Azido-Adamantyl Tin Sulfide Clusters for Bioconjugation

Article abstract of DOI:10.1021/acs.organomet.8b00734

We present a new versatile route toward biomolecule-functionalized tin sulfide clusters. A novel bifunctional orthogonal spacer was developed and used for the formation of a trifold azido-adamantyl-terminated cluster, serving as a building block for click reactions. The azido cluster was quantitatively bioconjugated via a strain-promoted 1,3-dipolar cycloaddition, affording a peptide-decorated cluster.

Full text of DOI:10.1021/acs.organomet.8b00734

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Azido-Adamantyl Tin Sulfide Clusters for Bioconjugation
Jan-Philipp Berndt,†,‡ Annikka Engel,§ Radim Hrdina,†,‡ Stefanie Dehnen,*,§
and Peter R. Schreiner*,†,‡
†Institute of Organic Chemistry and ‡Laboratory of Materials Research (LaMa), Justus Liebig University, 35392 Giessen, Germany
§Department of Chemistry and Wissenschaftliches Zentrum fu
̈
r Materialwissenschaften (WZMW), Philipps-Universitat Marburg,
̈
Hans-Meerwein-Straße 4, 35037 Marburg, Germany
S
* Supporting Information
ABSTRACT: We present a new versatile route toward biomolecule-
functionalized tin sulfide clusters. A novel bifunctional orthogonal spacer
was developed and used for the formation of a trifold azido-adamantyl-
terminated cluster, serving as a building block for click reactions. The azido
cluster was quantitatively bioconjugated via a strain-promoted 1,3-dipolar
cycloaddition, affording a peptide-decorated cluster.
postfunctionalization with biomolecules, such as peptides,
INTRODUCTION
■
consequently affecting biocompatibility and bioactivity of the
clusters. Cell-penetrating peptides (CPPs) are well-known as
cellular delivery agents and facilitate the transport of a variety
of therapeutic agents,12 polymers,13 and nanoparticles14 into
cells.15 The attachment of such biomolecules may permit the
specific delivery of polar and potentially hydrolyzable tin
chalcogenide moieties into cells, allowing their targeted use as
inhibitors or cytotoxic agents.
The functionalization of keto-terminated tin sulfide clusters
with hydrazides via hydrazone formation is well-known.8a−h
However, there are still challenges to be met for an efficient
functionalization of these clusters, e.g., yields are often low due
to isolation or stability issues and cross-reactivities with amines
are observed. Inspired by previous reports on bioconjugations,
we envisioned a modular approach for the functionalization of
chalcogenide clusters to be an efficient and versatile route to
prepare biomolecule-functionalized clusters.16 These reactions
have to meet certain criteria, such as no cross-reactivity with
any natural functional group (bioorthogonality), fast reaction
rates, and high yields, ideal requirements for the functionaliza-
tion of chalcogenides. Polyoxometalates (POMs) and nano-
particle materials can be assembled via Huisgen 1,3-dipolar
cycloadditions, peptide and related bond formations, and
Sonogashira or Heck cross-coupling reactions.17 However, to
the best of our knowledge, the previously mentioned reactions
have never been applied for the functionalization of tin sulfide
clusters. Such a modular approach requires the design of a
The sensitivity of many organometallic compounds toward air
and moisture makes their application as drugs rather
counterintuitive. Still, there is a variety of metal-based
therapeutic agents for medicinal applications.1 Platinum
complexes are essential in the field of cancer chemotherapy.1e,2
Ferrocene derivatives display a broad range of biomedical
activities as anticonvulsant, antimalarial, antioxidant, and
antitumor agents.3 Gold compounds are used for treatment
