ 8.2 Hz), 8.18 (d, 2H, quinoline
H-2, J ¼ 7.4 Hz), 8.05 (d, 2H, quinoline H-8, J ¼ 8.5 Hz), 7.94 (dd, 2H,
quinoline H-7, J1 ¼ 7.7 Hz, J2 ¼ 8.5 Hz), 7.71 (t, 2H, quinoline H-6,
J ¼ 7.7 Hz), 7.37 (d, 2H, phenol H-3,5, J ¼ 7.8 Hz), 6.85 (t, 1H, phenol
H-4, J ¼ 7.8 Hz), 6.74 (d, 2H, quinoline H-3, J ¼ 7.4 Hz), 4.74 (s, 4H,
NHCH2), 4.48 (brs, 4H, NCH2), 1.81 (brs, 4H, NCH2CH2), 0.9 (brs, 2H,
NCH2CH2CH2). HPLC: (A/B ¼ 60/40), Rt ¼ 7.1 min. Purity ¼ 100%.
Anal. Calcd. for [C31H32N4O]2þ 2[CF3CO2]ꢃ, 0.5CF3CO2H, 0.5H2O.
6.1.24. 2,6-Diaza-1,7(1,4)diquinolina-4(1,3)-benzenacyclododeca-
phanium di-trifluoroacetate (23)
6.1.27. 42-Hydroxy-45-iodo-2,6-diaza-l,7(1,4)-diquinolina-4(1,3)-
benzenacyclododecaphanium di-trifluoroacetate hemihydrate (26)
To compound 25 (0.03 g, 0.043 mmol) and NaI (0.008 g,
0.051 mmol) in DMF (1 mL) was added Chloramine T (0.014 g,
0.051 mmol) and the mixture was stirred for 1 h at Rt, then diluted
with water and acidified with HCl. The precipitated product was
filtered off, washed with water, then purified by preparative HPLC
to give 22 mg (63% yield) of the iodinated compound, mp: 256e
N,N0-di(quinolin-4-yl)-1,3-(diaminomethyl)benzene [19] (0.5 g,
1.28 mmol) with 1,5-diiodopentane (0.6 g, 1.85 mmol) were treated
as for (1) to give 0.79 g of crude product. Half of the latter was
purified by preparative HPLC and then dissolved in iPrOH, filtered,
and evaporated to yield 130 mg (30%) of the product, mp: 2l0e
213 ꢁC; MS (ESPþ): 459 [M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 10.08
(br s, 2H, NH), 8.51 (d, 2H, quinoline H-5, J ¼ 8.4 Hz), 8.06 (m, 4H,
quinoline H-2,8), 7.95 (t, 2H, quinoline H-7, J ¼ 7.7 Hz), 7.72 (t, 2H,
quinoline H-6, J ¼ 7.7 Hz), 7.46 (m, 4H, phenylene H’s), 6.50 (d, 2H,
quinoline H-3, J ¼ 7.4 Hz), 4.77 (s, 4H, NHCH2), 4.53 (m, 4H, NCH2),
1.82 (br s, 4H, NCH2CH2), 0.70 (br s, 2H, NCH2CH2CH2); HPLC: (A/
B ¼ 65/35) Rt ¼ 6.9 min, purity 99.2%. Anal. Calcd. for [C31H32N4]2þ
2[CF3CO2]ꢃ, 0.lCF3CO2H.
259 ꢁC. MS (ESPþ): 601 [M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 8.46 (m,
4H, quinoline H-2,5), 8.10 (d, 2H, quinoline H-8, J ¼ 8.9 Hz), 7.96 (t,
2H, quinoline H-7, J ¼ 7.9 Hz), 7.77 (s, 2H, phenol), 7.74 (t, 2H,
quinoline H-6, J ¼ 7.9 Hz), 6.83 (d, 2H, quinoline H-3, J ¼ 7.3 Hz),
4.73 (s, 4H, NCH2), 4.53 (s, 4H, NHCH2), 1.81 (br s, 4H, NCH2CH2),
0.98 (m, 2H, NCH2CH2CH2). HPLC: (A/B ¼ 65/35), 100%, Rt ¼ 7.0 min.
Anal. Calcd. for [C31H31IN4O]2þ 2[CF3CO2]ꢃ, 0.2CF3CO2H, 0.5H2O.
6.1.25. 42-Methoxy-2,6-diaza-l,7(1,4)-diquinolina-4(1,3)-benzena-
cyclododecaphanium di-trifluoroacetate hemihydrate (24)
6.1.28. 2,6-Diaza-1,7(1,4)-diquinolina-4(1,4)-cyclohexanacyclo-
dodecaphanium di-trifluoroacetate dehydrate (27)
N,N0-di(quinolin-4-yl)-2,6-(diaminomethyl)anisole (0.21 g,
0.50 mmol) and 1,5-diiodopentane (0.3 g, 0.93 mmol) was treated
as for (1) to give 250 mg of solid, half of which was purified by
preparative HPLC to give 55 mg (26% yþield) of the pure product, mp:
N,N0-di(quinolin-4-yl)-1,4-diaminomethylcyclohexane (0.25 g,
0.63 mmol) and 1,5-diiodopentane (0.25 g, 7.71 mmol) were
treated as for (1) to give 12 mg (3.8% yield) of the product, mp: 172e
232e236 ꢁC. MS (ESPþ): 489 [M ꢃ H] . 1H NMR (DMSO-d6)
d: l0.10
176 ꢁC; MS (ESPþ): 465 [M ꢃ H]þ, 233 [M]2þ. 1H NMR (DMSO-d6)
d:
(br t, 2H, NH, J ¼ 6.5 Hz), 8.52 (d, 2H, quinoline H-5, J ¼ 8.5 Hz), 8.41
(d, 2H, quinoline H-2, J ¼ 7.3 Hz), 8.09 (d, 2H, quinoline H-8,
J ¼ 9.0 Hz), 7.97 (t, 2H, quinoline H-7, J ¼ 7.8 Hz), 7.74 (t, 2H,
quinoline H-6, J ¼ 7.8 Hz), 7.54 (d, 2H, anisole H-3,5, J ¼ 7.7 Hz), 7.18
(t, anisole H-4, J ¼ 7.7 Hz), 6.76 (d, 2H, quinoline H-3, J ¼ 7.3 Hz),
4.78 (br s, 4H, NCH2), 4.52 (br s, 4H, NHCH2), 1.82 (br s, 4H,
NCH2CH2), 1.03 (d, 3H, 2-propanol equivalent in intensity to 1/
2 ꢂ 3H), 0.95 (br s, 2H, NCH2CH2CH2). HPLC: (A/B ¼ 60/40),
8.99 (br s, 2H, NH), 8.56 (d, 2H, quinoline H-5 or 8, J ¼ 8.6 Hz), 8.14
(d, 2H, quinoline H-2, J ¼ 7.0 Hz), 8.08 (d, 2H, quinoline H-8 or 5,
J ¼ 8.6 Hz), 7.97 (dd, 2H, quinoline H-7 or 6, J1 ¼7.2 Hz, J2 ¼ 8.2 Hz),
7.71 (dd, 2H, quinoline H-7 or 6, J1 ¼7.2 Hz, J2 ¼ 7.9 Hz), 6.89 (d, 2H,
quinoline H-3, J ¼ 7.0 Hz), 4.59 (br s, 4H, NCH2), 3.63 (br s, 4H,
NHCH2), 2.08 (br s, 2H, NHCH2CH), 1.89 (br s, 2H, NCH2CH2), 1.42
(m, 8H, NHCH2CHCH2), 1.11 (br s, 2H, NCH2CH2CH2); HPLC: (A/
B ¼ 60/40), Rt ¼ 6.6 min. Purity ¼ 100%. Anal. Calcd. for:
[C31H38N4]2þ 2[CF3CO2]ꢃ, 1.3CF3CO2H, 2H2O.
