The 1,2,3-triazole ring as a peptido- and olefinomimetic element: Discovery of click yanilloids and cannabinoids

Article abstract of DOI:10.1002/anie.200703590

(Chemical Equation Presented) Fooling nature: The replacement of amide and alkene groups in a biological setting with the 1,2,3-triazole group led to the discovery of compounds with a unique vanilloid/cannabinoid mixed profile. For example, the natural amides (see picture, above) and their triazole mimics (below) exhibit similar agonistic (X = H) or antagonistic (X = I) activity towards the TRPV1 receptor; however, only the triazole derivatives also show cannabinomimetic activity.

Full text of DOI:10.1002/anie.200703590

Communications
DOI: 10.1002/anie.200703590
Drug Design
The 1,2,3-Triazole Ring as a Peptido- and Olefinomimetic Element:
Discovery of Click Vanilloids and Cannabinoids**
Giovanni Appendino,* Sara Bacchiega, Alberto Minassi, Maria Grazia Cascio,
Luciano De Petrocellis, and Vincenzo Di Marzo*
Over the past few years, the 1,3-dipolar cycloaddition of
azides and alkynes has emerged as an important “stitching”
maneuver to connect structural units through a readily
introduced permanent link endowed with unparalleled chem-
ical and biological stability.[1] Although apparently metabol-
ically inert, the 1,2,3-triazole ring could, in principle, be
biologically visible, as it features a combination of H-bond
donor and acceptor sites capable of mimicking the hydrogen-
bonding acidity and basicity of a peptide bond.[2] As the 1,2,3-
triazole ring is not susceptible to hydrolytic cleavage or redox
modification,[1] potential advantages of this system over other
types of peptidomimetics exist, and preliminary evidence to
justify the systematic scrutiny of this issue has been reported.
Thus, X-ray crystallographic analysis of the HIV protease
bound to the amide inhibitor amprenavir and of the same
protease bound to two 1,2,3-triazole analogues showed
excellent overlap of the binding mode of the amide moiety
with that of the 1,4-substituted triazole ring.[3] Similarly, the
immunostimulating activity of aGal-Cer, an analogue of the
marine natural product a-galactosylceramide, was relatively
insensitive to the replacement of the amide moiety with a
triazole unit.[4] These observations with respect to the triazole
analogues of amprenavir and aGal-Cer suggest that the
amide bond and the 1,2,3-triazole ring are potentially
bioequivalent. However, the significance of these findings is
somewhat undermined by the paucity of information avail-
able on the relevance of the amide bond for the bioactivity of
both leads, and/or by the additional modifications carried out
on their structure. Furthermore, the multiple recognition
domains of structurally complex molecules such as amprena-
vir and aGal-Cer could “dilute” the effect of the isosteric
modification in terms of binding to a macromolecular target.
Finally, no information has been reported on the ability of the
amide-to-triazole isosteric exchange to sustain reversal of
activity or modulation of target selectivity, while the effect of
the triazole substitution pattern on its amidomimetic proper-
ties has not yet been investigated.
To clarify these points, we investigated the effect of
amide-to-triazole point mutations in structurally unsophisti-
cated compounds whose peptide bond is critical for activity.
Although there is no shortage of candidates to address this
issue, few can rival capsaicinoids in terms of the simplicity of
the pharmacophore (a vanillyl group linked to an aliphatic
chain by an amide bond) and the pleiotropy of the target.[5]
Indeed, the relevance of the amide bond for the pungency of
capsaicin (1a) is one of the oldest observations in the realm of
structure–activity relationships. Only the thiourea group has
been identified in modern studies as an equipotent bioiso-
steric replacement.[6] Furthermore, the discovery that certain
fatty-acid-derived capsaicinoids can interact not only with the
vanilloid receptor (TRPV1)[7] but also with proteins of the
endocannabinoid system (mainly CB2 and FAAH)[8] has
expanded the range of known biomolecules capable of
recognizing the key amide linker of these compounds. As
the amide linker is a major site of metabolic lability of the
capsaicinoids,[9] its replacement with hydrolytically stable
groups could both alter its activity towards macromolecules
that recognize capsaicinoids and dramatically improve their
pharmacokinetic profile.
