Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: Elucidation of discrete molecular targets with therapeutic potential

Article abstract of DOI:10.1021/np800339e

The first total synthesis of dispyrin, a recently reported bromopyrrole alkaloid from Agelas dispar with an unprecedented bromopyrrole tyramine motif, was achieved in three steps on a gram scale (68.4% overall). No biological activity was reported for dispyrin, so we evaluated synthetic dispyrin against >200 discrete molecular targets in radioligand binding and functional assays. Unlike most marine natural products, dispyrin (1) possesses no antibacterial or anticancer activity, but was found to be a potent ligand and antagonist of several therapeutically relevant GPCRs, the α_1D and α_2A adrenergic receptors and the H2 and H3 histamine receptors.

Full text of DOI:10.1021/np800339e

J. Nat. Prod. 2008, 71, 1783–1786
1783
Total Synthesis and Biological Evaluation of the Marine Bromopyrrole Alkaloid Dispyrin:
Elucidation of Discrete Molecular Targets with Therapeutic Potential
J. Phillip Kennedy, John T. Brogan, and Craig W. Lindsley*
Department of Chemistry, Department of Pharmacology, Vanderbilt Program in Drug DiscoVery, Vanderbilt Institute of Chemical Biology,
Vanderbilt UniVersity, Vanderbilt Medical Center, NashVille, Tennessee 37232-6600
ReceiVed June 9, 2008
The first total synthesis of dispyrin, a recently reported bromopyrrole alkaloid from Agelas dispar with an unprecedented
bromopyrrole tyramine motif, was achieved in three steps on a gram scale (68.4% overall). No biological activity was
reported for dispyrin, so we evaluated synthetic dispyrin against >200 discrete molecular targets in radioligand binding
and functional assays. Unlike most marine natural products, dispyrin (1) possesses no antibacterial or anticancer activity,
but was found to be a potent ligand and antagonist of several therapeutically relevant GPCRs, the R1D and R2A adrenergic
receptors and the H2 and H3 histamine receptors.
Sponges of the genus Agelas, found throughout the world’s
tropical reefs, have provided a wealth of bromopyrrole carboxamide-
containing alkaloids derived biosynthetically from oroidin. Ex-
amples include the tetracyclic alkaloid (-)-dibromophakelin and
the tetrasubstituted cylobutane marine alkaloid (-)-sceptrin.1
Recently, Crews and co-workers reported on the discovery of a
new bromopyrrole alkaloid, dispyrin (1), from the Carribean sponge
Agelas dispar (Figure 1).2 Unlike many laboratories that rely on
Figure 1. Structure of the dispyrin (1), a bromopyrolle alkaloid
from Agelas dispar.
biofractionation, triaging natural product extracts or sponge/soil
samples for antibacterial or anticancer activities, the Crews effort
was focused on discovering compounds with novel molecular
architectures.2,3 Dispyrin (1) is unique in that it contains a novel
bromopyrrole tyramine motif that has no precedent in marine natural
products research. Moreover, unlike all bromopyrrole carboxamide
alkaloids discovered from Agelas thus far, dispyrin is not biosyn-
thetically derived from oroidin, but rather has an independent
biosynthetic pathway.2 Crews and co-workers did not ascribe any
biological activity for dispyrin 1; therefore, our laboratory initiated
a program to synthesize dispyrin 1 and elucidate the molecular
target(s) of this unique bromopyrrole carboxamide alkaloid.
As outlined in Scheme 1, our retrosynthetic analysis of dispyrin
(1) envisaged an amide coupling between 4-bromo-2-carboxypyrrole
(2) and 3-bromo-4-hydroxyphenethylamine (3), followed by an
alkylation or Mitsunobu reaction with N,N-dimethyl-3-chloropro-
pylamine or N,N-dimethyl-3-hydroxypropylamine (4), respectively.
