Controlling multivalency and multimodality: Up to pentamodal dendritic platforms based on diethylenetriaminepentaacetic acid cores

Article abstract of DOI:10.1021/ol500022n

A highly versatile synthetic strategy is described to generate multimodal and multivalent platforms based on a diethylenetriaminepentaacetic (DTPA) core. Compounds with different functionalization patterns, from mono- to pentamodal, have been prepared using robust and simple chemistry.

Full text of DOI:10.1021/ol500022n

Letter
pubs.acs.org/OrgLett
Controlling Multivalency and Multimodality: Up to Pentamodal
Dendritic Platforms Based on Diethylenetriaminepentaacetic Acid
Cores
Daniel Pulido,†,‡ Fernando Albericio,*,‡,§,∥ and Miriam Royo*,†,‡
†Combinatorial Chemistry Unit, Barcelona Science Park, 08028 Barcelona, Spain
‡CIBER-BBN, 08028 Barcelona, Spain
§Institute for Research in Biomedicine, 08028 Barcelona, Spain
∥Organic Chemistry Department, University of Barcelona, 08028 Barcelona, Spain
S
* Supporting Information
ABSTRACT: A highly versatile synthetic strategy is described
to generate multimodal and multivalent platforms based on a
diethylenetriaminepentaacetic (DTPA) core. Compounds with
different functionalization patterns, from mono- to pentam-
odal, have been prepared using robust and simple chemistry.
tate-of-the-art techniques used in chemistry, biology, and
transversal disciplines such as nanotechnologies have
easily desymmetrized;8c,f (3) linkage of two distinct dendritic
wedges to generate Janus dendrimers, mainly taking advantage
of the emergence of chemoselective ligations;8d,e and (4)
convergent synthesis based on the control of the reactivity of a
particular core unit.8a,9c,10a,b Most of these approaches focus on
the introduction of diversity at late stages of the synthesis. In
contrast, our method is more oriented to control the
differentiation from the very beginning, at the core level.
Diethylenetriaminepentaacetic acid (DTPA) is a molecule used
traditionally as a chelating agent.11 It contains five carboxylic
acids and can serve as a source of multivalency and, with proper
modification, also of multimodality. Here we describe the
synthesis of these versatile compounds derived from DTPA and
their use for the preparation of monodisperse oligoethylene
glycol first-generation dendritic platforms, as representative
models of the multimodal and multivalent platforms that can be
generated with this strategy. Several functionalities varying from
1 to 5 can be incorporated in different ratios, giving rise to up
to pentamodal structures (Figure 1). These products can be
considered not only as scaffolds to display diverse function-
alities in a single molecule but also as pieces to create higher
generation dendrimers12 and can also be used to introduce
controlled biofunctionality in other molecular systems (e.g.,
hydrogels, biomaterial surfaces, proteins, antibodies, nano-
particles).
S
contributed to the advancement of biomedical research,
yielding the development of innovative strategies for therapy,1
diagnostics,2 or a combination of the two, namely, theranos-
tics.3 To make further progress, new methodologies to facilitate
combination therapies,4 improved systems to deliver drugs at a
precise tissue or organ, and better imaging agents,5 as well as
new multifunctional molecules designed to study complicated
biological processes, are required. In this regard, the generation
of new well-defined multimodal molecules that allow the
incorporation of functionalities such as drugs, imaging agents,
targeting molecules, or a combination of the same, onto a single
scaffold, in a precise and controlled manner is particularly
relevant. From a chemical point of view, these types of
platforms are considered a synthetic challenge or, as mentioned
elsewhere, a synthetic “tour-de-force”.6
Our laboratory has spent recent years working on the
preparation of dendritic-type structures based on oligoethylene
glycol (OEG) moieties. Dendrimers have become attractive
scaffolds in nanomedicine;7 however, their usefulness in future
biomedical applications demands well-defined monodisperse
compounds whose surfaces can be modified with different
molecules in controlled ratios, thus avoiding statistical
modifications that would give rise to undesired polydisperse
materials.6 To date, few examples of these new generation
dendritic structures have been described, these mainly with two
differentiated functionalities,8 some with three,9 and very few
with more than three.10 Their syntheses rely on several
strategies: (1) appropriate combination of diverse functional
groups;8b,9a (2) incorporation of predifferentiated bifunctional
molecules (e.g., amino acids)9b,d or building blocks that are
Three DTPA derivatives, 8, 9, and 10 (Scheme 1), were
prepared as cores, covering all possibilities in terms of
multimodality (Figure 1). Compound 8 (DTPA bisanhydride)
Received: January 3, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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(reduced to amine with phosphines or to be used directly in
click chemistry17). The corresponding protected OEGs were
prepared from commercially available Boc-OEG (1-(tert-
butoxycarbonyl-amino)-4,7,10-trioxa-13-tridecanamine).