[*] Prof. G. Appendino, Dr. S. Bacchiega, Dr. A. Minassi
Dipartimento di Scienze Chimiche, Alimentari
Farmaceutiche e Farmacologiche
Università del Piemonte Orientale
Via Bovio 6, 28100 Novara (Italy)
E-mail: appendino@pharm.unipmn.it
Dr. M. G. Cascio, Prof. V. Di Marzo
Endocannabinoid Research Group
Institute of Biomolecular Chemistry, CNR
Via Campi Flegrei 34, 80078 Pozzuoli (NA) (Italy)
E-mail: vdimarzo@icmb.na.cnr.it
Dr. L. De Petrocellis
Therefore, the vanilloid and cannabinoid profiles of the
TRPV1 agonist nonivamide (synthetic capsaicin, 1b)[10] and
the TRPV1 antagonist 6’-iodononivamide (1c)[11] were com-
pared with those of the corresponding 1,4- and 1,5-triazole
analogues 4a,b and 5a,b. These compounds were prepared by
combining a pivaloyl-protected vanillazide (3a or 3b) with
Endocannabinoid Research Group
Institute of Cybernetics “Eduardo Caianiello”, CNR
Via Campi Flegrei 34, 80078 Pozzuoli (NA) (Italy)
[**] We are grateful to MURST for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 1: Vanilloid and cannabinoid activity of capsaicin (1a), capsaici-
noids 1b–1d, and their triazole analogues 4a,b, 5a,b, 8, and 9.
commercial 1-decyne by click chemistry under regiocomple-
mentary copper(I) or ruthenium(II) catalysis[12] followed by
deprotection with a base (Scheme 1).[13] Surprisingly, a
complete lack of regioselectivity was observed in the ruth-
Cmpd.
hTRPV1
hTRPV1
hCB1
hCB2
EC50 ÆSE [nm]
IC50 ÆSE [mm][a]
Ki [mm]
Ki [mm]
1a
1b
1c
1d
4a
4b
5a
5b
8
30.2Æ3.9
63.1Æ4.2
>10000
0.7Æ0.3
170Æ38
>10000
661Æ167
>10000
67.6Æ9.0
42.7Æ5.7
>5.6
>5.6
>5.6
>5.6
4.0
0.44
>5.6
5.6
>7.9
>7.9
>7.9
>7.9
7.9
7.9
7.9
7.9
>7.9
>7.9
0.01Æ0.002
0.69Æ0.16
3.7Æ0.5
5.6
5.6
9
[a] Only compounds inactive as TRPV1 agonists (EC50 >10000 nm) were
tested as TRPV1 antagonists. SE=standard error.
an amide bond is functional and translated into a biological
event.
The relevance of the 1,2,3-triazole ring as a pharmaco-
phore was further substantiated by the results obtained when
the triazole adducts were assayed against the cannabinoid
receptors CB1 and CB2. Although capsaicin (1a), nonivamide
(1b), and 6’-iodononivamide (1c) show no cannabinomimetic
activity, the two 1,4-adducts, 4a,b, showed CB1-selective
cannabinoid affinity (Table 1), whereas the corresponding
1,5-adducts, 5a,b, were essentially inactive. Cannabinoid
affinity is not unprecedented for capsaicinoids, but is essen-
tially limited to affinity for CB2.[8a,b] A significant (submicro-
molar) affinity for CB1, the psychotropic cannabinoid recep-
tor, is unprecedented for TRPV1 ligands.[14] Compound 4b
was tested in a functional assay for activity towards the CB1
receptor, namely, for its effect on the forskolin-induced
formation of cAMP in intact mouse N18TG2 neuroblastoma
cells that selectively express CB1 receptors. It was inactive at a
low concentration of 0.1 mm and acted as an inverse agonist at
1 and 10 mm; that is, it elevated forskolin-induced cAMP
formation by 113.2 Æ 5.2 and 138.0 Æ 8.1% (5.2 and 8.1 are the
standard deviation (SD), n = 3), respectively, when forskolin
was present at a concentration of 1 mm. When assayed at 1 mm,
compound 4b also antagonized the effect of the CB1/CB2
agonist WIN 55,212-2 by attenuating the reduction of cAMP
levels that is induced by WIN 55,212-2 (0.1 mm) from 25.3 Æ
3.2 to 1.1 Æ 1.0% (that is, Æ SD, n = 3). In view of its dual and
unique TRPV1/CB1 antagonism, 4b can be used as a new
template for drug development.[15]
As a flat bivalent element, a triazole ring can also mimic
the conformational constraint imposed on alkyl chains by a