of rheumatoid arthritis,4 and organotin compounds show great
potential in anticancer therapy.5 Furthermore, organotin
compounds also possess biocidal properties and are used as
antifouling agents,6 fungicides, acaricides, and antimicrobials.7
The multifaceted applications of metal compounds result from
their vast structural diversity. Coordination modes can vary
from two to ten, thus providing access to a large variety of
structural entities. Moreover, ligand design allows fine-tuning
of properties such as reactivity, solubility, hydrolytic stability,
and in the case of drugs, specificity for target recognition and
absorption.1b
On the basis of our experience in functionalization of tin
chalcogenides,8 we showed that the aggregation level and
hence composition and structures of tin sulfide clusters can be
controlled by introducing highly rigid organic ligands.9 The
embedding of chalcogenide clusters into organic shells
facilitates the property tuning, affects solubility, enhances
stability, and enables further postfunctionalization.8e,10 Re-
cently, we demonstrated the functionalization of tin
chalcogenide clusters with amino acids and oligopeptides.11
The logical extension of this work is the design of ligands
enabling control of the aggregation level as well as
Received: October 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00734
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Scheme 1. Modular Approach toward Biomolecule-Functionalized Tin Sulfide Clusters
a
Scheme 2. Synthesis and Molecular Structure of 2
a
(A) Synthesis of 3-azido-adamantanecarboxylic acid hydrazide 2. (B) Molecular structure of an H-bonded dimer of compound 2. Ellipsoids are
drawn at 50% probability. Nonrelevant hydrogen atoms are omitted for clarity. Ranges of selected bond length [Å]: N1−N2 1.419(3), N6−N7
1.420(3), C1−O1 1.235(3), C12−O2 1.232(3), N3−N4 1.229(4), N4−N5 1.137(4), N8−N9 1.229(3), N9−N10 1.130(4), C1−N1 1.342(3),
C12−N7 1.343(3), O2−H2B 2.1250(16), O1−H6A 2.139(2).
bifunctional spacer such as 2, consisting of a hydrazide for
condensation with keto-terminated cluster 1 and a second
orthogonal functionality for the bioconjugation (Scheme 1).
The development of such a spacer enables the direct
conjunction of tin sulfide clusters with biomolecules without
any additional protection or deprotection step. Azides are
outstanding substituents that provide excellent chemoselectiv-
ity, while possessing intrinsically high reactivity. Structural
moieties can be easily connected via Huisgen 1,3-dipolar
cycloadditions catalyzed with Cu(I) (CuAAC) or Ru(II)
(RuAAC) or strain-promoted with alkynes (SPAAC).18
Moreover, the traceless Staudinger ligation provides the
necessary chemoselectivity for modification and derivatization
by amide bond formation (Scheme 1).19 Adamantane is an
ideal scaffold for this purpose. Its incorporation in peptides or
drugs leads to enhanced lipophilicity, rigidity, and stability.20
Moreover, based on our previous findings, diamondoid-
decorated tin sulfide clusters exhibit enhanced stability toward
moisture and can control the cluster aggregation level
depending on the substitution pattern.9,21
3-azido-adamantanecarboxylic acid hydrazide 2, in 45% overall
yield over seven steps. Slow evaporation of a solution of 3-
azido-adamantanecarboxylic acid hydrazide 2 (R1) in deu-
terated chloroform afforded colorless crystals (Scheme. 2B).
The compound crystallizes in the monoclinic space group P21
(Z = 4). In the unit cell, two molecules are connected via two
hydrogen bonds between the terminal amino group and the
oxygen atom of the carbonyl group. The azide units are nearly
linear, with dihedral angles of 172.754(2) and 173.542(2)°. All
bond lengths are in the expected range.