Rt ¼ 8.4 min. Purity ¼ 100%. Anal. Calcd. for [C32H34N4O]2þ
2
[CF3CO2]ꢃ, 1.1CF3CO2H, 0.5H2O, 0.5C3H7OH.
6.1.29. 6,10-Diaza-1,5(1,4)-diquinolina-3(1,3)-benzena-8(1,4)-
cyclohexanacyclodeca-phanium di-trifluoroacetate monohydrate (28)
N,N0-di(quinolin-4-yl)-1,4-diaminomethylcyclohexane (0.4 g,
6.1.26. 42-Hydroxy-2,6-diaza-1,7(1,4)-diquinolina-4(1,3)-benzena-
cyclododecaphanium di-trifluoroacetate hemihydrate (25)
To a cooled suspension of N,N0-di(quinolin-4-yl)-2,6-diamino-
methylanisole (0.6 g, 1.43 mmol) in dry CH2Cl2 at ꢃ5 ꢁC, BBr3
(7 ml, 1 M solution in CH2Cl2) was slowly added with stirring under
N2. After 30 min the reaction was shown to be completed (TLC,
eluent CH2Cl2/MeOH/NH4OH (15/2/1)); the CH2Cl2 was then
evaporated to dryness and, to the residue, water was added. It was
then dissolved in MeOH (5 mL) and basified with 10% NaOH until
pH >9. The resulting product of N,N0-di(quinolin-4-yl)-2,6-(dia-
minomethyl)phenol was filtered off and washed with water; yield
0.5 g (86%); mp: 200e203 ꢁC. MS (APCIþ): 407 [M þ H], fragments
at m/z 329, 263, 176 Acc. Mass: 407.1869, Calc Acc. Mass: 407.18718.
1.01 mmol) in DMF (30 mL) and a,a
0-dibromo-m-xy1ene (0.45 g,
1.71 mmo1) were heated at 110 ꢁC under N2 for 2 days. After
cooling, a small amount of Et2O was added and the resulting solid
was filtered off and washed with Et2O to give 600 mg of the crude
product; 300 mg were then purified by preparative HPLC to give
18 mg (4.2% yield) of the product, mp: 172e176 ꢁC. MS (ESPþ): 499
[M ꢃ H]þ;1H NMR (DMSO-d6)
d: 9.11 (br s, 2H, NH), 8.45 (d, 2H,
quinoline H-5 or 8, J ¼ 8.1 Hz), 8.29 (d, 2H, quinoline H-2, J ¼ 7.4 Hz),
7.80 (m, 4H, quinoline H-6 or 7 and H-8 or 5), 7.57 (m, 5H,quinoline
H-6 or 7,phenylene H-3,4,5), 6.90 (d, 2H, quinoline H-3, J ¼ 7.4 Hz),
5.72 (s,4H, NCH2), 3.63 (br s, 4H, NHCH2), 2.04 (br s, 2H,NHCH2CH),
1.56(br s, 4H, z), NHCH2CHCH2), 1.51 (br s, 4H,NHCH2CHCCH2).
1H NMR (DMSO-d6/D2O)
d: 8.19 (m, 2H, quinoline H-2, H-5 or 8),

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
919
HPLC: (A/B ¼ 65/35), Rt ¼ 8.6 min. Purity ¼ 100%. Anal. Calcd. for
6.1.34. 16,76-Difluoro-8,14-diaza-1,7(1,4)-diquinolinacyclotetradeca-
[C34H36N4]2þ 2[CF3CO2]ꢃ, 0.9CF3CO2H, H2O.
phanium di-trifluoroacetate hemihydrate (33)
N,N0-di(6-fluoroquinolin-4-yl)-1,5-diaminopentane
(0.3
g,
6.1.30. 6,12-Diaza-3(1,4)-benza-l,5(1,4)-di-quinolinacyclododeca-
phanium di-trifluoroacetate hemihydrate (29)
0.77 mmol) and 1,5-diiodopentane (0.3 g, 0.93 mmol) were treated
as for (32) for 6 days. The crude product (450 mg) was washed with
Et2O and 225 mg were purified by preparative HPLC to give 30 mg
(9% yield) of the pure product, mp: 216e225 ꢁC. MS (APCIþ): 461
N,N0-bis(4-quinolinyl)pentane-1,5-diamine, (0.43 g, 1.0 mmol)
in 2-butanone (50 mL) and DMF (10 mL) and
a,a
0-dibromo-p-
xylene (0.4 g, 1.5 mmol), were heated under reflux for 3 days, it was
then cooled. The resulting precipitate was purified by preparative
HPLC to give a white solid which was crystallized from MeOH/Et2O,
to give 70 mg (8.6% yield) of product, mp: 220 ꢁC (decomp). MS
(FAB): 459 (M ꢃ 1)þ; HPLC (A/B ¼ 65/35): 100% purity, Rt ¼ 7.3 min.
[M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 9.07 (br t, 2H, NH), 8.28 (m, 4H,
quinoline H-2,5), 8.13 (dd, 2H, quinoline H-8, J1 ¼ 4.8 Hz,
J2 ¼ 9.8 Hz), 7.84 (ddd, 2H, quinoline H-7, J1 ¼ 2.5 Hz, J2 ¼ 7.7 Hz,
J3 ¼ 9.8 Hz), 6.73 (d, 2H, quinoline H-3, J ¼ 7.4 Hz), 4.57 (br s, 4H,
NCH2), 3.60 (br s, 4H, NHCH2), 1.76e1.70 (m, 8H, NCH2CH2,
NHCH2CH2), 1.43 (m, 2H, NHCH2CH2CH2), 0.73 (br s, 2H,
NCH2CH2CH2). HPLC: (A/B ¼ 60/40), Rt ¼ 8.0 min. Purity ¼ 100%.