double bond.[16] Capsaicinoids offer opportunities to inves-
tigate the olefin bioisostery of the 1,2,3-triazole ring in a
complex biological process: the translocation of biomolecules
through membranes. Indeed, fatty-acid vanillamides provide
some of the most spectacular examples of the biological
relevance of a double bond, as the presence of at least one
unit of unsaturation (in either the cis or the trans config-
uration)[17] is apparently necessary for the translocation of
these highly lipophilic compounds across the cell membrane
and for their interaction with the intracellular vanilloid-
recognition site of TRPV1.[18] Thus, whereas olvanil (1d), the
Scheme 1. Reagents and conditions: a) 1. Et3N, PivCl, THF, 98%; for
3a: 2. NaBH4, EtOH/CH2Cl2 (10:1), 87%; 3. DBU, DPPA, NaN3,
toluene, 65%; for 3b: 2. CF3CO2Ag, I2, CH2Cl2, 93%; 3. NaBH4, EtOH/
CH2Cl2 (10:1), 87%; 4. DBU, DPPA, NaN3, toluene, 65%; b) 1. 1-
decyne, CuI, DIPEA, CH3CN; 2. NH2NH2, toluene, 70% for 4a, 51%
for 4b; c) 1. 1-decyne, [Cp*Ru(PPh3)2Cl], benzene, D; 2. LiOH·H2O,
H2O/THF (2:1), 34% for 5a/4a (1:1), 25% for 5b/4b (1:1) (see the
Supporting Information for their separation). DIPEA=diisopropylethyl-
amine, Piv=2,2-dimethylpropanoyl, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DPPA=diphenylphosphoryl azide, Cp*=pentame-
thylcyclopentadienyl.
enium(II)-catalyzed coupling, but the mixtures of isomeric
vanillyl triazoles (4a/5a) and iodovanillyl triazoles (4b/5b)
could be resolved by preparative HPLC on silica gel, and the
final compounds were purified further by crystallization.[13]
A
remarkable affinity was retained in the agonistic and antag-
onistic activity of these capsaicinoid analogues towards
TRPV1 (Table 1), whereby the anti (1,4) adducts (4a, 4b)
were found to be more potent than the corresponding syn
(1,5) regioisomers (5a, 5b), especially in terms of TRPV1
antagonism. The reversal of activity by aromatic iodination
and the dependence of the activity on the substitution pattern
of the triazole ring suggest that these compounds interact in a
specific way with TRPV1 and show convincingly that the
triazole ring serves as a good mimic of an amide bond.
Furthermore, the recognition of the triazole ring as if it were
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Communications
vanillamide derivative of oleic acid,[17] shows subnanomolar
an isosteric surrogate for a double bond. A certain degree of
caution should therefore be exerted in the use of the triazole
element in bioconjugation experiments.
affinity for hTRPV1, vanilloid activity was not detected for its
saturated analogue at concentrations at least five orders of
magnitude higher.[19] To evaluate the double-bond mimicry of
the triazole ring in this molecular setting, the two isomeric
triazole analogues 8 and 9 of olvanil (1d) were prepared by
combining the w-azidovanillamide 7 with 1-decyne by click
chemistry under complementary CuI or RuII catalysis
(Scheme 2). The vanilloid activity of 8 and 9 was weaker
Received: August 7, 2007
Published online: October 29, 2007
Keywords: cannabinoids · cycloaddition · drug design ·
.
triazoles · vanilloids
[1] For recent reviews, see: a) J. E. Moses, A. D. Moorhouse, Chem.
Soc. Rev. 2007, 36, 1249 – 1262; b) P. Wu, V. V. Fokin, Aldrichi-
mica Acta 2007, 40, 7 – 17; c) M. V. Gil, M. J. ArØvalo, Ó. López,
Synthesis 2007, 1589 – 1620; d) J. F. Lutz, Angew. Chem. 2007,
119, 1036 – 1043; Angew. Chem. Int. Ed. 2007, 46, 1018 – 1025;
e) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51 – 68.