The synthesis of organo-functionalized tin sulfide cluster 3Cl
was carried out in two steps (Scheme 3A). A condensation
reaction of 3-azido-adamantanecarboxylic acid hydrazide 2
with 4-methyl-4-(trichlorostannyl)-pentane-2-one 10
(R2SnCl3) afforded azido-adamantyl-terminated organotin
trichloride 11 (R3SnCl3) in 98% yield, which was characterized
by NMR spectroscopy (Supporting Information). Structure 11
was characterized by single crystal X-ray analysis after
crystallization from the reaction solution in dichloromethane
at −20 °C for 4 months, affording approximately 5% crystalline
yield. The organotin trichloride 11 crystallizes in the
monoclinic space group P21/c (Z = 4) (Chart 1) with Sn−
Cl bond lengths of 2.3601(12)−2.5484(12) Å, which is slightly
longer compared to the keto-functionalized organotin tri-
chloride parent compound (2.3286(7)−2.3866(8) Å).24 One
chlorine atom engages in two intermolecular hydrogen bonds,
one to nitrogen-bonded H2 (2.4404(12) Å) and one to the
adamantyl hydrogen atom H9B (2.6980(12) Å). This way, the
molecules form an H-bonded chain along the crystallographic c
axis. The tin atom is part of one nearly planar five-membered
N−N···Sn···O−C ring, together with the nitrogen and oxygen
atoms that coordinate to the tin atom in an intramolecular
RESULTS AND DISCUSSION
■
3-Bromo-adamantanecarboxylic acid 5 was synthesized from
adamantanecarboxylic acid 4 according to known procedures
(Scheme 2A).22 The key step for the synthesis of building
block 2 is the incorporation of the azide moiety, afforded by a
stannic chloride catalyzed substitution with azidotrimethylsi-
lane.23 Optimization studies indicated the need for the
esterification of carboxylic acid 5 prior azide incorporation.
Subsequent hydrolysis of ester 7, followed by introduction of
the hydrazide moiety via an EDC-mediated coupling with Boc-
hydrazide, and Boc-deprotection afforded bifunctional spacer,
B
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a
Scheme 3. Synthesis, Structure, and ESI-MS Spectrum of [(R3Sn)3S4Cl] (3Cl)
a
(A) Synthesis of azido-adamantyl-terminated tin sulfide cluster cation [(R3Sn)3S4Cl] (3Cl), starting from 3-azido-adamantanecarboxylic acid
hydrazide 2 and 4-methyl-4-(trichlorostannyl)-pentan-2-one (R2SnCl3). (B) ESI(+)-MS mass spectrum of a solution of the redissolved reaction
product containing cluster cations [(R3Sn)3S4]+ (3+). The signal with the highest intensity at m/z = 1434.2389 can be assigned to the desired
product 3+, while the signal at m/z = 1215.1073 correlates with sum formula [C40H63N10O3S4Sn3]+, thus illustrating [(R3Sn)2(R2Sn)S4]+ (3a+), in
which one original R2 ligand group is recovered.
a
Chart 1. Packing and Structure of 11
manner to complete its distorted octahedral environment. The
N3−N4−N5 angle is within the range for azides (172.9(7)°).
In the second step, azido-adamantyl-terminated organotin
trichloride 11 (R3SnCl3) was reacted with 1.3 equiv of
(TMS)2S, in order to form the corresponding azido terminated
tin sulfide cluster [(R3Sn)3S4Cl] (3Cl) in 45% yield. The
cluster [(R3Sn)3S4Cl] (3Cl) was characterized by NMR
spectroscopy (1H, 13C, 119Sn), ESI(+)-MS, and X-ray
diffraction. The 119Sn NMR spectrum shows only one peak
(−103 ppm, see the Supporting Information) shifted down-
field with regard to azido-adamantyl-terminated organotin
trichloride R3SnCl3, as expected. Consequently, organotin
trichloride 11 (R3SnCl3) was completely converted. The
ESI(+)-MS mass spectrum shows a mixture of two clusters
with different substitution patterns (Scheme 3B). The main
signal at m/z = 1434.2389 agrees with a composition of
[C51H78N15O3S4Sn3]+, according to desired cluster cation 3+
bearing three R3 substituents. The weaker signal at m/z =
1215.1073 (relative intensity of approximately 5%) can be
assigned to a sum formula of [C40H63N10O3S4Sn3]+, according
to cluster cation [(R3Sn)2(R2Sn)S4]+ (3a+) binding two
adamantyl-terminated ligands R1 and one original ligand R2
(Scheme 3A). We assume that formation of 3a+ takes place
under ESI(+)-MS conditions by fragmentation of 3+, as the
119Sn NMR spectrum shows only one peak. If fragmentation
occurred in solution, a second signal with a slightly different
a
Top: Packing of the molecules in the crystal. Ellipsoids are drawn at
50% probability. Nonrelevant hydrogen atoms were omitted for
clarity. Bottom: Molecular structure of R3SnCl3 organotin trichloride
11.
