Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

Article abstract of DOI:10.1016/j.bmcl.2008.09.084

A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate w

Full text of DOI:10.1016/j.bmcl.2008.09.084

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5753–5757
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Tetrakis-azaaromatic quaternary ammonium salts: Novel subtype-selective
antagonists at neuronal nicotinic receptors that mediate nicotine-evoked
dopamine release
Zhenfa Zhang, Guangrong Zheng, Marharyta Pivavarchyk, A. Gabriela Deaciuc, Linda P. Dwoskin,
*
Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Rose Street, Lexington, KY 40536-0082, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 June 2008
Revised 21 September 2008
Accepted 22 September 2008
Available online 26 September 2008
A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds
with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that
mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhi-
bit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC50 = 3, 28 and
56 nM, respectively) antagonists at these receptors. These compounds represent a novel structural class
of nicotinic receptor antagonists.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Nicotinic acetylcholine receptor
Quaternary ammonium
Dopamine release
Nicotine addiction
Nicotine evokes striatal dopamine release through stimulating
neuronal nicotinic acetylcholine receptors (nAChRs) on dopami-
nergic neurons, which underlies reward produced by nicotine.1,2
nAChRs are believed to be homomeric or heteromeric pentamers
tained for some analogues depending upon the length of the N-n-
alkyl group.16b Although N-n-dodecylnicotinium iodide (Fig. 1,
NDDNI, 1a,) was the most potent (IC50 = 9 nM) inhibitor of nico-
tine-evoked DA overflow from striatal slices, this analogue had
only 15-fold selectivity, since it also inhibited [3H]nicotine binding
to the high-affinity nAChR. An improvement in selectivity was ob-
tained with N-n-octanylnicotinium iodide (NONI, 1b); however
this analog was 70-fold less potent than NDDNI.16b Second gener-
ation compounds based upon a bis-quaternary ammonium scaffold
(see Fig. 1) identified N,N0-dodecane-1,12-diyl-bis-3-picolinium
dibromide (Fig. 1, bPiDDB; 2) as a highly potent and selective
antagonist for nAChR subtypes that mediate nicotine-evoked stria-
composed of a heterogeneous family of subunits (a2–7, and b2–
4) potentially forming a plethora of subtypes with a broad range
of pharmacological and electrophysiological properties.3 Multiple
subunit combinations also mediate nicotine-evoked dopamine
(DA) release at striatal presynaptic DA terminals. The following
subtypes have been implicated in mediating nicotine-evoked stri-
atal dopamine release:
4b2*, and 5b2*.4–6
Nicotine-evoked DA release is completely inhibited by the non-
a a4a a a4a
6b2b3*, 6b2b3*, 6b2*, 6b2*,
a
a4a
tal DA release.17 bPiDDB had no affinity for either the 4b2* or 7*
a a
selective, noncompetitive nAChR antagonist mecamylamine.7 Mec-
amylamine has been investigated as a smoking cessation therapy,
but peripheral side-effects precluded its clinical development.8–10
In our continued search for effective therapies to treat nicotine
addiction, we have focused on the development of subtype-selec-
tive antagonists that target nAChRs that mediate nicotine-evoked
DA release. Such a strategy may provide novel treatments which
circumvent the untoward side-effects of mecamylamine.11–15
Modification of the nicotine molecule by quaternization of the
pyridine-N atom with a lipophilic substituent to afford N-substi-
tuted analogues converts nicotine from a nAChR agonist to an
antagonist.16a Moreover, emergence of subtype selectivity was ob-
nAChR binding sites in rat brain membranes, but potently inhibited
nicotine-evoked DA overflow (IC50 = 2 nM), demonstrating high
potency and selectivity for these receptors.17 bPiDDB has also been
demonstrated subsequently to be brain bio-available and enters
the CNS compartment by facilitated transport via the blood–brain
barrier choline transporter.18 bPiDDB has similar affinity for this
transporter as the natural substrate, choline.18 In behavioral
studies, bPiDDB has been shown to decrease nicotine self-adminis-
tration in rats.19
Further structural elaboration of the bPiDDB molecule resulted
in the synthesis of a series of compounds in which a central phenyl
core was utilized to append three linker units terminating in azaa-
20
romatic quaternary ammonium head groups.