[2] In 1,4-substituted triazoles, the carbon atom at the 4-position and
À
the C H bond can act as an electrophilic site and a hydrogen-
bond donor, respectively, whereas the pyridine-type lone pair of
electrons on the nitrogen atom at the 3-position serves as a
hydrogen-bond-acceptor element. The overall dipolar moment
of the triazole system is larger than that of the amide bond, and
its hydrogen-bond donor and acceptor properties are therefore
more marked that those of an amide bond. The larger dipole
moment may compensate for the increased distance between the
substituents relative to the distance between substituents on a Z
amide bond (3.9 versus 5.0 Š).[1d] Although this geometrical
mismatch does not exist in 1,5-substituted derivatives, the degree
to which they mimic an E amide bond is undermined somewhat
by the poor electrophilicity of the pyrrole-like nitrogen atom
relative to that of a carbonyl carbon atom. For a discussion, see:
H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 24,
1128 – 1137.
Scheme 2. Reagents and conditions: a) 8-azidooctanoic acid, Et3N,
PPAA, 53%; b) 1-decyne, tert-butanol/water, CuSO4·5H2O, sodium
ascorbate, 50%; c) 1-decyne, [Cp*Ru(PPh3)2Cl], benzene, 6%.
PPAA=propanephosphonicacid anhydride.
than that of 1d by approximately two orders of magnitude,
presumably as a result of the greater polarity of the triazole
ring relative to that of a carbon–carbon double bond.[2]
Interestingly, the syn adduct 9 was more potent than the
anti adduct 8. This difference in activity parallels the higher
activity of the cis isomer of olvanil relative to that of its trans
counterpart.[16] Polarity, although an asset for mimicking an
amide functionality, may be detrimental in the case of olefin
isostery in biological processes in which the double bond is
involved directly.[20] Cannabinoid activity was marginal for
both triazole analogues.
In summary, we have identified an interesting new class of
potential pharmacological agents: mixed CB1/TRPV1-antag-
onists. Our results highlight the possibility of developing the
1,2,3-triazole group as a peptidomimetic element capable of
both sustaining and modulating amide-related bioactivity. On
the other hand, this highly polar group can have a detrimental
effect on bioactivity when implanted in a lipophilic moiety as
[3] A. Brik, J. Alexandratos, Y.-C. Lin, J. H. Elder, A. J. Olson, A.
Wlodawer, D. S. Goodsell, C.-H. Wong, ChemBioChem 2005, 6,
1167 – 1169.
[4] T. Lee, M. Cho, S. Y. Ko, H.-J. Youn, D. J. Baek, W.-J. Cho, C.-Y.
Kang, S. Kim, J. Med. Chem. 2007, 50, 585 – 589; for a related
study involving a cellular endpoint (induction of apoptosis), see:
S. Kim, M. Cho, T. Lee, S. Lee, H.-Y. Min, S. Kook, Bioorg. Med.
Chem. Lett. 2007, 17, 4584 – 4587.
[5] For a recent review on the structure–activity relationships of
capsaicinoids, see: G. Appendino in Modern Alkaloids: Struc-
ture, Isolation, Synthesis and Biology (Eds.: E. Fattorusso, O.
Taglialatela-Scafati), Wiley-VCH, Weinheim, 2007, pp. 75 – 112.
[6] C. S. J. Walpole, R. Wrigglesworth, S. Bevan, E. A. Campbell, A.
Dray, I. F. James, K. J. Masdin, M. N. Perkins, J. Winter, J. Med.
Chem. 1993, 36, 2373 – 2380.
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Chemie
[7] M. J. Caterina, M. A. Schumacher, M. Tominaga, F. T. A. Rosen,
J. D. Levine, D. Julius, Nature 1997, 389, 816 – 824.
impurity, iodine-induced reversal of activity was observed, as
expected, for 4b. Taken together, these observations make it
unlikely that transition-metal contaminants have affected the
bioactivity data. For recent examples of the mediation of the
activity of proteins within the endocannabinoid system by
spurious metal impurities, see: S. Vandevoorde, K. O. Jonsson,
G. Labar, E. Persson, D. M. Lambert, C. J. Fowler, Br. J.
Pharmacol. 2007, 150, 186 – 191; J. K. Makara, M. Mor, D.
Fegley, S. I. Szabó, S. Kathuria, G. Astarita, A. Duranti, A.
Tontini, G. Tarzia, S. Rivara, T. T. Freund, D. Piomelli, Nat.
