Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors

Article abstract of DOI:10.3762/bjoc.11.72

In this article a series of divalent and trivalent carbohydrate mimetics on the basis of an enantiopure aminopyran and of serinol is described. These aminopolyols are connected by amide bonds to carboxylic acid derived spacer units either by Schotten-Baumann acylation or by coupling employing HATU as reagent. The O-sulfation employing the SO₃·DMF complex was optimized. It was crucial to follow this process by 700 MHz ¹H NMR spectroscopy to ensure full conversion and to use a refined neutralization and purification protocol. Many of the compounds could not be tested as L-selectin inhibitor by SPR due to their insolubility in water, nevertheless, a divalent and a trivalent amide showed surprisingly good activities with IC₅₀ values in the low micromolar range.

Full text of DOI:10.3762/bjoc.11.72

Synthesis of multivalent carbohydrate mimetics
with aminopolyol end groups and their evaluation
as L-selectin inhibitors
Joana Salta1, Jens Dernedde2 and Hans-Ulrich Reissig*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 638–646.
1Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustrasse 3, D-14195 Berlin, Germany and 2Charité
Universitätsmedizin Berlin, Institut für Laboratoriumsmedizin,
Klinische Chemie und Pathobiochemie, Campus Virchow Klinikum,
Augustenburger Platz 1, D-13353 Berlin, Germany
doi:10.3762/bjoc.11.72
Received: 26 February 2015
Accepted: 21 April 2015
Published: 05 May 2015
Email:
This article is part of the Thematic Series "Multivalency as a chemical
organization and action principle".
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
* Corresponding author
Guest Editor: R. Haag
Keywords:
© 2015 Salta et al; licensee Beilstein-Institut.
License and terms: see end of document.
aminopolyols; carbohydrate mimetics; carboxylic acid amides;
inhibition; multivalency; selectins; sulfation
Abstract
In this article a series of divalent and trivalent carbohydrate mimetics on the basis of an enantiopure aminopyran and of serinol is
described. These aminopolyols are connected by amide bonds to carboxylic acid derived spacer units either by Schotten–Baumann
acylation or by coupling employing HATU as reagent. The O-sulfation employing the SO3·DMF complex was optimized. It was
crucial to follow this process by 700 MHz 1H NMR spectroscopy to ensure full conversion and to use a refined neutralization and
purification protocol. Many of the compounds could not be tested as L-selectin inhibitor by SPR due to their insolubility in water,
nevertheless, a divalent and a trivalent amide showed surprisingly good activities with IC50 values in the low micromolar range.
Introduction
In a series of publications [1-6] our group reported on the peutics [19-23]. In a previous report [24] we described the syn-
syntheses of carbohydrate mimetics [7-11] that are based on thesis of divalent carbohydrate mimetics connecting amino-
aminopyrans, aminooxepanes or other aminopolyols. These pyran 1 or its simplified analog serinol (2) (Scheme 1) to
compounds and their conjugates were prepared to be examined different linker units by reductive amination of aldehydes. We
as selectin inhibitors. There we have found that sulfated now enclose our results on the preparation of related di- and
aminopyrans connected by amide bonds to gold nanoparticles trivalent carbohydrate mimetics in which compounds 1 or 2 are
are highly potent inhibitors of L- and P-selectin with IC50 connected to carboxylic acid cores by amide bonds. A series of
values in the subnanomolar range [12,13]. These lectins are compounds with spacer units of different length and rigidity
crucial in the inflammatory process [14-18] and hence com- were prepared in order to find smaller inhibitors than the above
pounds inhibiting their activity are of interest as potential thera- mentioned nanoparticles and also to examine multivalency
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Beilstein J. Org. Chem. 2015, 11, 638–646.
Scheme 1: General approach to divalent or trivalent carbohydrate mimetics on the basis of aminopyran 1 or serinol (2) and their evaluation as
selectin inhibitors.
effects [25,26]. Several of these compounds could successfully able hexanoyl chloride affording the desired amide 4 in excel-
be sulfated and tested as L-selectin inhibitors.
lent yield. After cleavage of the TBS protecting groups, the
fully deprotected monovalent aminopyran derivative 5 was
isolated in quantitative yield.
Results and Discussion
Aminopyran 1 was easily available following the previously
reported synthetic route [24,27,28], whereas serinol (2) is After the successful synthesis of the monovalent compound 5,
commercially available. As a first approach to construct amide the same conditions were examined for the synthesis of related
derivatives we envisioned the Schotten–Baumann acylation divalent systems. When these reaction conditions were applied
using acid chlorides. For this purpose a protection of the to protected aminopyran 3 with succinic acid dichloride, the
hydroxy groups of aminopyran 1 with the tert-butyl- desired divalent product 6 was not formed (Scheme 3). After
dimethylsilyl (TBS) group was chosen. Reaction of 1 with tert- several attempts changing reaction time and equivalents of
butyldimethylsilyl triflate (TBSOTf) and a tertiary amine as protected aminopyran 3 and succinic acid dichloride, neither the
base under standard conditions furnished compound 3 desired product 6 nor the corresponding pyrrolidine-2,5-dione
(Scheme 2). This transformation required remarkably long reac- resulting from an intramolecular reaction were formed.
tion times when applied to compound 1 and only after 5 days a
yield of 97% could be obtained. As a first model reaction It was quite unexpected that we could not achieve this transfor-
protected aminopyran 3 was treated with commercially avail- mation since in the literature similar conditions were found for
Scheme 2: Hydroxy group protection of aminopyran 1 to give compound 3, synthesis of amide 4 and subsequent deprotection. Conditions:
a) TBSOTf, Et3N, DMAP, DMF, 5 d, 0 °C to rt; b) hexanoyl chloride, Et3N, CH2Cl2, 18 h, rt; c) HF∙pyridine, 24 h, 0 °C to rt.
639