This expedited route should allow for the synthesis of gram
quantities of dispyrin (1) to facilitate biological evaluation as well
as an opportunity to readily prepare libraries of unnatural ana-
logues.4
As shown in Scheme 2, our synthesis began with commercially
available acid 2, which was coupled to 3-bromo-4-methoxyphen-
ethylamine (5) to provide 6 in 93% yield. Subsequent deprotection
of the methyl ether with BBr3 afforded 7 (92% yield). Multiple
alkylation protocols were attempted, as well as Mitsunobu protocols,
but all failed to deliver dispyrin in reasonable yields. Ultimately,
phenol 7 was successfully alklyated with N,N-dimethyl-3-chloro-
propylamine (4), under a microwave-assisted protocol (160 °C, 20
min), to deliver dispyrin (1) in 80% isolated yield. Thus, the first
total synthesis of dispyrin (1) was completed on a 1 g scale in three
synthetic steps (overall yield of 68.4%).5 In the original disclosure
by Crews et al., spectroscopic data were reported for what was
depicted as the free base of dispyrin (1). The spectroscopic data
(1H, 13C NMR and MS) we obtained for synthetic 1 were not in
Scheme 1. Retrosynthetic Analysis of Dispyrin (1)
complete accordance with those reported for dispyrin (1) by Crews
and co-workers.2,5
We rationalized that the discrepancies observed could arise if
the spectroscopic data reported for 1 were of the corresponding
protonated salt form of the distal dimethylamino moiety. To evaluate
this possibility, we synthesized the corresponding HCl salt of our
synthetic dispyrin (1). As shown in Scheme 3, dispyrin (1) was
dissolved in MeOH, and HCl gas was bubbled through the solution
for 10 min. The reaction solution was concentrated and washed
with dry Et2O. The resulting white solid, the HCl salt of dispyrin
(8), provided spectroscopic data (1H, 13C NMR and MS) in complete
accordance with those reported for dispyrin (1) by Crews and co-
workers; thus, the original report of natural dispyrin (1) character-
ized a protonated salt form, such as 8, and not the free-base 1.2,5
With a large quantity of dispyrin (1) in hand, we embarked
on the daunting task of identifying potential molecular target(s)
for dispyrin (1). With thousands of discrete molecular targets
known, it was a challenge to develop a plan to evaluate dispyrin
(1) against all potential biological targets; moreover, unlike
traditional natural products research, we did not want to focus
* To whom correspondence should be addressed. Tel: 615-322-8700.
Fax: 615-343-6532. E-mail: craig.lindsley@vanderbilt.edu.
10.1021/np800339e CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/19/2008

1784 Journal of Natural Products, 2008, Vol. 71, No. 10
Scheme 2. Total Synthesis of Dispyrin (1)
Notes
Scheme 3. Synthesis of the HCl Salt of Dispyrin (8)
solely on antibacterial and anticancer activity. After careful
consideration, we pursued multiple screening avenues. In the
pharmaceutical industry, medicinal chemists evaluate late stage
preclinical candidates against large panels of discrete molecular
targets in an attempt to identify ancillary pharmacology and
potential problems. In a paradigm change, we took advantage
of this approach, but employed the power of these large panels
of G protein-coupled receptors (GPCRs), ion channels, transport-
ers, and kinases to potentially elucidate a molecular target(s)
for dispyrin (1). Utilizing panels of radioligand binding assays
from several companies, dispyrin (1) was evaluated against >200
discrete molecular targets over the course of two months. The
MDS Pharma Services panel identified multiple activities for
dispyrin 1).6 In the initial screen at a single 10 µM concentration,
dispyrin (1), as we had anticipated based on its amphoteric
properties, was found to provide modest inhibition (50-60% at
10 µM) of calcium (L-type) and potassium (hERG) ion channels,
but none with significant activity after full concentration-response
curves were obtained (no Ki’s or IC50’s < 10 µM).5,6
Importantly, the MDS panel identified four G protein-coupled
receptors (adrenergic R1D, adrenergic R2A, H2, and H3 receptors)
against which 1 showed promising therapeutic potential.7-10 Among
the adrenergic family of GPCRs, the R1D and R2A subtypes are
well-documented targets for hypertension, as they contribute to
smooth muscle contraction and neural baroreflex control of blood
pressure.11,12 A number of H2 receptor antagonists are on the
market for the treatment of peptic ulcer disease, and the H3 receptor
is a well-validated target for a number of CNS pathologies including
depression, schizophrenia, ADHD, dementia, and sleep disorders.13,14
As shown in Table 1, dispyrin (1) displayed significant inhibition
in a single-point screen at 10 µM against these four GPCRs, which
justified obtaining full dose-response curves. Dispyrin (1) showed
mid to high nanomolar binding and inhibition of both the adrenergic
R1D receptor (Ki ) 275 nM, IC50 ) 560 nM) and the R2A receptor
(Ki ) 69 nM, IC50 ) 185 nM), while affording low micromolar
binding and inhibition of both the H2 receptor (Ki ) 1.02 µM,
IC50 ) 1.25 µM) and the Η3 receptor (Ki ) 1.04 µM, IC50 ) 2.35
µM).5,6 Thus, dispyrin (1) represents a new chemotype and a
potential novel lead compound for these therapeutically important
Table 1. Biological Evaluation of Dispyrin (1)
target
% inhibition (10 µM)a
Ki (µM)a
IC50 (µM)a
Adren R1D
Adren R2A
H2
91
97
91
91
0.275
0.069
1.02
0.560
0.185
1.25
H3
1.04
2.35
a All determinations are the average of at least three independent
experiments.7-10
molecular targets, and a rare example of a marine natural product
as a ligand for such GPCRs.
