Solid -P h a se Syn th esis of Rigid
Acylp olya m in es Usin g Tem p or a r y
N-4,4′-Dim eth oxytr ityl P r otection in th e
P r esen ce of Tr ityl Lin k er s
Christian A. Olsen,† Matthias Witt,‡
J erzy W. J aroszewski,† and Henrik Franzyk*,†
Department of Medicinal Chemistry, The Danish University
of Pharmaceutical Sciences, Universitetsparken 2,
DK-2100 Copenhagen, Denmark, and Bruker Daltonik
GmbH, Fahrenheitstrasse 4, D-28359 Bremen, Germany
hf@dfuni.dk
Received April 29, 2004
Abstr a ct: An N-protection protocol employing the 4,4′-
dimethoxytrityl (Dmt) group in combination with borane
reduction of resin-bound polyamides was shown to be an
efficient methodology that enables synthesis of novel ana-
logues of natural acylpolyamine toxins. Thus, three philan-
thotoxins containing polyamine chains with piperidyl and
cyclohexyl structural elements, which introduce conforma-
tional rigidity, increased lipophilicity, and altered proteolytic
properties, were obtained in 39-44% overall yield.
F IGURE 1. Structures of philanthotoxins1-4.
phase synthesis6,7 (SPS) of acylpolyamine toxins has
attracted considerable interest, and several structure-
activity relationship (SAR) studies have been performed
with philanthotoxins on various receptor types.6,7
Simple natural polyamines, such as spermidine and
spermine, are ubiquitous in eukaryotic cells, and they
play important roles in cellular physiology.1 Polyamine
derivatives have been the subject of extensive investiga-
tions due to their ability to interact with ion channels in
the central and in the peripheral nervous system.2-4
Among the naturally occurring polyamine derivatives,
acylpolyamine toxins comprise a class of compounds that
antagonize various types of ionotropic receptors, e.g.,
nicotinic acetylcholine receptors (nAChR) and ionotropic
glutamate receptors (iGluR).5-7 An example of a natural
neuroactive acylpolyamine is philanthotoxin-433 (PhTX-
433, 1, Figure 1) from the venom of the female Egyptian
digger wasp Philanthus triangulum.8,9 Due to the thera-
peutic potential of such polyamine-containing com-
pounds,10-12 solution-phase synthesis13,14 as well as solid-
In particular, the development of sequential SPS
methodologies has facilitated the synthesis of polyamine
moieties, whereas the attachment of amino acid or acyl
residues is readily achieved by conventional solid-phase
peptide synthesis (SPPS) procedures. The synthetic
strategies previously used for SPS of polyamines may be
classified into three major groups: (i) N-alkylation
reactions,15-18 (ii) Mitsunobu reactions,19-21 and (iii)
reductive methods based on intermediary imines22,23 or
amides.24
In the present paper, we report on the development of
a novel N-protection strategy, which in combination with
* To whom correspondence should be addressed. Phone: +45-
35306255. Fax: +45-35306040.
(11) Blagbrough, I. S.; Carrington, S.; Geall, A. J . Pharm. Sci. 1997,
3, 223-233.
† The Danish University of Pharmaceutical Sciences.
‡ Bruker Daltonik GmbH.
(12) Casero, R. A.; Woster, P. M. J . Med. Chem. 2001, 44, 1-26.
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(16) Manov, N.; Tzouros, M.; Chesnov, S.; Bigler, L.; Bienz, S. Helv.
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10.1021/jo049278q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/12/2004
J . Org. Chem. 2004, 69, 6149-6152
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