Anal. Calcd. for [C28H32F2N4]2þ 2[CF3CO2]ꢃ, 1.5CF3CO2H, 0.5H2O
1H NMR (DMSO-d6)
d: 9.24 (br t, 2H, NH), 8.56 (d, 2H, quinoline H-2,
J ¼ 9.2 Hz), 8.45 (d, 2H, quinoline H-5, J ¼ 7.8 Hz), 8.37 (d, 2H,
quinoline H-8, J ¼ 8.2 Hz), 7.96 (t, 2H, quinoline H-7, J ¼ 7.7 Hz), 7.62
(t, 2H, quinoline H-6, J ¼ 7.65 Hz), 7.40 (s, 4H, p-xylene), 6.78 (d, 2H,
quinoline H-3, J ¼ 7.7 Hz), 5.67 (m, 4H, NCH2), 3.55 (m, 4H, NHCH2),
1.63 (m, 4H, CH2), 1.12 (m, 2H, CH2). Anal. Calcd. for [C31H32C12N4]2þ
2[CF3CO2]ꢃ, CF3CO2H, 0.5H2O.
6.1.35. 16,76-Dichloro-8,14-diaza-1,7(1,4)-diquinolinacyclotetra-
decaphanium di-trifluoroacetate sesquihydrate (34)
N,N0-di-(6-chloroquinolin-4-yl)-1,5-diaminopentane (0.49 g,
1.15 mmol) and 1,5-diiodopentane (0.5 g, 1.5 mmol) were treated as
for (1); 300 mg of the resulting product gave 25 mg (2.3% yield) of
the pure product, mp: 205e210 ꢁC. MS (ESPþ): 493 [M ꢃ H]þ, 247
6.1.31. 16,76-Dinitro-8,14-diaza-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate hemihydrate (30)
N,N0-di(6-nitroquinolin-4-yl)-1,5-diaminopentane
(0.63
g,
[M]2þ, 1H NMR (DMSO-d6)
d
: 9.30 (br t, 2H, NH, J ¼ 5.7 Hz), 8.57 (d,
1.41 mmol) and 1,5-diiodopentane (0.63 g, 1.85 mmol) were treated
2H, quinoline H-5, J ¼ 2.1 Hz), 8.29 (d,2H, quinoline H-2, J ¼ 7.5 Hz),
8.07 (d, 2H, quinoline H-8 J ¼ 9.4), 7.94 (dd, 2H, quinoline H-7,
J1 ¼ 2.1 Hz, J2 ¼ 9.4 Hz), 6.78 (d, 2H,quinoline H-3, J ¼ 7.5 Hz), 4.55
(br s, 4H, NCH2), 3.58 (br s, 4H, overlaps with H2O-seen with D2O
shake, NHCH2), 1.70 (m, 8H, NCH2CH2 & NHCH2CH2), 1.41 (m, 2H,
NHCH2CH2CH2), 0.77 (br s, 2H, NCH2CH2CH2); HPLC: (A/B ¼ 55/45),
as for (1) to give 50 mg (4.3% yield) of the product, mp: 236e239 ꢁC.
MS (ESPþ) 515 [M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 9.89 (br s, 2H, NH),
9.43 (d, 2H, quinoline H-5, J ¼ 2.2 Hz), 8.54 (dd, 2H, quinoline H-7,
J1 ¼2.2 Hz, J2 ¼ 9.7 Hz), 8.32 (d, 2H, quinoline H-2, J ¼ 7.5 Hz), 8.20 (d,
2H, quinoline H-8, J ¼ 9.7 Hz), 6.87 (d, 2H, quinoline H-3, J ¼ 7.5 Hz),
4.58 (br s, 4H, NCH2), 3.66 (br s, 4H, NHCH2), 1.73 (br m, 8H,
NCH2CH2, NHCH2CH2), 1.42 (br s, 2H, NHCH2CH2CH2), 0.84 (br m,
2H, NCH2CH2CH2). HPLC: (A/B ¼ 60/40), Rt ¼ 7.7 min. Purity ¼ 100%;
Anal. Calcd. for [C28H32N6O4]2þ 2[CF3CO2]ꢃ, 0.7CF3CO2H, 0.5H2O.
Rt ¼ 13.2 min. Purity ¼ 98.6%. Anal. Calcd. for [C28H32Cl2N4]2þ
2
[CF3CO2]ꢃ, 1.8CF3CO2H, 1.5H2O.
6.1.36. 16,76-Dimethyl-8,14-diaza-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate hemihydrate (35)
6.1.32. 16,76-Diamino-8,14-diaza-1,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate monohydrate (31)
N,N0-di(6-methylquinolin-4-yl)-1,5-diaminopentane (0.5 g,
1.30 mmol) similarly afforded 35 mg (3.3%þyield) of the product,
To compound 30 (0.02 g, 0.027 mmol) in acetic acid (0.4 mL), a
suspension of SnCl2.H2O (0.05 g) in HCl/H2O (0.8 mL/0.1 mL) was
added and heated at 65 ꢁC for 45 min. When HPLC showed no
starting material and formation of a new peak the mixture was
cooled, 10% NaOH was added and the solution was evaporated to
dryness. The residue was then purified by preparative HPLC to give
11 mg (5.5% yield) of the pure product, mp: 225e227 ꢁC. MS
mp: 220e230 ꢁC. MS (ESPþ): 453 [M ꢃ H] , 227 [M]2þ
;
1H NMR
(DMSO-d6)
d: 9.13 (br s, 2H, NH), 8.25 (d, 2H, quinoline H-2,
J ¼ 7.2 Hz), 8.23 (s, 2H, quinoline H-5), 7.93 (s, 2H, quinoline H-8,
J ¼ 8.9 Hz), 7.73 (d, 2H, quinoline H-7, J ¼ 8.9 Hz), 6.71 (d, 2H,
quinoline H-3, J ¼ 7.2 Hz), 4.54 (br s, 4H, NCH2), 3.60 (br s, 4H,
NHCH2), 2.42 (s, 6H, CH3), 1.71 (br s, 8H, NCH2CH2 and NHCH2CH2),
1.22 (br s, 2H, NHCH2CH2CH2), 0.71 (br s, 2H, NCH2CH2CH2. HPLC:
(A/B ¼ 60/40), Rt ¼ 15.6 min. Purity ¼ 100%. Anal. Calcd. for
[C30H38N4]2þ 2[CF3CO2]ꢃ, CF3CO2H, 0.5H2O.
(FABþ): 455 [M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 8.56 (br s, 2H, NH),
7.96 (d, 2H, quinoline H-2, J ¼ 7.2 Hz), 7.76 (d, 2H, quinoline H-8,
J ¼ 9.1 Hz), 7.24 (m, 4H, quinoline H-7,5), 6.45 (d, 2H, quinoline H-3,
J ¼ 7.2 Hz), 5.72 (d*-uneven, 4H, quinoline NH2), 4.46 (br s, 4H,
NCH2), 3.52 (br s, 4H, NHCH2), 1.71 (m, 8H, NCH2CH2, NHCH2CH2),
1.41 (m, 2H, NHCH2CH2CH2), 0.71 (br s, 2H, NCH2CH2CH2) HPLC: (A/
B) ¼ 70/30), Rt ¼ 6.9 min. Purity ¼ 100%; Anal. Calcd. for
[C28H36N6]2þ 2[CF3CO2]ꢃ, 0.5CF3CO2H, H2O.