One of the strong points of the synthesis lies in the
robustness of the chemical reactions used, which consist mainly
of the removal of protecting groups and the formation of amide
bonds, either by acylation using the phosphonium salt PyBOP
as the coupling reagent18,19 or by preparing cyclic anhydrides to
activate the corresponding carboxylic acids (Scheme 2). We
achieved clean reaction crude products and were able to isolate
the desired compounds using simple workup procedures based
on aqueous (basic and/or acidic) extractions and precipitation
protocols, thereby avoiding more tedious chromatographic
purifications.
The simplest compound containing five equivalent positions
was prepared by the coupling of five branches of Boc-OEG to
core 8 using PyBOP as activating agent. Compound 1 was
obtained with 96% yield. The differentiation of two positions
was designed with two distinct ratios, the 3−2 (2) and the 4−1
(3). In the former, DTPA bisanhydride (8) was reacted with
Cbz-OEG to incorporate two OEG chains (23). Afterward, the
remaining three carboxylic acids were acylated with Boc-OEG
using PyBOP as activating agent to afford 2 with an overall
yield of 74% (2 steps). The preparation of the 4−1 version (3)
was achieved by incorporation of a Boc-OEG moiety to each of
the four carboxylic acids of 9, mediated by the action of
PyBOP. The benzyl group of 24 was then removed by catalytic
hydrogenation, and the resulting carboxylic acid was derivatized
to the amide with Cbz-OEG and PyBOP, furnishing compound
3 with 70% yield (3 steps). Once the simplest platforms had
been prepared, the use of protecting groups, selective
elimination, and amide formation was not enough to gain
additional differentiation capacity. It was then necessary to
distinguish between free carboxylic acids once they were
deprotected. This was accomplished taking advantage of the
favored formation of six-membered ring cyclic anhydrides
between pairs of carboxylic acids in a DTPA-like molecule.
These cyclic anhydrides were easily desymmetrized by reaction
with only 1 equiv of amino-OEG to form the amide, rendering
a free carboxylic acid that could be acylated in a further step
using an orthogonally protected amino-OEG and PyBOP.
Combining the use of protecting groups, cyclic anhydride
formation, and subsequent desymmetrization, scaffolds 9 and
10 were precursors of two platforms with three differentiated
positions, 2−2−1 (4) and 3−1−1 (5), respectively. In the first
case, core 9 was treated with Ac2O in pyridine at 65 °C, and the
corresponding bisanhydride was formed. This derivative reacted
Figure 1. Multivalent and multimodal dendritic platforms 1−7 based
on DTPA core and OEG branches.
was obtained easily in a single-step synthesis starting from
commercial DTPA by reaction with a mixture of Ac2O and
pyridine at 65 °C.13,14 Compound 9 was prepared following a
four-step synthesis, previously described by our group.12 Briefly,
ethanolamine was dialkylated with tert-butyl bromoacetate, then
the hydroxyl group was replaced by bromine, and this bromo
derivative 11 was used to dialkylate glycine benzyl ester. tert-
Butyl ester groups of 13 were removed by treatment with acid
(HCl). The overall yield of the synthesis was 46%. Finally,
trimodal scaffold 10 was prepared as follows: N-benzylglycine
(14) was converted to the corresponding methyl ester by
treatment with methanol under acidic catalysis. The resulting
hydrochloride salt 15 was alkylated with 1 equiv of bromo
derivative 11 under mild basic conditions to afford 16. After
removal of the benzyl group by Pd/C-catalyzed hydrogenolysis,
compound 1715 was alkylated with bromo derivative 12. This
four-step synthesis was performed in low-gram scale (1−2 g)
with an overall yield of 26%. Using these three core
compounds, we successfully prepared 1−7 (Figure 1). Here
we used short and monodisperse diamino oligoethylene glycol
(OEG) branches to prepare the dendritic compounds. Diversity
was achieved using a different set of compatible protecting
groups to mask one amino function of the OEG moieties: Boc
(removed by treatment with acid); Cbz (removed by
hydrogenation); trifluoroacetylamide (removed by basic treat-
ment); PhAc16 (removed by penicillin G acylase); and N3
Scheme 1. Synthesis of Cores 8, 9, and 10
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Scheme 2. Synthesis of Dendritic Platforms 1−7
with Boc-OEG, and two chains were incorporated to form 26.