C
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a
Chart 2. Molecular Structure of [(R3Sn)3S4Cl] Cluster 3Cl in Two Different Views
a
Ellipsoids are drawn at 50% probability. Nonrelevant hydrogen atoms were omitted for clarity. The disorder of one of the azide groups is indicated
by drawing one of the disorder positions in half transparent mode.
a
Scheme 4. SPAAC and ESI-MS Spectrum of 3Cl
a
(A) SPAAC of azido cluster 3Cl and BCN-containing peptide 12. Note that the substituents are given only once in their full extension, while we
abbreviate them elsewhere by using R3 and R4 for clarity. (B) ESI(+) mass spectrum of a solution of the reaction solution from compound 3Cl with
12 with structure proposal for the correlated signals; R3 = CMe2CH2C(NNHC(O)(C10H14N3))Me, R4 = CMe2CH2C(NNHC(O)-
(C39H53N6O6))Me.
shift is expected to occur in the 119Sn NMR spectrum. This
assumption was proven by MS-MS experiments of 3+ (m/z =
1434.2389), in which the second MS experiment led again to
the detection of fragmented cluster 3a+ at m/z = 1215.1019
(Figure S24). The structures in Scheme 5B are plausible
suggestions, based on X-ray crystal analysis of trifold azido-
adamantyl-terminated cluster 3+ (Chart 2). A solution of the
crude compound in dichloromethane was stored at −20 °C for
5 months, leading to crystals of desired product 3Cl in
approximately 5% crystalline yield. According to X-ray
D
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a
Scheme 5. Low-Field Sections of the 13C NMR Spectra of 12 and 13Cl
a
(A) 13C NMR of BCN-containing peptide 12 in CDCl3. (B) 13C NMR of the crude reaction mixture of SPAAC in CD2Cl2 of 3Cl and 12,
displaying cluster 13Cl as product, R4 = CMe2CH2C(NNHC(O)(C39H53N6O6))Me. The reaction mixture includes naphthalene (crossed peaks),
deriving from the synthesis of sodium sulfide, which is used in the synthesis of the tin sulfide cluster.25
diffraction, the single-crystals comprise a chloride of the cluster
cation, [(R3Sn)3S4Cl]·4CH2Cl2 (3Cl). It crystallizes in the
triclinic space group P1 (Z = 2), with four highly disordered
̅
(2.317(13) Å-2.477(13) Å),9 which is ascribed to the presence
of the sterically demanding adamantane substituents.
With azido tin sulfide cluster 3Cl in hand, we focused on the
postfunctionalization of 3Cl by a strain-promoted azide−
alkyne cyclization (SPAAC, Scheme 4A). We have chosen
SPAAC for postfunctionalization of azido cluster 3Cl as only a
cyclooctyne moiety is needed for the postfunctionalization.
Thus, quantitative cyclization would afford postfunctionalized
cluster without any side products. BCN (bicyclononyne) was
chosen as cyclooctyne derivative, due to its ready accessibility
(4 steps)24 and high reactivity in SPAACs.18a Corresponding
peptide S4 was synthesized by liquid-phase peptide synthesis
and subsequently coupled to the BCN, affording BCN-
containing peptide 12, respectively. SPAAC was performed
in an equimolar ratio with respect to the azido group (Scheme
4A). Analysis of the crude reaction mixture after 16 h by NMR
showed high dynamic behavior of functionalized cluster 13Cl.
Thus, spectroscopy was only possible at 253 K. The 13C NMR
displayed quantitative formation of triply functionalized tin
sulfide cluster 13Cl, as illustrated in Scheme 5B. The signal
corresponding to alkynyl carbons of 12 at 98.9 ppm
disappeared (Scheme 5A), and characteristic signals for the
triazole carbons (133.5, 146.9 ppm) appeared (Scheme 5B).