In order to evaluate functional activity, dispyrin (1) was also
placed on the screening deck of the Vanderbilt Screening Center
for GPCRs, Ion Channels and Transporters, a member of the
Molecular Library Screening Center Network, which employs cell-
based functional assays.15 Thus far, 1 has been evaluated against
nine targets in agonist, antagonist, and potentiator mode; however,
dispyrin (1) has yet to be identified as a hit, but it will remain on
the screening deck and will be evaluated in ∼20 assays/year.
In summary, we have completed the first total synthesis of
dispyrin (1) on a 1 g scale and demonstrated that the spectroscopic
data reported for the natural product 1 were that of a protonated
salt form, such as 8, and not the free base (as reported), and that
dispyrin is a potent ligand for therapeutically important GPCRs
(the adrenergic R1D, adrenergic R2A, H2, and H3 receptors).
Although the role of natural products discovery efforts within the
pharmaceutical industry is being significantly reduced, despite
overwhelming success, the biological activity of dispyrin argues
further that natural products are viable leads for therapeutically
relevant targets.
Experimental Section
General Experimental Procedures. All NMR spectra were recorded
on a 400 MHz Bruker AMX NMR spectrometer. H chemical shifts
1
are reported in δ values in ppm downfield from TMS as the internal
standard in DMSO-d6. 13C chemical shifts are reported as δ values in
ppm with the DMSO-d6 carbon peak set to 39.5 ppm. UV absorption
was recorded on a DU 800 spectrophotometer and reported in nm. IR
spectra were recorded on KBr plates using a Thermo IR 100

Notes
Journal of Natural Products, 2008, Vol. 71, No. 10 1785
spectrometer and reported in cm-1. Low-resolution mass spectra were
obtained on an Agilent 1200 LCMS with electrospray ionization. High-
resolution mass spectra were recorded on a Waters QToF-API-US plus
Acquity system with electrospray ionization. Analytical thin-layer
chromatography was performed on 250 µM silica gel 60 F254 plates.
Merck silica gel (60, particle size 0.040-0.063 mm) was used for flash
column chromatography. Analytical HPLC was performed on an Agilent
1200 analytical LCMS with UV detection at 214 and 254 nm along
with ELSD detection. All reactions were carried out under an argon
atmosphere employing standard chemical techniques. Solvents for
extraction, washing, and chromatography were HPLC grade. All
reagents were purchased from Aldrich Chemical Co. at the highest
commercial quality and were used without purification. Microwave-
assisted reactions were conducted using a Biotage Initiator-60. All yields
refer to analytically pure and fully characterized materials (1H NMR,
13C NMR, analytical LCMS, and HRMS).
4-Bromo-N-(3-bromo-4-methoxyphenethyl)-1H-pyrrole-2-car-
boxamide (6). To a stirred solution of acid 1 (1.00 g, 5.3 mmol),
N-hydroxybenoztriazole (HOBt) (1.50 g, 11.0 mmol), and amine 5 (1.21
g, 5.3 mmol) in 9:1 CH2Cl2/DIEA at 25 °C was added diisopropyl-
carbodiimide (DIC) (1.33 g, 10.6 mmol), and the mixture was stirred
overnight. After quenching with 250 mL of H2O, the reaction was added
to a 500 mL separatory funnel and washed with 3 × 200 mL of CH2Cl2.