This led to the
identification of 1,3,5-tri-{5-[1-(3-picolinium)]-pent-1-ynyl}ben-
* Corresponding author. Tel.: +1 859 257 1718; fax: +1 859 257 7585.
zene tribromide (Fig. 1, tPy3PiB, 3), a compound which exhibited
E-mail address: pcrooks@email.uky.edu (P.A. Crooks).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.09.084

5754
Z. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5753–5757
I
I
I
I
N
N
H5IO6/KI
H2SO4
OH
n
I
5
1a, (NDDNI, n=5)
1b, (NONI, n=1)
4
Pd(PPh3)2Cl2
Et3N
OH
OH
OH
OH
Br
N
N
Br
2 (bPiDDB)
Pd-C/H2
N
N
6
9
OH
OH
PPh3/CBr4
OH
OH
Br
3Br
PPh3/CBr4
Br
Br
Br
3 (tPy3PiB)
N
Figure 1. Structures of three generations of azaaromatic quaternary ammoniun
salts acting as nAChR antagonists at subtypes mediating nicotine-evoked DA
release.
7
10
Br
N
Br
N
Br
N
Br
R
R
R
high potency and selectivity for nAChR subtypes mediating nico-
tine-evoked [3H]dopamine release with an IC50 of 0.2 nM.20
Continuing in the structural evolution of the above sublibraries,
i.e., the mono- to bis- to tris-azaaromatic quaternary ammonium
analogs, an additional quaternary ammonium head group was
introduced into the tris-scaffold to afford a series of tetrakis ana-
logs. This modification was investigated to determine if analogs
in the tetrakis series would have enhanced potency and selectivity
due to the greater number of cationic interaction points with the
receptor protein. Thus a novel series of tetrakis-quaternary ammo-
nium analogs have been synthesized and evaluated for their ability
to inhibit nicotine-evoked striatal DA release. It should be noted
that receptor kinetic studies within the bis-series of compounds
indicated that such compounds interact in an orthosteric manner
with the nAChR target,21 although this has not yet been established
for the tris and tetrakis analogs.
R
R
R
N
N
N
Br
Br
Br
Br
Br
R
Br
N
N
Br
R
Br
N
N
R
8
11
R
Two series of tetrakis-azaaromatic quaternary ammonium com-
pounds, i.e., 1,2,4,5-tetrakis-(pent-1-ynyl-5-azaaromatic quater-
nary ammonium)-benzene salts (8 series, Scheme 1), and 1,2,4,5-
tetrakis-(n-pentanyl-5-azaaromatic quaternary ammonium)-ben-
zene salts (11 series), were prepared. The synthesis of these com-
pounds is illustrated in Scheme 1. Sonagashira coupling of an
appropriate bromobenzene precursor with an alkynol were em-
ployed extensively in the synthesis of the bis-quaternary ammo-
nium and tris-quaternary ammonium analogues in our previous
study (Fig. 1).20 However, the Sonagashira coupling of 1,2,4,5-tet-
rabromobenzene with 4-pentyn-1-ol (5) in triethylamine in the
presence of tetrakis-(triphenylphospine)palladium(0) proved diffi-
cult, affording a mixture containing a plethora of components. This
failure is likely due to the sluggish reactivity of tetrabromobenzene
under Sonogashira coupling conditions. Thus, the alternative syn-
thon, 1,2,4,5-tetraiodobenzene (4) was utilized.22 Coupling of 4
with 5 afforded the desired 1,2,4,5-benzene-tetrakis-1-pentyn-5-
ol (6). The pentyn-5-ol side chains of this compound were then
either directly transformed into the corresponding pentynyl bro-
mide side chains to provide 7, or catalytically reduced to the corre-
sponding pentan-1-ol side chains to produce 9. The resulting 9 was
subsequently brominated to give 10. Reaction of 7 or 10 with an
appropriate substituted pyridine or related azaaromatic precursor
Scheme 1. Synthesis of the tetrakis-azaaromatic quaternary ammonium com-
pounds series 8 and 11.