Furthermore, ESI(+)-MS data were recorded (Scheme 4). The
signal at m/z = 3010.1291 agrees with sum formula
dichloromethane molecules (Table S1). Although all Sn−S
bond lengths of 3Cl are within the normal range of similar
clusters, the angles within the inorganic core (Sn1−S2−Sn2
103.23(8)°, Sn1−S4−Sn3 103.30(9)°) indicate heavy dis-
tortion of the [Sn3S4] defect heterocubane unit. We ascribe
this to the steric influence of the adamantyl ligand, which is
supported by the fact that corresponding angles are typically
88−93° in comparable [(RSn)3S4Cl] clusters with smaller
ligands like hydrazone groups.8d The chlorine atom Cl1 forms
three intramolecular hydrogen bonds, one to each of the
organic ligands (Cl1···H48B 2.7500(22) Å, Cl1···H1C
2.7775(21) Å, Cl1···H34B 2.8120(33) Å). Two of the
hydrogen bonds involve adamantyl substituents, which causes
the respective adamantyl groups to be fixed at this position.
The interaction with H1C, in contrast, addresses the CH3
group at the Sn-bonded carbon atom of the third organic
ligand. Thus, the third adamantane substituent is free to rotate,
which is reflected in a rotational disorder, of which two
positions were refined (Chart 2). Further mobility of these
groups, however, is indicated by a considerable deviation of the
N−N−N angle of one of the disorder positions from linearity
(N3A−N4A−N5A 148(6)° and N3B−N4B−N5B 175(2)°,
whereas the angles of the azides at the rigid adamantyl groups
are in the common range (N8−N9−N10 170.8(15)° and
N13−N14−N15 171.1(12)°). Atom N5B of the disordered
azide is located on the inversion center between two molecules
in the unit cell that therefore need to show different rotational
positions of their respective azide group. The Sn···N distances
in the almost planar five-membered ring range between
2.4328(99) and 2.4471(67) Å, whereas that of Sn1···N1
(2.3765(81) Å) is significantly shorter owing to the hydrogen
bond between Cl1 and H1C in trans position. All Sn···N
contacts are elongated compared to those in a related cluster
+
C138H195N24O21S4Sn3 , thereby illustrating that a 3-fold “click
reaction” took place, affording postfunctionalized cluster
[(R4Sn)3S4]+ (13+). Additionally the spectrum displays cluster
3+ [(R3Sn)3S4]+ at m/z = 1432.2497, monofunctionalized
cluster 13b+ ([(R3Sn)2(R4Sn)S4]+) at m/z = 1959.5434, and
difunctionalized cluster 13a+ ([(R3Sn)(R4Sn)2S4]+) at m/z =
2484.8382. On the basis of the analysis via 13C NMR, we
assume that the observed signals 3+, 13a+, and 13b+ result from
the retrocyclization during the ESI(+)-MS measurement.
This proof-of-concept illustrates that the SPAAC is an
efficient method for the quantitative postfunctionalization of
tin sulfide clusters with biomolecules.
E
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CONCLUSION
■
A novel bifunctional orthogonal spacer was synthesized and
applied in the bioconjugation of a tin sulfide cluster via a
strain-promoted Huisgen cycloaddition. The spacer, 3-azido-
adamantanecarboxylic acid hydrazide 2, was condensed with
an keto-functionalized organotin trichloride, which was reacted
to a trifold azido-adamantyl-terminated cluster [(R3Sn)3S4Cl]
(3Cl, R3 = CMe2CH2C(NNHC(O)(C10H14N3))Me). The
cluster was characterized by means of NMR, HRMS, and X-ray
crystal structure analysis. Postfunctionalization of this cluster
was quantitatively achieved by strain-promoted azide−alkyne
cycloaddition “click-reaction”, affording a peptide decorated
cluster. Future work will focus on the exploration of the
resulting cluster properties.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00734.