The free carboxylic acids were then transformed into the
corresponding amides performing the coupling reaction with
Cbz-OEG to obtain 27. Finally, benzyl ester was removed by
treatment with NaOH in CH2Cl2/MeOH,20 and the derivative
TFA-OEG was used to form the amide bond with the resulting
carboxylic acid, affording 4 with an overall yield of 42% (5
steps). For the 3−1−1 version (5), the starting point was the
core 10. tert-Butyl groups were removed by treatment with acid
(HCl), and the two carboxylic acids were desymmetrized, first
by formation of the cyclic anhydride and subsequent opening
by Boc-OEG (30), followed by acylation with PhAc-OEG (36).
Benzyl and methyl esters were removed by basic treatment with
NaOH in CH2Cl2/MeOH, and the TFA-OEG branches were
introduced in the three carboxylic acids formed. This route
rendered compound 5 with 44% yield (6 steps). Core 10 was
also used to prepare the tetramodal platform 2−1−1−1 (6). As
in the previous example, tert-butyl groups were removed;
however, in this case, both carboxylic acids were derivatized to
amides with Boc-OEG to obtain 31. Benzyl esters were
removed by catalytic hydrogenation, and the desymmetrization
via cyclic anhydride was performed using Cbz-OEG first (33)
and N3-OEG later to obtain compound 34. Finally, methyl
ester was removed by basic treatment with NaOH in CH2Cl2/
MeOH, and the carboxylic acid was acylated with TFA-OEG to
complete the synthesis of 6 with a 28% overall yield (8 steps).
Finally, the highest degree of multimodality was reached in the
platform 1−1−1−1−1 (7). After conversion of trimodal core
10 into 36, benzyl esters were removed by catalytic
hydrogenation. A second desymmetrization via cyclic anhydride
was achieved using Cbz-OEG in the first step (39) followed by
N3-OEG coupling (40). Finally, methyl ester was removed with
NaOH in CH2Cl2/MeOH, and TFA-OEG was incorporated,
furnishing the pentamodal platform 7 (27% yield, 10 steps).
In this set of multimodal platforms, amines or masked
amines were selected as functional groups. Nonetheless, other
functional groups, such as carboxylic acids, alcohols, or thiols,
among others, can also be introduced easily into these synthetic
protocols. The platforms described comprised OEG chains;
however, it is important to highlight that the versatility of the
cores and the synthetic procedures shown here go beyond the
scope of short OEGs. Thus, many other “puzzle pieces” of
distinct natures could be used to build these multimodal
platforms, depending on the final applications. Several examples
containing peptides, different length OEGs, fluorophores, or
aliphatic chains are described in Supporting Information
(compounds 42 (3−2 platform), 43 (2−2−1 platform), and
44 and 45 (4−1 platforms)).
In conclusion, here we prepared a new class of multimodal
platforms based on a DTPA core. These platforms were
functionalizable “a la carte”, ranging from mono- to pentamodal
patterns. The compounds were obtained using robust and
scalable synthetic protocols in combination with a set of
compatible protecting groups, and avoiding tedious purification
steps. With this methodology complicated chemical structures
become accessible by using simple chemical reactions.
ASSOCIATED CONTENT
* Supporting Information
■
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Experimental procedures; spectroscopic and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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(15) See Supporting Information for an alternative synthesis of 17.
(16) Gongora-Benítez, M.; Basso, A.; Bruckdorfer, T.; Royo, M.;
́
Tulla-Puche, J.; Albericio, F. Chem.Eur. J. 2012, 18, 16166.
(17) (a) Franc, G.; Kakkar, A. Chem. Commun. 2008, 42, 5267.
(b) Fransen, P.; Pulido, D.; Royo, M.; Albericio F. Submitted for
publication.
(18) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
(19) More common reagents, such as carbodiimides, were less
effective in coupling reactions, and a stronger activating agent was
needed.
(20) Theodorou, V.; Skobridis, K.; Tzakos, A. G.; Ragoussis, V.
Tetrahedron Lett. 2007, 48, 8230.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: albericio@irbbarcelona.org.
*E-mail: mroyo@pcb.ub.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was funded by the Spanish government (SAF2011-
30508-C02-01 (MR), CTQ2012-30930 (FA)), CIBER-BBN
(CB06_01_0074 (FA)) and the Generalitat de Catalunya
(2009SGR1024).
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