Neurosci. 2007, 10, 134.
[8] a) G. Appendino, L. De Petrocellis, M. Trevisani, A. Minassi, N.
Daddario, A. Schiano Moriello, D. Mazzieri, A. Ligresti, B.
Campi, G. Fontana, C. Pinna, P. Geppetti, V. Di Marzo, J.
Pharmacol. Exp. Ther. 2004, 312, 561 – 570; b) G. Appendino,
M. G. Cascio, S. Bacchiega, A. Schiano Moriello, A. Minassi, A.
Thomas, R. Ross, R. Pertwee, L. De Petrocellis, V. Di Marzo,
FEBS Lett. 2006, 580, 568 – 574.
[9] C. A. Reilly, W. J. Ehlardt, D. A. Jackson, P. Kulanthaivel, A. E.
Mutlib, R. Espina, D. E. Moody, D. J. Crouch, G. S. Yost, Chem.
Res. Toxicol. 2003, 16, 336 – 349.
[10] Nonivamide is actually a minor constituent of the mixture of
capsaicinoids present in hot pepper (H. Constant, G. A. Cordell,
D. P. West, J. H. Johnson, J. Nat. Prod. 1995, 58, 1925 – 1928). Its
biological profile is very similar to that of capsaicin, whose acyl
chain contains unsaturation and branching that are redundant
for its activity.[5]
[14] The most potent capsaicinoid ligand developed so far for the CB1
receptor is the arachidonic acid derivative arvanil, which has a
Ki value of approximately 1–2 mm for CB1: D. Melck, T. Bisogno,
L. De Petrocellis, H. Chuang, D. Julius, M. Bifulco, V. Di Marzo,
Biochem. Biophys. Res. Commun. 1999, 262, 275 – 284.
[15] V. Di Marzo, T. Bisogno, L. De Petrocellis, Chem. Biol. 2007, 14,
741 – 756.
[11] G. Appendino, N. Daddario, A. Minassi, A. Schiano Morello, L.
De Petrocellis, V. Di Marzo, J. Med. Chem. 2005, 48, 4663 – 4669.
[12] L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B.
Sharpless, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127,
15998 – 15999.
[13] TRP channels are sensitive to metal inhibition, and the dye
ruthenium red is a general inhibitor of this type of channel (A.
Szallasi, G. Appendino, J. Med. Chem. 2004, 47, 2717 – 2723). In
previous studies involving metathesis reactions, we observed
that capsaicinoids strongly retain metal impurities.[19] The final
products were therefore purified carefully by crystallization and
preparative HPLC, and examined for inorganic contaminants by
atomic spectroscopy. A copper or ruthenium content of less than
3 ppm was found. Furthermore, 4a showed the same activity
against the three endpoints investigated (TRPV1, CB1, and CB2)
regardless of whether it had been obtained under CuI or RuII
catalysis. Despite the presence of the same potential copper
[16] F. Pagliai, T. Pirali, E. Del Grosso, R. Di Brisco, G. C. Tron, G.
Sorba, A. A. Genazzani, J. Med. Chem. 2006, 49, 467 – 470.
[17] J. M. Janusz, B. L. Buckwalter, P. A. Young, T. R. LaHann, R. W.
Farmer, G. B. Kasting, M. E. Loomans, G. A. Kerkaert, C. S.
Maddin, E. F. Berman, R. L. Bohne, T. L. Cupps, J. R. Milstein,
J. Med. Chem. 1993, 36, 2595 – 2604.
[18] J. Lazar, D. C. Braun, A. Tóth, Y. Wang, L. V. Pearce, V. A.
Pavlyukovets, P. M. Blumberg, S. H. Garfield, S. Wincovitch,
H. K. Choi, J. Lee, Mol. Pharmacol. 2006, 69, 1166 – 1173.
[19] G. Appendino, A. Minassi, A. Schiano Moriello, L. DePetrocel-
lis, V. Di Marzo, J. Med. Chem. 2002, 45, 3739 – 3745.
[20] A similar observation was made for a series of phosphatidylcho-
line-derived bolaamphiphiles, whereby the presence of a 1,4-
triazole moiety in the lipid linker was detrimental to vesicle
formation: E. J. OꢀNeil, K. M. DiVittorio, B. D. Smith, Org. Lett.
2007, 9, 199 – 202.
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