afforded the desired azaaromatic quaternary ammonium salt, 8
and 11, respectively. Characterization data for selected compounds
are provided.23
The above tetrakis-azaaromatic quaternary ammonium com-
pounds were initially evaluated for inhibition of nAChRs mediating
nicotine-evoked [3H]DA release from superfused rat striatal slices
using a probe concentration of 100 nM in a rapid screening assay.
Also, interaction of these analogs with a a
4b2* and 7* nAChR sub-
types was assessed in rapid-throughput [3H]nicotine and
[3H]methyllycaconitine (MLA) binding assays, respectively, using
the same probe concentration. The three most active antagonists
at nAChRs mediating nicotine-evoked DA release (i.e., 11f, 11g,
and 11j) were then evaluated across a full concentration range to
determine their IC50 values.
[3H]Nicotine and [3H]MLA binding assays were performed
according to previously reported methods,16a using 3 and 2.5 nM
concentrations of radioligand, respectively, and 10
and 10 M nicotine, respectively, to assess nonspecific binding to
whole brain membranes. Analogs were evaluated at a probe con-
lM cytisine
l

Z. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5753–5757
5755
Table 1
centration of 100 nM. Amount of inhibition is presented as a per-
Inhibition of [3H]NIC binding (probing
a
4b2* nAChRs) and [3H]MLA binding (probing
centage of radioligand binding in the absence of analogue (control).
[3H]DA release assays were performed according to a previously
published method.16b Analog-induced inhibition of nicotine-
a
7* nAChRs) to rat brain membranes, and nicotine-evoked [3H]DA release from
superfused rat striatal slicesa
Compound
NIC binding
(% inhibition
at 100 nM)
MLA binding
(% inhibition
at 100 nM)
DA release
(% inhibition
at 100 nM)
evoked [3H]DA release was determined using 10
lM nicotine and
100 nM analog concentrations. Amount of inhibition is presented
as a percentage of the response to nicotine under control condi-
tions (in the absence of analog) and the values are provided in Ta-
R
N
ble 1. Full concentration response (1 nM–10 lM) was performed
for the three most promising analogs and IC50 values were deter-
mined using an iterative nonlinear least-squares curve-fitting pro-
gram, PRISM version 4.0 (GraphPAD Software, Inc., San Diego, CA).
The construction of the tetrakis-quaternary ammonium com-
pounds are based on a skeleton incorporating four identical quater-
nary ammonium moieties attached to a central phenyl ring at the
1, 2, 4, and 5 positions, each through a 5-carbon linker unit. The
underlying rational was that increasing the number of quaternary
ammonium moieties in the molecule from two to three to four
would increase progressively the ionic interaction of such mole-
cules with the putative negatively charged binding sites on the tar-
get protein. Either a flexible or slightly more rigid linker that
resulted in a more extensively planarized central aromatic core
moiety, was utilized to probe the likely conformational orientation
and the intramolecular distances between the head groups in the
molecule. In addition, a variety of different quaternary ammonium
head group structures was introduced into the tetrakis scaffold.