6.1.37. 16,76-Dimethoxy-8,14-diaza-1,7(1,4)-diquinolinacyclotetra-
decaphanium di-trifluoroacetate (36)
N,N0-di(6-methoxyquinolin-4-yl)-1,5-diaminopentane (0.6 g,
1.44 mmol) similarly afforded 40 mg (3.7%þyield) of the product,
;
1H NMR
mp: 229e232 ꢁC. MS (APCIþ): 485 [M ꢃ H] , 243 [M]2þ
(DMSO-d6)
d
: 9.03 (br t, 2H, NH, J ¼ 5.5 Hz), 8.21 (d, 2H, quinoline H-
6.1.33. 16,76-Ditrifluoromethyl-8,14-diaza-l,7(1,4)-diquinolina)-
cyclotetradecaphanium di-trifluoroacetate (32)
2, J ¼ 7.3 Hz), 7.97 (d, 2H, quinoline H-8, J ¼ 9.6 Hz), 7.75 (d, 2H,
quinoline H-5, J ¼ 2.3 Hz), 7.51 (dd, 2H, quinoline H-7, J ¼ 2.3 Hz,
J2 ¼ 9.6 Hz), 6.70 (d, 2H, quinoline H-3, J ¼ 7.3 Hz), 4.54 (br s, 4H,
NCH2), 3.88 (s, 6H, OCH3), 3.62 (br s, 4H, NHCH2), 1.72 (m, 8H,
NCH2CH2, NHCH2CH2), 1.41 (br s, 2H, NHCH2CH2CH2), 0.70 (br s, 2H,
NCH2CH2CH2); HPLC: (A/B ¼ 55/45), Rt ¼ 6.2 min. Purity ¼ 100%.
Anal. Calcd. for [C30H38N4O2]2þ 2[CF3CO2]ꢃ, 0.3CF3CO2H.
N,N0-bis(6-trifluoromethylquinolin-4-yl)pentane-1,5-diamine
(0.49 g, 1.0 mmol) in 2-butanone (80 mL) and 1,5-diiodopentane
(0.49 g, 1.5 mmol) were heated under reflux for 3 days, then
cooled, and from the resulting precipitate (0.8 g), 300 mg was puri-
fied by preparative HPLC to give a pale yellow solid; recrystallization
from MeOH/Et2O yielded 86 mg, 28%, mp: 236 ꢁC. MS (FAB): 561
(M ꢃ 1)þ; HPLC (A/B ¼ 50/50): 99.4% purity, Rt ¼ 13.6 min. lH NMR
6.1.38. 16,76-Dihydroxy-8,14-diaza-1,7(1,4)-diquinolinacyclotetra-
decaphanium di-trifluoroacetate sesquihydrate (37)
(DMSO-d6) d: 9.64 (br t, 2H, NH), 8.89 (s, 2H, quinoline H-5), 8.43 (d,
2H, quinoline H-2), 8.22 (m, 4H, quinoline H-7,8), 6.87 (d, 2H, quin-
oline H-3), 4.56 (m, 4H, NCH2), 3.67 (m, 4H, NHCH2),1.41 (m, 2H),1.24
(m, 2H). Anal. Calcd. for [C30H32F6N4]2þ 2[CF3CO2]ꢃ, 0.2CF3CO2H.
Compound 36 (0.040 g, 0.06 mmol) was heated under reflux in
HBr (2 mL). After 2 h, HPLC analysis showed the reaction to be
complete. The reaction mixture was evaporated to dryness and the

920
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
residue was purified by preparative HPLC to yield 20 mg (52%), mp:
1.80 (br s, 4H, NCH2CH2), 1.69 (br s, 4H, NHCH2CH2), 1.40 (br s, 2H,
307e311 ꢁC. MS (ESPþ): 457 [M ꢃ H]þ. 1H NMR (DMSO-d6)
d
:8.80
NHCH2CH2CH2), 0.79 (br s, 2H, NCH2CH2CH2). HPLC: (A/B ¼ 60/40),
(br s, 2H, NH), 8.10 (d, 2H, quinoline H-2, J ¼ 7.0 Hz), 7.92 (d, 2H,
quinoline H-8, J ¼ 9.4 Hz), 7.64 (d, 2H,quinoline H-5, J ¼ 1.8 Hz), 7.42
(dd, 2H, quinoline H-7, J1 ¼1.8 Hz, J2 ¼ 9.4 Hz), 6.57 (d, 2H, quinoline
H-3, J ¼ 7.0 Hz), 4.51 (br s, 4H, NCH2), 3.79 (br s, 4H, NHCH2), 1.74(br
s, 4H, NCH2CH2), 1.68 (br s, 4H,NCH2CH2), 1.20 (br s, 2H,
NHCH2CH2CH2), 0.7(br s, 2H, NCH2CH2CH2) HPLC: (A/B ¼ 65/35)
Rt ¼ 12.6 min. Purity ¼ 99.3% Anal. Calcd. for [C30H38N4O2]2þ
2
[CF3CO2]ꢃ, 3.6CF3CO2H, 1.5H2O.
6.1.43. 15,17,75,77-Tetrachloro-8,14-diaza-1,7(1,4)-diquinolinacyclo-
tetradecaphanium di-trifluoroacetate dihydrate (42)
N,N0-di(5,7-dichloroquinolin-4-yl)-1,5-diaminopentane (0.5 g,
1.01 mmol) with 1,5-diiodopentane (0.5 g, 1.54 mmol) similarly
afforded 25 mg (2.7% yield) of the pure product, mp: 197e202 ꢁC,
Rt ¼ 8.5 min. Purity ¼ 100%. Anal. Calcd. for [C28H34N4O2]2þ
2
[CF3CO2]ꢃ, 0.2CF3CO2H.
; d: 9.02
MS (ESPþ): 563 [M ꢃ H]þ, 282 [M]2þ 1H NMR (DMSO-d6)
6.1.39. 17,77-Ditrifluoromethyl-8,14-diaza-1,7(1,4)-diquinolinacyclo-
tetradecaphanium di-trifluoroacetate (38)
(br s, 2H, NH), 8.25 (d, 2H, quinoline H-2, J ¼ 7.6 Hz), 8.14 (d, 2H,
quinoline H-6 or 8, J ¼ 1.8 Hz), 7.92 (d, 2H, quinoline H-6 or 8,
J ¼ 1.8 Hz), 6.87 (d, 2H, quinoline H-3, J ¼ 7.6 Hz), 4.55 (br s, 4H,
NCH2), 3.67 (br s, 4H, NHCH2), 1.72 (br s, 8H, NCH2CH2, NHCH2CH2),
1.49 (br m, 2H, NHCH2CH2CH2), 0.83 (br s, 2H, NCH2CH2CH2); HPLC
(A/B ¼ 50/50), Rt ¼ 6.6 min. Purity ¼ 97.1%. Anal. Calcd. for
[C28H30Cl4N4]2þ 2[CF3CO2]ꢃ, 0.9CF3CO2H, 2H2O.