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Spectroscopy and spectrometry, synthesis of the ligand,
conjugated peptide, tin sulfide cluster, and crystallo-
graphic details (PDF)
Accession Codes
CCDC 1870760−1870762 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: dehnen@chemie.uni-marburg.de. Web: https://www.
uni-marburg.de/fb15/ag-dehnen (S.D.).
*E-mail: prs@uni-giessen.de. Web: https://www.uni-giessen.
de/fbz/fb08/Inst/organische-chemie/agschreiner (P.R.S.).
ORCID
Radim Hrdina: 0000-0001-5060-6666
Stefanie Dehnen: 0000-0002-1325-9228
Peter R. Schreiner: 0000-0002-3608-5515
■
(8) (a) Fard, Z. H.; Halvagar, M. R.; Dehnen, S. Directed Formation
of an Organotin Sulfide Cavitand and Its Transformation into a
Rugby-Ball-like Capsule. J. Am. Chem. Soc. 2010, 132 (9), 2848−
2849. (b) Halvagar, M. R.; Fard, Z. H.; Dehnen, S. Directed
derivatization of organotin sulfide compounds: synthesis and self-
assembly of an SnS backpack-like cage and a CuSnS ternary cluster.
Chem. Commun. 2010, 46 (26), 4716−4718. (c) Barth, B. E. K.;
Leusmann, E.; Harms, K.; Dehnen, S. Towards the installation of
transition metal ions on donor ligand decorated tin sulfide clusters.
Chem. Commun. 2013, 49 (59), 6590−6592. (d) Eußner, J. P.; Barth,
B. E. K.; Leusmann, E.; You, Z.; Rinn, N.; Dehnen, S. Functionalized
Organotin-Chalcogenide Complexes That Exhibit Defect Hetero-
cubane Scaffolds: Formation, Synthesis, and Characterization. Chem. -
Eur. J. 2013, 19 (41), 13792−13802. (e) Fard, Z. H.; Xiong, L.;
Author Contributions
J.-P.B. and A.E. are considered equal first authors.
Notes
The authors declare no competing financial interest.
́
Muller, C.; Hołynska, M.; Dehnen, S. Synthesis and Reactivity of
̈
ACKNOWLEDGMENTS
■
Functionalized Binary and Ternary Thiometallate Complexes
[(RT)4 S6 ], [(RSn)3 S4 ]2 −, [(RT)2 (CuPPh3 )6 S6 ], and
[(RSn)6(OMe)6Cu2S6]4− (R = C2H4COOH, CMe2CH2COMe; T
= Ge, Sn). Chem. - Eur. J. 2009, 15 (27), 6595−6604. (f) Halvagar, M.
R.; Hassanzadeh Fard, Z.; Dehnen, S. Controlling the Architecture of
Discrete Organotin Sulfide Molecules by Optimization of the
Intramolecular Spacer Length. Chem. - Eur. J. 2011, 17 (16),
4371−4374. (g) You, Z.; Dehnen, S. Directed Formation of a
Ferrocenyl-Decorated Organotin Sulfide Complex and Its Controlled
Degradation. Inorg. Chem. 2013, 52 (21), 12332−12334. (h) Eußner,
J. P.; Dehnen, S. Bronze, silver and gold: functionalized group 11
organotin sulfide clusters. Chem. Commun. 2014, 50 (77), 11385−
11388. (i) Eußner, J. P.; Barth, B. E. K.; Justus, U.; Rosemann, N. W.;
Chatterjee, S.; Dehnen, S. Revisiting [(RSnIV)6SnIII2S12]: Directed
Synthesis, Crystal Transformation, and Luminescence Properties.
This work was financially supported by LOEWE “SynChem-
Bio”. We thank Eugenie Geringer, Carsten Donsbach, and Eike
Dornsiepen for their help with the X-ray diffraction experi-
ments and the crystal structure solutions.
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DOI: 10.1021/acs.organomet.8b00734
Organometallics XXXX, XXX, XXX−XXX