The results are summarized in Table 1. Overall, seven out of the
20 tetrakis-analogs evaluated inhibited nicotine-evoked DA release
in striatal slices by >40%, and an additional five inhibited nicotine-
evoked DA release by 30–40%. This high hit rate of the tetrakis-ana-
logs confirmed the feasibility of the SAR approach. There are note-
worthy structure–activity relationships among these series of
molecules. First, all the analogs in series 11 (i.e., analogs with fully
saturated linkers), with the exception of 11a and 11i, exhibited
greater inhibition of nicotine-evoked striatal DA release than their
structural counterparts in the series 8 analogs (i.e., analogs with
linkers containing an acetylene bond). Six out of seven of the most
active inhibitors contained a saturated linker, that is, 11b, 11d, 11e,
11f, 11g, and 11j. It is interesting to note that the most active com-
pound in the 8 series (i.e., 8j) and the most active compound in the
11 series (11j) both contained the same 3-(4-hydroxypropyl)pyrid-
inium head group. Similarly, the second most active compound in
both the 8 and 11 series (8g and 11g) both contained an isoquino-
linium head group. Thus, this result indicates that the nature of the
head group is important in the optimization of compounds inhib-
iting nicotine-evoked DA release. Interestingly, compounds 8f
and 8i, both of which incorporate large lipophilic substituents into
the pyridinium head groups, exhibited significant inhibition in the
MLA assay, consistent with our previous findings with the structur-
ally-related tris-azaaromatic quaternary ammonium compounds.20
Several compounds with head groups containing one or more
lipophilic substituents on the pyridine ring exhibited good activity
inhibiting nicotine-evoked striatal DA release. For example, tetra-
kis-isoquinolinium, 4-picolinium and nicotinium heads with both
saturated linkers (i.e., 8g, 8b, and 8e) and unsaturated linkers
(i.e., 11g, 11b, and 11e) inhibited nicotine-evoked striatal DA re-
lease (35–63%). This is consistent with our previous observations
in the bis- and tris-analog series. Surprisingly, the 3-picolinium
head group, which afforded quite robust antagonist activity in
the previous bis-(bPiDDB) and tris-(tPy3PiB) quaternary ammo-
nium scaffolds in their inhibition of nicotine-evoked striatal DA re-
lease, combined with either saturated or unsaturated linkers in the
current study, turned out to be poor antagonists in the tetrakis ser-
ies of compounds. However, it must be emphasized that the tetra-
kis-series of analogs do not contain within their structure the
1,3,5-phenyl substitution pattern present in the tris-scaffold.
8a
11 11
24 5.5
18 7.8
3.0 3.0
16 13
35 14
N
8b
N
8c
9.8 1.2
0.6 0.6
17
12
6
5
N
8d
0
0
3.9 3.9
15 2.0
N
8e
38 7.4
2.9 2.9
31 13
N
CH3
N
N
Bn
8f
53 3.5
4.9 3.8
17 8.9
53 0.8
5.7 5.7
17 17
8g
8h
8i
0
0
39 17
N
N
9.7 9.7
0.3 0.3
24 14.3
37 15
Ph
N
N
OH
8j
0
0
41 15
2
bPiDDB
Ki = 48.6
12 4.4
12 8.3
0.5 0.5
l
Mb
Ki > 100
12 6.9
8.0 5.3
18 10
l
Mb
IC50 = 2 nMb
11a
11b
11c
8
4
5
N
46
N
N
36 11
11d
11e
3.7 3.7
7.4 4.7
15 8.0
26 14
45 14
43 21
N
N
CH3
N
(continued on next page)

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Z. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5753–5757
Table 1 (continued)
4.0
control
NMPi (100 nM)
Compound
NIC binding
(% inhibition (% inhibition (% inhibition
at 100 nM)
MLA binding DA release
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
R
MEC (10 μM)
at 100 nM)
at 100 nM)
ANALOG
N
NICOTINE
Bn
11f
13 3.3
6.5 6.5
16 8.0
24 13
54 10,
IC50 = 28 11 nMc
N
11g
63 12,
IC50 = 56 45 nMc
N
0
8
16 24 32 40 48 56 64 72 80 88
Time (min)
11h
0.9 0.9
6.6 4.5
27 15
33 17
27
2
Figure 3. S(ꢀ)-Nicotine-evoked fractional release of [3H]DA from rat striatal slices
superfused with 100 nM N-methylpyridinium iodide (NMPi). Data are expressed as
means SEM fractional release as a percent of tissue tritium content. Control
represents the amount of fractional release evoked by S(ꢀ)-nicotine in the absence
of compound. The effect of mecamylamine (MEC) was determined as a positive
control. Two-way ANOVA was performed to analyze the ability of MEC and NMPi (a
between-subject factor) to inhibit S(ꢀ)-nicotine-evoked [3H]DA fractional release
and time was a within-subject factor. Significant inhibition was obtained with MEC,
but NMPi did not produce a significant inhibitory effect. n = 4–6 rats/analog.