The organic layers were combined and washed with 500 mL of saturated
aqueous brine solution. The organic layer was dried over MgSO4 and
concentrated in Vacuo to yield the crude coupled product. The crude
material was then subjected to flash chromatography (EtOAc/hexanes,
1:1) to give pure 6 as a white solid (1.98 g, 4.9 mmol, 93% yield): UV
(MeOH) λmax (log ε) 288 (2.06) nm; IR (KBr) νmax 3224, 2941, 1631,
1565, 1521, 1495, 1455, 1429, 1383, 1345, 1325, 1276, 1255, 1130,
1055, 1019, 921, 823, 759, 744, 600 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 8.13 (t, J ) 5.6 Hz, 1H), 7.43 (d, J ) 2.0 Hz, 1H), 7.17 (dd, J
) 1.6, 8.4 Hz, 1H), 7.00 (d, J ) 8.4 Hz, 1H), 6.96 (m, 1H), 6.82 (s,
1H), 3.80 (s, 3H), 3.40 (q, J ) 6.8 Hz, 2H), 2.74 (t, J ) 7.2 Hz, 2H);
13C NMR (100 MHz, DMSO-d6) δ 159.5, 153.7, 133.3, 132.9, 129.1,
126.9, 121.1, 112.5, 111.3, 110.4, 94.9, 56.1, 40.1, 33.8; HRMS (Q-
TOF) m/z 400.9517 (calc for C14H14Br2N2O2, 400.9500).
Hz, 1H), 7.14 (dd, J ) 2.0, 8.4 Hz, 1H), 6.93 (d, J ) 8.4 Hz, 1H),
6.89 (d, J ) 1.2 Hz, 1H), 6.70 (d, J ) 1.6 Hz, 1H), 4.05 (t, J ) 6.0
Hz, 2H), 3.47 (t, J ) 7.6 Hz, 2H), 2.78 (t, J ) 7.2 Hz, 2H), 2.61 (t, J
) 7.6 Hz, 2H), 2.30 (s, 6H), 1.99 (m, 2H); 13C NMR (100 MHz, MeOH-
d4) δ 162.5, 155.2, 134.5, 130.1, 127.6, 122.7, 114.6, 113.1, 112.9,
97.4, 68.2, 57.4, 49.0, 45.4, 42.0, 35.6, 28.0; HRMS (Q-TOF) m/z
472.0243 (calc for C18H23Br2N3O2, 472.0235).
4-Bromo-N-(3-bromo-4-(3-(dimethylamino)propoxy)phenethyl)-
1H-pyrrole-2-carboxamide Hydrochloride, Dispyrin-HCl (8). Dis-
pyrin (1) (400 mg, 845 mmol) was dissolved in MeOH (20 mL). HCl
gas was bubbled through the solution for 10 min. The solvent was
removed in situ and washed with anhydrous ether (3 × 20 mL) to afford
Dispyrin-HCl (8) as a white solid (420 mg, 98%): UV (MeOH) λmax
(log ε) 287 (1.48) nm; IR (KBr) νmax 3232, 2955, 2360, 2341, 1676,
1
1629, 1566, 1496, 1466, 1253, 1202, 1132, 1055, 799, 721 cm-1; H
NMR (400 MHz, MeOH-d4) δ 7.45 (d, J ) 2.0 Hz, 1H), 7.17 (dd, J )
2.0, 8.0 Hz, 1H), 6.97 (d, J ) 8.0 Hz, 1H), 6.90 (d, J ) 1.6 Hz, 1H),
6.72 (d, J ) 1.6 Hz, 1H), 4.15 (t, J ) 5.6 Hz, 2H), 3.48 (t, J ) 7.6 Hz,
2H), 3.39 (t, J ) 7.6 Hz, 2H), 2.96 (s, 6H), 2.80 (t, J ) 7.2 Hz, 2H),
2.25 (m, 2H); 13C NMR (100 MHz, MeOH-d4) δ 162.6, 154.7, 135.3,
134.6, 130.4, 127.6, 122.8, 114.8, 113.3, 112.9, 97.5, 67.5, 57.2, 43.8,
42.0, 35.6, 25.7; HRMS (Q-TOF) m/z 472.0235 (calc for
C18H24Br2N3O2, 472.0234).