N,N0-bis(7-trifluoromethylquinolin-4-yl)pentane-1,5-diamine
(0.49 g, 1.0 mmol) and l,5-diiodopentane (0.49 g, 1.5 mmol) were
treated as for (32) to give a pale yeþllow solid (90 mg, 11% yield),
mp: 234 ꢁC. MS (FAB): 561 (M ꢃ 1) ; HPLC (A/B ¼ 50/50): 99.3%
purity, Rt ¼ 10.3 min, lH NMR (DMSO-d6)
d: 9.56 (br, 2H, NH), 8.67
(d, 2H, quinoline H-2), 8.43 (d, 2H, quinoline H-5), 8.34 (s, 2H,
quinoline H-8), 8.01 (d, 2H, quinoline H-6), 6.89 (d, 2H, quinoline
H-3), 4.67 (m, 4H, NCH2), 3.56 (m, 4H, NHCH2), 1.84 (m, 8H, CH2),
6.1.44. 16,56-Dinitro-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate (43)
2þ
1.45 (m, 2H), 0.91 (m, 2H). Anal. Calcd. for [C30H32
0.2CF3CO2H.
N
2[CF3CO2]ꢃ,
N,N0-di-(6-nitroquino1in-4-y1)-1,4-diamino-methy1benzene
4]
(0.2 g, 0.42 mmo1) and a,a
0-dibromo-m-xy1ene (0.2 g, 0.76 mmo1)
was treated as for (28) to give 60 mg (16% yielþd) of the pure product,
6.1.40. l7,77-Dichloro-8,14-diaza-l,7(1,4)-diquinolinacyclotetradeca-
phanium di-trifluoroacetate sesquihydrate (39)
mp: above 300 ꢁC. MS (APCIþ): 583 [M ꢃ H] ; 1H NMR (DMSO-d6)
d: 10.82 (br s, 2H, NH), 9.56 (d, 2H, quinoline H-5, J ¼ 2.1 Hz), 8.62
N,N0-bis(7-chloroquinolin-4-yl)pentane-1,5-diamine [50] (0.43 g,
1.0 mmol) in DMF (80 mL), and l,5-diiodopentane (0.49 g, 1.5 mmol)
were heated at 100 ꢁC for 48 h, then cooled, and the resulting pre-
cipitate was purified by preparative HPLC to give a pale yellow solid
which was crystallized from MeOH/Et2O, (70 mg, 8% yield), mp:
232 ꢁC decomp. MS (FAB): 493 (M ꢃ 1)þ; HPLC (A/B ¼ 55/45): 100%
(dd, 2H, quinoline H-7, J1 ¼ 2.1 Hz, J2 ¼ 9.6 Hz), 8.49 (d, 2H, quin-
oline H-2), 8.36 (d, 2H, quinoline H-8, J ¼ 9.6 Hz), 7.76 (d, m-phe-
nylene H-4,6, J ¼ 7.7 Hz), 7.54 (t, 1H, m-phenylene H-5, J ¼ 7.7 Hz),
7.48 (s, 4H, p-phenylene-H), 6.78 (s, 1H, m-phenylene H-2), 6.53 (d,
2H, quinoline H-3, J ¼ 7.5 Hz), 5.68 (s, 4H, NCH2), 4.82 (s, 4H,
NHCH2); HPLC: (A/B2 ¼ 65/35), Rt ¼ 7.3 min. Purity ¼ 98.3%. Anal.
Calcd. for [C34H28N6O4]2þ 2[CF3CO2]ꢃ, 0.9CF3CO2H.
purity, Rt ¼ 9.8 min, lH NMR (DMSO-d6)
d: 9.17 (br t, 2H, NH), 8.36 (d,
2H, quinoline H-2), 8.31 (d, 2H, quinoline H-5), 8.20 (s, 2H, quinoline
H-8), 7.78 (d, 2H, quinoline H-6), 6.81 (d, 2H, quinoline H-3), 4.58 (m,
4H, NCH2), 3.57 (m, 4H, NHCH2), 1.82 (m, 8H, CH2), 1.43 (m, 2H),
1.12 (m, 2H). Anal. Calcd. for [C28H32Cl2N4]2þ 2[CF3CO2]ꢃ, 0.9CF3CO2H,
1.5H2O.
6.1.45. 16,56-Diamino-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate sesquihydrate (44)
A mixture of 43 (40 mg, 0.049 mmo1) and Pd/C (60 mg) was
stirred in MeOH under a H2 atmosphere for 24 h, then filtered
through celite and the solvent removed in vacuo. Preparative HPLC
gave 15 mg (37% yield) of pure product, mp: above 300 ꢁC. MS
6.1.41. 6,12-Diaza-3(1,4)-benza-1,5(l,4)-di(7-chloroquinolinacyclo-
dodecaphanium di-trifluoroacetate (40)
(ESPþ): 523 [M ꢃ H]þ, 262 [M]2þ; 1H NMR DMSO-d6)
d: 9.48 (br s,
N,N0-bis(7-chloroquinolin-4-yl)pentane-1,5-diamine (0.3 g,
2H, NH), 8.22 (d, 2H, quinoline H-2, J ¼ 7.2 Hz), 7.91 (d, 2H, quin-
oline H-8, J ¼ 9.6 Hz), 7.71 (d, 2H, m-pheny1ene H-4,6, J ¼ 7.6 Hz),
7.47 (t, 1H, m-pheny1ene H-5, J ¼ 7.6 Hz), 7.40 (s, 4H, p-pheny1ene
H’s), 7.26 (m, 4H, quinoline H-5,7), 6.84 (s, 1H, m-pheny1ene H-2),
6.21 (d, 2H, quinoline H-3, J ¼ 7.2 Hz), 5.87 (br s, 4H, NH2), 5.53 (s,
4H, NCH2), 4.67 (d, 4H, NHCH2, J ¼ 4.5 Hz). HPLC: (A/B ¼ 75/25),
0.7 mmol) and
a,a
0-dibromo-p-xylene (0.4 g, 1.5 mmol) were
heated in DMF (100 mL) at 110 ꢁC for 3 h, and then evaporated. The
residue was triturated with MeOH/AcOEt. The resulting precipitate
was purified by preparative HPLC to give a white solid which was
crystallized from MeOH/Et2O, (70 mg, 13% yield), mp: 224 ꢁC
decomp. MS (FAB): 527 [M ꢃ 1]þ; HPLC (A/B ¼ 60/40): 100% purity,
Rt ¼ 9.5 min. Purity ¼ 100%. Anal. Calcd. for [C34H32N6]2þ
2
Rt ¼ 14.1 min, 1H NMR (DMSO-d6)
d
: 9.31 (br t, 2H, NH), 8.64 (s, 2H,
[CF3CO2]ꢃ, 0.8CF3CO2H, 1.5H2O.