N
Ph
11i
19 15
N
OH
11j
9.6 5.2
10 1.9
20 13
64 15,
IC50 = 3.38 2.62 nMc
N
tors, it is possible that hydrogen bonding interactions involving the
1-hydroxypropanyl substituent may also play a significant role.
This may open up another area of structural optimization worthy
of investigation.
3
tPy3PIB
0
0
40 12,
IC50 = 0.2 0.07 nM c
a
Percentage of inhibition at 100 nM are presented unless otherwise specified.
Each value represents data from at least three independent experiments, each
performed in duplicate.
It should be noted that evaluation of a molecule representing
just the pyridinium headgroup moiety alone, that is, N-methylpy-
ridinium iodide (NMPi), afforded weak inhibitory properties in
the dopamine release assay (Fig. 3). This indicates that the tetrakis
scaffold can position four of these quaternary ammonium head-
groups in a preferable orientation for favorable interaction with
the receptor binding site, lowering the entropic barrier for receptor
interaction.
In conclusion, a novel series of tetrakis-quaternary ammonium
compounds has been synthesized and evaluated for their ability to
potently and selectivity inhibit striatal nicotine-evoked DA release.
A high hit rate was achieved. The results suggest that the novel
strategy to identify highly potent nAChR ligands through progres-
sive introduction of cationic moieties around a common phenyl
ring core structure can lead to potent inhibition of nAChR involved
in nicotine-evoked DA release. Thus, compound 11j represents a
tetrakis analog with an unique 3-N-(3-hydoxypropanyl)-pyridini-
um head group, this compound and afforded the highest potency
in this SAR study. This observation may offer the opportunity for
further structural optimization in this interesting series of tetrakis
analogs.
b
Ki from full concentration response assay; data from
4 to 5 independent
experiments, each performed in duplicate.
c
IC50 from full concentration response assays; data from 4 to 5 independent
experiments, each performed in duplicate.
Interestingly, introduction of a 1-hydroxypropanyl substituent
into the pyridine ring resulted in the highly potent nAChR antago-
nists 8j and 11j. Compound 11j is the most potent compound in the
series 11 analogs, with an IC50 of 3 nM (Fig. 2); whereas 8j is the
most potent inhibitor in series 8 analogs. This observation uncov-
ers an additional site of interaction with respect to the interaction
of the quaternary ammonium head group substituent with the
nAChR binding site(s). While ionic interaction of the head groups
with the nAChR binding site may be one of the most important fac-
2.0
1.5
IC50 = 3.38 2 .62 nM
Imax= 63 4%
Acknowledgment
1.0
This research was supported by NIH Grant U19DA017548.
References and notes
OH
HO
HO
Br
Br
N
N
N
N
0.5
OH
Br
Br
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-10
-9
-8
-7
-6
-5
log [Compound 11j] (M)
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Figure 2. Compound 11j inhibited S(ꢀ)-nicotine-evoked [3H]DA overflow from rat
striatal slices in concentration-dependent manner. Slices were superfused in the
absence (control) or presence of analog for 36 min prior to S(ꢀ)-nicotine addition to
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Control represents [3H]DA overflow in response to nicotine (10
lM). Data are
expressed as means SEM [3H]DA overflow. n = 4 rats/analog.

Z. Zhang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5753–5757
5757
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for [C58H70N4O44+]: 221.63, 221.89, 222.39.)