Biological Assays. All biological assays were conducted at MDS
Pharma according to published protocols.7-10
Acknowledgment. The authors thank the Vanderbilt Department
of Pharmacology and the Vanderbilt Institute of Chemical Biology
(VICB) for support of this research. J.P.K. thanks the VICB for a
predoctoral fellowship.
Supporting Information Available: General experimental proce-
1
dures, preparation of compounds 1, 6, 7, and 8, along with H NMR,
13C NMR, and high-resolution mass spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
References and Notes
4-Bromo-N-(3-bromo-4-hydroxyphenethyl)-1H-pyrrole-2-car-
boxamide (7). To a stirred solution of coupled material 6 (1.00 g, 2.5
mmol) in anhydrous CH2Cl2 under argon at -78 °C was added BBr3
(10 mL, 10 mmol, 1.0 M solution in CH2Cl2) over 20 min. The solution
was stirred at -78 °C for 30 min and then allowed to warm to 25 °C
for 1.5 h. The reaction was slowly quenched with saturated aqueous
NaHCO3 until slightly basic by pH paper. This solution was added to
a 1 L separatory funnel containing 500 mL of H2O and extracted with
3 × 300 mL of CH2Cl2. The combined organic layers were washed
with 500 mL of saturated aqueous brine solution. The organic layer
was dried over MgSO4 and concentrated in Vacuo to yield the
deprotected product 7 (0.89 g, 2.3 mmol, 92% yield). This material
was used without further purification. UV (MeOH) λmax (log ε) 288
(1.57) nm; IR (KBr) νmax 3409, 1608, 1564, 1508, 1425, 1384, 1327,
921, 600 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 9.98 (br s, 1H) 8.11
(t, J ) 5.2 Hz, 1H), 7.33 (d, J ) 1.6 Hz, 1H), 7.02 (dd, J ) 2.0, 8.4
Hz, 1H), 6.95 (m, 1H), 6.85 (d, J ) 8.0 Hz, 1H), 6.80 (d, J ) 2.0 Hz,
1H), 3.37 (m, 2H), 2.68 (t, J ) 6.8 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 159.5, 152.3, 132.7, 131.6, 128.9, 126.9, 121.0, 116.2,
111.3, 109.0, 94.9, 40.2, 33.9; HRMS (Q-TOF) m/z 386.9359 (calc for
C13H12Br2N2O2, 386.9344).
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4-Bromo-N-(3-bromo-4-(3-(dimethylamino)propoxy)phenethyl)-
1H-pyrrole-2-carboxamide, Dispyrin (1). In a 20 mL microwave vial
containing 4 (1.0 g, 2.6 mmol), amine 7 (0.49 g, 3.1 mmol), KI (1.29
g, 7.8 mmol), and Cs2CO3 (2.54 g, 7.8 mmol) was added anhydrous
DMF (15 mL). This was heated under microwave conditions at 160
°C for 20 min. The reaction was filtered, concentrated in Vacuo, and
purified via reversed-phase HPLC to obtain pure dispyrin as the TFA
salt. This material was dissolved in a minimal amount of MeOH and
added to a 60 mL SCX solid-phase extraction column, which was
washed with 2 column volumes of MeOH. The material was removed
from the column by eluting with 2 column volumes of 2 M NH3 in
MeOH. This was again concentrated in Vacuo to obtain pure dispyrin
(1) as the free base (0.98 g, 2.1 mmol, 80% yield): UV (MeOH) λmax
(log ε) 293 (2.40) nm; IR (KBr) νmax 3223, 2948, 2864, 2825, 2780,
2360, 2340, 1629, 1565, 1523, 1495, 1467, 1386, 1325, 1279, 1253,
1
1054, 668 cm-1; H NMR (400 MHz, MeOH-d4) δ 7.42 (d, J ) 2.0

1786 Journal of Natural Products, 2008, Vol. 71, No. 10
Notes
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NP800339E