quinoline H-8), 8.51 (d, 2H, quinoline H2), 8.29 (d, 2H, quinoline H-
5), 7.67 (d, 2H, quinoline H-6), 7.44 (s, 4H, p-xylylene), 6.84 (d, 2H,
quinoline H-3), 5.67 (s, 4H, CH2N), 3.55 (m, 4H, NH-CH2), 1.4 (m, 4H,
6.1.46. 16,56-Ditrifluoromethyl-6,10-diaza-1,5(1,4)-diquinolina-
3(1,3),8(1,4)-dibenzenacyclodecaphanium di-trifluoroacetate (45)
N,N0-di-(6-trifluoromethy1quinolin-4-yl)-1,4-diamino-
2ꢂCH2), 1.02 (m, 2H, CH2). Anal. Calcd. for [C31H30Cl2N4]2þ
2
[CF3CO2]ꢃ, 0.1CF3CO2H.
methylbenzene (0.28 g, 0.532 mmol) was treated with a, -
a0
dibromo-m-xylene (0.28 g, 1.06 mmo1) as for (28) to afford 70 mg
6.1.42. 17,77-Dimethoxy-8,14-diaza-1,7(1,4)-diquinolinacyclotetra-
(13% yield) of pure product, mp: 225e240 ꢁC. MS (FAB): 629
decaphanium di-trifluoroacetate sesquihydrate (41)
[M ꢃ H]þ, 315 [M]2þ
; d: 10.73 (br s, 2H, NH),
1H NMR (DMSO-d6)
N,N0-di(7-methoxyquinolin-4-yl)-1,5-diaminopentane (0.65 g,
1.6 mmol) was treated with 1,5-diiodopentane (0.65 g, 2.01 mmol)
as for (1) to give 20 mg (1.1% yield) of the product, mp: 170e175 ꢁC,
9.05 (s, 2H, quinoline H-5), 8.57 (d, 2H, quinoline H-2, J ¼ 7.4 Hz),
8.36 (d, 2H, quinoline H-8, J ¼ 9.2 Hz), 8.25 (d, 2H, quinoline H-7,
J ¼ 8.8 Hz), 7.76 (d, 2H, m-pheny1ene H-4,6, J ¼ 7.4 Hz), 7.52 (t, 1H,
m-phenylene H-5, J ¼ 7.6 Hz) 7.48 (s, 4H, p-phenylene H’s), 6.79 (s,
1H, m-pheylene H-2), 6.53 (d, 2H, quinoline H-3, J ¼ 7.6 Hz), 5.68
(s, 4H, NCH2), 4.81 (s, 4H, NHCH2). HPLC: (A/B2 ¼ 65/35),
MS (FAB): 243 [M]2þ, 485 [M ꢃ H]þ; 1H NMR (DMSO-d6)
d: 8.97 (br
s, 2H, NH), 8.30 (d, 2H, quinoline H-5, J ¼ 9.5 Hz), 8.16 (d, 2H,
quinoline H-2, J ¼ 7.2 Hz), 7.28 (d, 2H, quinoline H-6, J ¼ 9.5 Hz),
7.22 (s, 2H, quinoline H-8), 6.61 (d, 2H, quinoline H-3, J ¼ 7.2 Hz),
4.53 (br s, 4H, NCH2), 3.95 (br s, 6H, OCH3), 3.56 (br s, 4H, NHCH2),
Rt ¼ 23.9 min. Purity ¼ 100%. Anal. Calcd. for [C36H28F6N4]2þ
2
[CF3CO2]ꢃ, 1.1CF3CO2H.

D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
921
6.1.47. 16,56-Difluoro-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
6.1.51. 16,56-Ditrifluoromethoxy-6,10-diaza-1,5(1,4)-diquinolina-
3(1,3),8(1,4)-dibenzenacyclodecaphanium di-trifluoroacetate (50)
dibenzenacyclodecaphanium di-trifluoroacetate (46)
Similarly N,N0-di-(6-fluoroquinolin-4-yl)-1,4-diaminomethyl-
Similarly N,N0-di-(6-trifluoromethoxyquinolin-4-yl)-l,4-diamino-
benzene (0.095 g, 0.22 mmol) and
a
,
a
0-dibromo-m-xylene
methylbenzene (0.2 g, 0.36 mmol) anda,a
0-dibromo-m-xylene (0.2 g,
(0.095 g, 0.36 mmol) gave 23 mg of the puþre product (11% yield),
0.76 mmol) gave 45 mg (13% yield) of pure product, mp: 242e250 ꢁC.
mp: 242e250 ꢁC. MS (ESPþ): 529 [M ꢃ H] ; 1H NMR (DMSO-d6)
MS (APCIþ): 661 [M ꢃ H]þ, 331 [M]2þ; 1H NMR (DMSO-d6)
d:10.44
d
: 10.22 (br t, 2H, NH, J ¼ 5.2 Hz), 8.54 (d, 2H, quinoline H-2,
(br s, 2H, NH), 8.60 (s, 2H,quinoline H-5), 8.55 (d, 2H, quinoline H-2,
J ¼ 7.7 Hz), 8.37 (d, 2H, quinoline H-8, J ¼ 9.4 Hz), 8.02 (d, 2H,
quinoline H-7, J ¼ 9.4 Hz), 7.76 (d, 2H, m-phenylene H-4,6, J ¼ 7.7 Hz),
7.51 (t, 1H, m-phenylene H-5, J ¼ 7.7 Hz), 7.44 (5, 4H, p-phenylene-H),
6.92 (s, 1H, m-phenylene H-2), 6.46 (d, 2H, quinoline H-3, J ¼ 7.2 Hz),
5.66 (s, 2H, NCHz), 4.78 (s, 2H, NHCH2). HPLC: (A/B2 ¼ 55/45)
J ¼ 7.6 Hz), 8.41 (dd, 2H, quinoline H-5, Jj ¼ 2.3 Hz, J2 ¼ 9.6 Hz),
8.28 (dd, 2H, quinoline H-8, J1 ¼ 4.5 Hz, J2 ¼ 9.6 Hz), 7.92 (ddd,
2H, quinoline H-7, J1 ¼ 2.3 Hz, J2 ¼ 9.2 Hz), 7.76 (d, 2H, m-phe-
nylene H-4,6,
J
¼
8.0 Hz), 7.51 (t, 1H, m-phenylene H-5,
J ¼ 8.0 Hz), 7.45 (s, 4H, p-phenylene-H), 6.81 (s, 1H, m-phenylene
H-2), 6.45 (d, 2H, quinoline H-3, J ¼ 7.6 Hz), 5.66 (s, 2H, NCH2),
Rt ¼ 8.4 min. Purity ¼ 100%. Anal. Calcd. for [C36H28F6N4O2]2þ
2
4.76 (d, 2H, NHCH2,
J
¼
4.5 Hz) HPLC: (A/B2
¼
70/30),
[CF3CO2]ꢃ, 0.5CF3CO2H.
Rt ¼ 11.6 min. Purity ¼ 100%. Anal. Calcd. for [C34H28F6N4]2þ
2
[CF3CO2]ꢃ, 2CF3CO2H.