Compound 11f: A
mixture of 5,50,500,5000-(1,2,4,5-benzentetrayl)tetrakis-[1-
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bromopentane] (10) (330 mg, 0.49 mmol) and 3-benzyl-pyridine (390 mg,
2.3 mmol) was heated at 60–70 °C for 18 h. The resulting mixture was
treated with diethyl ether and then dissolved in water (15 mL), the aqueous
solution was extracted extensively with chloroform (5ꢁ 30 mL). Water was
removed through lyophilization to afford 575 mg of the title compound.
Yield: 87%. 1H NMR (300 MHz, CD3OD) d 9.20 (s, 4H), 8.97 (d, J 6.0 Hz, 4H),
8.41 (d, J 8.1 Hz, 4H), 8.00 (dd, 4H), 7.19–7.34 (m, 20H), 6.91 (s, 2H), 4.70 (t,
J 7.5 Hz, 8H), 4.27 (s, 8H), 2.51–2.57 (m, 8H), 2.01–2.11 (m, 8H), 1.56–1.62
(m, 8H), 1.43–1.50 (m, 8H) ppm. 13C NMR, 145.61, 144.26, 143.36, 142.56,
138.18, 137.35, 130.18, 129.13, 129.06, 128.01, 127.17, 61.81, 38.03, 32.11,
31.56, 31.07, 26.23 ppm. ESI-MS: m/z. 1169.3, 1270.3, 1271.2, 1272.1 (Calcd
for [C74H86Br3N4+], 1269.44, 1270.44, 1271.44, 1272.44.) m/z 594.2, 595.2,
595.7. Calcd for C74H86Br2N42+, 594.26, 595.26, 595.76.) m/z 369.9, 370.2,
370.5 (Calcd for C74H86BrN43+, 369.87, 370.20, 370.53).
Compound 11g:
A
mixture of 5,50,500,5000-(1,2,4,5-benzentetrayl)-tetrakis-[1-
bromopentane] (10) (330 mg, 0.49 mmol) and 3-(3-hydroxypropanyl)-
pyridine (300 mg, 2.3 mmol) was heated at 60–70 °C for 18 h. The resulted
mixture was treated with diethyl ether and then dissolved in water (15 mL),
the aqueous solution was extracted extensively with chloroform (5ꢁ 30 mL).
Water was removed through lyophilization to afford 460 mg of the title
compound. Yield: 79%. 1H NMR (300 MHz, CD3OD) d 10.15 (s, 4H), 8.78–8.81
(m, 4H), 8.49–8.54 (m, 8H), 8.27–8.32 (m, 4H), 8.17–8.28 (m, 4H), 8.00–8.05
(m, 4H), 6.80 (s, 2H), 4.87 (t, J 7.5 Hz, 8H), 2.44–2.51 (m, 8H), 2.15–2.22 (m,
8H), 1.46–1.58 (m, 16H) ppm. 13C NMR 149.62, 137.62, 137.18, 137.12,
134.77, 131.40, 130.42, 130.07, 127.84, 127.39, 126.38, 61.72, 31.97, 31.38,
30.94, 26.23 ppm. ESI-MS: m/z. 1109.1, 1110.1, 1111.1, 1112.1 (Calcd for
[C62H70Br3N4+]: 1109.31, 1110.32, 1111.31, 1112.31.) m/z 316.4, 316.8, 317.1
(Calcd for [C62H70BrN43+]: 316.49, 316.83, 317.16).
19. Neugebauer, N. M.; Zhang, Z.; Crooks, P. A.; Dwoskin, L. P.; Bardo, M. T.
Psychopharmacology 2006, 184, 426.
20. Zheng, G.; Sumithran, S. P.; Deaciuc, A. G.; Dwoskin, L. P.; Crooks, P. A. Bioorg.
Med. Chem. Lett. 2007, 17, 6701.
21. Dwoskin, L. P.; Wooters, T. E.; Sumethran, S. P.; Siripurapu, K. B.; Joyce, B. M.;
Lockman, P. R.; Manda, V. K.; Ayers, J. T.; Zhang, Z.; McIntosh, J. M.; Crooks, P.