6.1.52. 17,57-Ditrifluoromethyl-6,10-diaza-1,5(1,4)-diquinolina-
3(1,3),8(1,4)-dibenzenacyclodecaphanium di-trifluoroacetate
hemihydrate (51)
6.1.48. 16,56-Dichloro-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate monohydrate (47)
Similarly N,N0-di(7-trifluoromethylquinolin-4-yl)-1,4-diamino-
Similarly, N,N0-di-(6-ch1oroquinolin-4-yl)-1,4-diaminomethyl-
methylbenzene (0.50 g, 0.95 mmol) and a,a
0-dibromo-m-xylene
benzene (0.60 g, 1.30 mmol) and
a,
a
0-dibromo-m-xylene (0.60 g,
(0.50 g, 1.89 mmol) gave 100 mg (11% yield) of pure product, mp:
2.27 mmol) afforded 40 mg of the pure product (3.4% overall yield,
from 200 mg of the crude material) mp: 230e245 ꢁC. MS (APCIþ):
561 [M ꢃ H]þ; 1H NMR (DMSO-d6): 10.32 (br s, 2H, NH), 8.70 (d, 2H,
quinoline H-5, J ¼ 2.2 Hz), 8.48 (d, 2H, quinoline H-2, J ¼ 7.5 Hz),
8.18 (d, 2H, quinoline H-8, J ¼ 9.5 Hz), 8.00 (dd, 2H, quinoline H-7,
J1 ¼ 2.2 Hz, J2 ¼ 9.5 Hz), 7.74 (d, 2H, m-phenylene H-4,6, J ¼ 6.9 Hz),
7.51 (t, 1H, m-phenylene H-5, J ¼ 7.6 Hz), 7.46 (s, 4H, p-phenylene-
H), 6.71 (s, 1H, m-phenylene H-2), 6.46 (d, 2H, quinoline H-3,
J ¼ 7.5 Hz), 5.63 (s, 4H, NCH2), 4.76 (s, 4H, NHCH2). HPLC: (A/
B2 ¼ 60/40) Rt ¼ 7.4 min. Purity ¼ 99.1%. Anal. Calcd. For
[C34H28Cl2N2]2þ 2[CF3CO2]ꢃ, 0.8CF3CO2H, H2O.
220e235 ꢁC. MS (FAB): 629 [M ꢃ H]þ, 329 [M]2þ; 1H NMR (DMSO-
d6)
d
: 10.63 (br t, 2H, NH, J ¼ 5.7 Hz), 8.82 (d, 2H, quinoline H-5,
J ¼ 8.8 Hz), 8.51 (m, 4H, quinoline H-2,8), 8.11 (d, 2H, quinoline H-6,
J ¼ 8.8 Hz), 7.72 (d, 2H, m-phenylene H-4,6, J ¼ 7.7 Hz), 7.56 (t, 1H,
m-phenylene H-5, J ¼ 7.7 Hz) 7.46 (s, 4H, p-phenylene-H), 6.89 (s,
1H, m-phenylene H-2), 6.50 (d, 2H, quinoline H-3, J ¼ 7.5 Hz), 5.78
(s, 4H, NCH2), 4.80 (s, 4H, NHCH2) HPLC: (A/B2
¼
60/40)
Rt ¼ 15.1 min. Purity ¼ 100%. Anal. Calcd. for [C36H28F6N4]2þ
2
[CF3CO2]ꢃ, 0.9CF3CO2H, 0.5H2O.
6.1.53. 17,57-Dichloro-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate (52)
6.1.49. 16,56-Dimethyl-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate (48)
Similarly N,N0-di-(7-chloroquinolin-4-yl)-1,4-diaminomethyl-
benzene (0.37 g, 0.81 mmol) and a,a
0-dibromo-m-xylene (0.37 g,
Similarly N,N0-di-(6-methylquinolin-4-yl)-1,4-diaminomethyl-
1.40 mmol) gave 65 mg (8% yield) of pure product, mp: 225e233 ꢁC.
benzene (0.27 g, 0.65 mmol) and
a
,a
0-dibromo-m-xylene (0.27 g,
MS (FAB): 561 [M ꢃ H]þ, 281 [M]2þ; 1H NMR (DMSO-d6)
d:10.38(br
1.02 mmol) gave 270 mg of crude product. Preparative HPLC gave
product which was only 95% pure. Repeat preparative HPLC gave
80 mg (15% yield) of the pure compound, mp: 230e235 ꢁC. MS
t, 2H, NH, J ¼ 5.6 Hz), 8.56 (d, 2H, quinoline H-5, J ¼ 9.1 Hz), 8.42 (d,
2H, quinoline H-2, J ¼ 7.4 Hz), 8.29 (s, 2H,quinoline H-8), 7.86(dd,
2H,quinoline H-6, J1 ¼1.3 Hz, J2 ¼ 9.1 Hz), 7.74 (d, 2H, m-phenylene
H-4,6, J ¼ 7.7 Hz), 7.57 (t, 1H, m-phenylene H-5, J ¼ 7.7 Hz), 7.45 (s,
4H, p-phenylene-H), 6.75 (s, 1H, m-phenylene H-2), 6.43 (d, 2H,
quinoline H-3, J ¼ 7.4 Hz), 5.65 (s, 4H, NCH2), 4.75 (s, 4H, NHCH2).
HPLC: (A/B2 ¼ 70/30) Rt ¼ 19.6 min. Purity ¼ 99.7%. Anal. Calcd. for
[C34H28Cl2N2]2þ 2[CF3CO2]ꢃ, 1.7CF3CO2H.
(ESPþ): 521 [M ꢃ H]þ, 261 [M]2þ; 1H NMR (DMSO-d6)
d: 10.14 (br t,
2H, NH, J ¼ 5.4 Hz), 8.47 (d, 2H, quinoline H-2, J ¼ 7.2 Hz), 8.33 (s,
2H, quinoline H-5), 8.04 (d, 2H, quinoline H-8, J ¼ 8.8 Hz), 7.76 (m,
4H, m-phenylene H-4,6, quinoline H-7), 7.50 (t, 1H, m-phenylene H-
5, J ¼ 7.8 Hz), 7.45 (s, 4H, p-phenylene H), 6.73 (s, m-phenylene H-
2), 6.42 (d, 2H, quinoline H-3, J ¼ 7.2 Hz), 5.61 (s, 4H, NCH2), 4.74 (d,
4H, NHCH2, J ¼ 5.2 Hz), 2.47 (s, 6H, CH3). HPLC: (A/B2 ¼ 65/35)
6.1.54. 17,57-Dimethoxy-6,10-diaza-1,5(1,4)-diquinolina-3(1,3),
8(1,4) dibenzenacyclo-decaphanium di-trifluoroacetate mono-
hydrate (53)
Rt ¼ 8.7 min. Purity ¼ 99.4%. Anal. Calcd. for [C36H34N4]2þ
2
[CF3CO2]ꢃ, 0.6CF3CO2H.
Similarly N,N0-di-(7-methoxyquinolin-4-yl)-1,4-diaminometh-
ylbenzene (0.34 g, 0.76 mmol) gave 70 mg (10.5% yield) of pure
6.1.50. 16,56-Dimethoxy-6,10-diaza-1,5(1,4)-quinolina-3(1,3),8(1,4)-
dibenzenacyclodecaphanium di-trifluoroacetate monohydrate (49)
product, mp: 2l0e225 ꢁC. MS (FAB): 553 [M ꢃ H]þ,277 [M]2þ
.
1H
Similarly N,N0-di-(6-methoxyquinolin-4-y1)-1,4-diaminometh-
NMR (DMSO-d6) d: 10.06 (br s, 2H, NH), 8.43 (m, 4H, quinoline H-5
ylbenzene (0.25 g, 0.56 mmol) and
a
,
a
0-dibromo-m-xylene (0.25 g,
and 2), 7.76 (d, 2H, m-phenylene H-4,6, J ¼ 7.7 Hz), 7.54 (t, 1H, m-
phenylene H-5, J ¼ 7.7 Hz), 7.41 (m, 8H, p-phenylene-H and quin-
oline H-6,8), 6.88 (s, lH, m-phenylene H-2), 6.37 (d, 2H, quinoline H-
3, J ¼ 7.4 Hz), 5.63 (s, 4H, NCH2), 4.72 (s, 4H, NHCH2), 3.92 (s, 6H,
OCH3). HPLC: (A/B2 ¼ 65/35) Rt ¼ 7.4 min. Purity ¼ 99.0%. Anal.
Calcd. for [C36H28N4O2]2þ 2[CF3CO2]ꢃ, 0.7CF3CO2H, H2O.
0.95 mmol) gave 30 mg (6% yield) of pure product, mp: 242e246 ꢁC.
MS (ESPþ): 553 [M ꢃ H]þ, 227 [M]2þ
; d: 10.0l
1H NMR (DMSO-d6)
(br t, 2H, NH, J ¼ 5.7 Hz), 8.40 (d, 2H, quinoline H-2, J ¼ 7.3 Hz), 8.09
(d, 2H, quinoline H-8, J ¼ 9.6 Hz), 7.92 (d, 2H, quinoline H-5,
J ¼ 2.4 Hz), 7.73 (d, 2H, m-phenylene H-4,6, J ¼ 7.4 Hz), 7.57 (dd, 2H,
quinoline H-7, J1 ¼ 2.4 Hz, J2 ¼ 9.6 Hz), 7.50 (t,1H, m-phenylene H-5,
J ¼ 7.7 Hz), 7.46 (s, 4H, p-phenylene-H), 6.71 (s, 1H, m-phenylene H-
2), 6.41 (d, 2H, quinoline H-3, J ¼ 7.3), 5.62 (s, 4H, NCH2), 4.76 (d, 4H,
NHCH2, J ¼ 5.2 Hz), 3.93 (s, 6H, OCH3). HPLC: (A/B2 ¼ 65/35)
6.1.55. 15,17,55,57-Tetrachloro-6,10-diaza-1,5(1,4)-diquinolina-
3(1,3),8(1,4)-dibenzenacyclodecaphanium di-trifluoroacetate
hydrate (54)
Rt ¼ 9.6 min. Purity ¼ 100%. Anal. Calcd. for [C36H34N4O2]2þ
2
Similarly N,N0-di-(5,7-dichloroquinolin-4-yl)-1,4-diaminomet-
[CF3CO2]ꢃ, 0.6CF3CO2H, H2O.
hylbenzene (0.28 g, 0.53 mmol) and a,a
0-dibromo-m-xylene

922
D. Yang et al. / European Journal of Medicinal Chemistry 63 (2013) 907e923
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(0.28 g, 1.06 mmol) gave 55 mg (9%þyield) of pure product, mp:
d: 9.95
225e240 ꢁC. MS (APCIþ): 631 [M ꢃ H] ; 1H NMR (DMSO-d6)
(br t, 2H, NH, J ¼ 5.6 Hz), 8.31 (d, 2H, quinoline H-2, J ¼ 7.7 Hz), 8.20
(d, 2H, quinoline H-6 or 8, J ¼ 1.7 Hz), 8.03 (d, 2H, quinoline H-6 or
8, J ¼ 1.7 Hz), 7.71 (d, 2H, m-phenylene H-4,6, J ¼ 7.8 Hz), 7.59 (t, 1H,
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5.64 (s, 4H, NCH2), 4.90 (s, 4H, NHCH2), 2.05 (s, CH3CN) HPLC: (A/
B2 ¼ 65/35) Rt ¼ 18.7 min. Purity ¼ 99.3%. Anal. Calcd. for
[C34H26C14N4]2þ 2[CF3CO2]ꢃ, 2.1CF3CO2H, 0.75H2O, 0.75MeCN.
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Acknowledgments
We thank Mr Wasyl Tertiuk for helpful supervisions in the lab-
oratory. We are also grateful to Dr PM Dunn for advice on elec-
trophysiological recording, to Dr M Garbarg for her generous help
and to Ms Brenda Browning and her colleagues in the UCL Phar-
macology Tissue Culture Laboratory for the preparation of cultured
neurons. The work was partially supported by the Wellcome Trust,
which also provided a fellowship for DY, and by University College
London who provided a studentship for LA. DHJ held a Leverhulme
Emeritus Fellowship.
[20] R. Hosseini, D.C.H. Benton, P.M. Dunn, D.H. Jenkinson, G.W.J. Moss, SK3 is an
important component of Kþ channels mediating the afterhyperpolarization in
cultured rat SCG neurones, J. Physiol. 535 (2001) 323e334.
[21] D. Galanakis, C.R. Ganellin, J.Q. Chen, D. Gunasekera, P.M. Dunn, Bis-quinoli-
nium cyclophanes: toward
a pharmacophore model for the blockade of
apamin-sensitive SKCa channels in sympathetic neurons, Bioorg. Med. Chem.
Lett. 14 (2004) 4231e4235.
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of a pharmacophore of SKCa channel blockers, J. Enzyme Inhib. Med. Chem. 20
(2005) 517e523.
[23] J.Q. Chen, D. Galanakis, C.R. Ganellin, P.M. Dunn, D.H. Jenkinson, Bis-quinoli-
nium cyclophanes: 8,14-diaza-1,7(1,4)-diquinolinacyclo-tetradecaphane (UCL
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sensitive Ca2þ-activated Kþ channel, J. Med. Chem. 43 (2000) 3478e3481.
[24] D.C.H. Benton, P.M. Dunn, J.Q. Chen, D. Galanakis, C.R. Ganellin, M. Malik-Hall,
M. Shah, D.G. Haylett, D.H. Jenkinson, UCL 1848: a novel bis-quinolinium
cyclophane which blocks apamin-sensitive Kþ channels with nanomolar af-
finity, Br. J. Pharmacol. 128S (1999) 39P.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2013.02.029.
[25] J.M. Power, P. Sah, Competition between calcium-activated Kþ channels de-
termines cholinergic action on firing properties of basolateral amygdala
projection neurons, J. Neurosci. 28 (2008) 3209e3220.
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