A.; Bardo, M. T. J. Pharmacol. Exp. Ther. 2008, 326, 563.
Compound 11j:
A
mixture of 5,50,500,5000-(1,2,4,5-benzentetrayl)tetrakis-[1-
22. De Kort, M.; Correa, V.; Valentijn, A. R. P. M.; Van der Marel, G. A.; Potter, B V. L.;
Taylor, C. W.; Van Boom, J. H. J. Med. Chem. 2000, 43, 3295.
bromopentane] (330 mg, 0.49 mmol) and 3-(3-hydroxypropanyl)-pyridine
(325 mg, 2.3 mmol) was heated at 60–70 °C for 18 h. The resulting mixture
was treated with diethyl ether and then dissolved in water (15 mL), the
aqueous solution was extracted extensively with chloroform (5ꢁ 30 mL).
Water was removed through lyophilization to afford 371 mg of the title
compound. Yield: 62%. 1H NMR (300 MHz, CD3OD) d 9.07 (s, 4H), 8.94 (d, J
6.0 Hz, 4H), 8.50 (d, J 8.4 Hz, 4H), 8.05 (dd, 4H), 6.90 (s, 2H), 4.69 (t, J 7.5 Hz,
8H), 3.62 (t, J 6.0 Hz, 8H), 2.99 (t, J 7.8 Hz, 8H), 2.57 (t, J 7.5 Hz, 8H), 2.05–
2.12 (m, 8H), 1.93–1.98 (m, 8H), 1.57–1.62 (m, 8H), 1.46–1.50 (m, 8H) ppm.
13C NMR, 145.53, 144.24, 143.98, 142.24, 137.30, 130.15, 127.80, 61.77,
60.48, 33.08, 32.05, 31.55, 31.06, 29.12, 26.20 ppm. ESI-MS: m/z. 1141.3,
1142.3, 1143.2, 1144.1 (Calcd for [C58H86Br3N4O4+]: 1141.42, 1142.42,
1143.42, 1144.42.) m/z 531.2, 530.2, 531.7 (Calcd for [C58H86Br2N4O42+]:
531.25, 530.25, 531.75) m/z 327.2, 327.5, 327.8 (Calcd for [C58H86BrN4O43+]:
327.19, 327.53, 327.86).
23. Compound 8j:
bromo-4-pentyne]
A
mixture of 5,50,500,5000-(1,2,4,5-benzentetrayl)tetrakis-[1-
(7)
(300 mg,
0.46 mmol)
and
3-(1-
hydroxypropyl)pyridine (340 mg, 2.0 mmol) was heated at 60–70 °C for
18 hrs. The resulting mixture was treated with diethyl ether and then
dissolved in water (15 mL), the aqueous solution was extracted extensively
with chloroform (5ꢁ 30 mL). Water was removed by lyophilization to afford
350 mg of 8j. Yield: 63%. 1H NMR (300 MHz, CD3OD) d 9.14 (s, 4H), 9.04 (d, J
6.0 Hz, 4H), 8.45 (d, J 8.1 Hz, 4H), 8.05 (dd, J1 6.0 Hz, J2 8.1 Hz, 4H), 7.39 (s,
2H), 4.90 (t, J 6.9 Hz, 8H), 3.61 (t, J 6.0 Hz, 8H), 2.96 (t, J 7.8 Hz, 8H), 2.75 (t,
J
6.6 Hz, 8H), 2.36–2.45 (m, 8H), 1.88–1.97 (m, 8H) ppm. ESI-MS: m/z.
1125.1, 1127.1, 1128.1. [MꢀBr]1+ (Calcd for [C58H70Br3N4O4+]: 1125.29,
1126.30, 1127.29, 1128.29.) m/z 522.1, 523.1, 523.6 (Calcd for
[C58H70Br2N4O42+]: 522.19, 523.18, 523.69.) m/z 321.8, 322.1, 322.4 (Calcd