Beilstein J. Org. Chem. 2015, 11, 638–646.
Scheme 3: Attempt to synthesize protected divalent compound 6. Conditions: a) succinic acid dichloride, Et3N, CH2Cl2, 24 h, rt.
the synthesis of multivalent acetyl-protected carbohydrates [29]. (Table 1). The reaction with the aromatic linker terephthaloyl
As possible explanation we assume that the formation of prod- dichloride (7, Table 1, entry 1) afforded the desired protected
uct 6 is sterically too hindered due to the bulkiness of the TBS- divalent compound 10 in excellent yield. Using the aliphatic
protecting groups of 3 and the short distance between the two sebacoyl dichloride (8) as linker (Table 1, entry 2), the expected
aminopyran units. For this reason, other dicarboxylic acid product 11 could be isolated in 58% yield. The interesting
derivatives with longer chains and different flexibility were trans-azobenzene derivative 9 [30] was also employed as
tested and gratifyingly the desired products could be prepared precursor and the divalent compound 12 was obtained in excel-
Table 1: Synthesis of amides 10–12 and subsequent deprotection to give divalent compounds 13–15.
Entry
1
Acid dichloride
Time 1a [h]
20
Product
Yield [%]
quant.
Time 2b [h]
22
Product
Yield [%]
quant.
10
13
7
8
2
3
20
24
11
12
58
24
24
14
15
80
quant.
quant.
9
aFirst step; bsecond step.
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lent yield (Table 1, entry 3). This product is particular intriguing easily be removed in vacuo, making further purification unnec-
since it offers the possibility to generate a light-switchable diva- essary. First attempts with acetyl chloride (0.6 equivalents) as
lent carbohydrate mimetic. Deprotection using HF∙pyridine source of dry hydrochloric acid and methanol as protic solvent
complex proved to be an adequate method and all fully depro- gave only poor conversions, probably due to the low solubility
tected amides 13–15 were isolated in excellent yields.
of the starting material 18 in this alcohol. On the other hand,
excellent results could be achieved with 2-propanol as solvent.
As previously mentioned, an additional goal of this study was Under these conditions the fully deprotected divalent amides
the investigation of multivalent compounds starting from the 21–23 were isolated in an operationally very simple manner and
simple aminopolyol 2. Analogously to aminopyran 1, the in excellent yields (Table 2).
hydroxy groups of 2 were first protected with TBS groups under
standard conditions to furnish compound 16. To be able to In order to directly obtain the unprotected multivalent carbohy-
compare aminopyran 1 with aminopolyol 2 two divalent amides drate mimetics we looked for alternative methods not requiring
were synthesized from compound 16 using the same carboxylic the protection of the hydroxy groups of 1 or 2. The most
acid dichlorides 7 and 8 as linkers affording the desired com- common method in modern synthetic chemistry to generate
pounds 18 and 19 in excellent yields (Table 2, entries 1 and 2). amide bonds is the use of coupling reagents that first activate
Moreover, another divalent amide 20 with a longer spacer unit the carboxylic acid which subsequently reacts with an amine,
was synthesized using adipic acid dichloride (17) as precursor also in the presence of unprotected hydroxy groups. From the
(Table 2, entry 3). Although TBS deprotection with the many known coupling reagents [32,33] we selected HATU
HF∙pyridine complex proved to be a fairly efficient method (see (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
Table 1), other options were searched in order to find milder b]pyridinium-3-oxide hexafluorophosphate), a coupling reagent
conditions, cheaper reagents and a simpler work-up protocol for frequently used in peptide synthesis [34]. We applied standard
the very hydrophilic products. Acid-promoted solvolysis in the conditions for the preparation of one divalent and two trivalent
absence of water [31] was considered as good alternative that amides (Scheme 4). To our pleasure divalent compound 25,
should have the advantage of generating side products that can from reaction of unprotected aminopyran 1 and succinic acid
Table 2: Synthesis of amides 18–20 from protected serinol 16 and subsequent deprotection to give divalent compounds 21–23.
Entry
1
Acid dichloride
Time 1a [h]
17
Product
Yield [%]
83
Time 2b [h]
1.5
Product
Yield [%]
90
18
21
7
8
2
3
18
17
19
20
75
62
2.5
1.5
22
23
quant.
97
17
aFirst step; bsecond step.
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Beilstein J. Org. Chem. 2015, 11, 638–646.
(24), was isolated in good yield. This successful transformation received in very good yield. On the other hand, unprotected
is evidence that the TBS protected aminopyran 3 is probably compound 1 and tricarboxylic acid 28 did not furnish the
sterically too hindered to react with succinic acid dichloride (see expected product, most probably due to the high polarity of the
above, Scheme 3). Using this procedure, trivalent carbohydrate coupling product which is then lost during the attempted purifi-
mimetics 27 and 29 were synthesized in very good yields. Once cation by column chromatography. To overcome these difficul-
again it was noticed that the reaction proceeds efficiently even ties, TBS-protected aminopyran 3 was used and coupled with
without a large excess of the corresponding aminopyran 1. For 28 efficiently affording the protected trivalent compound 29.
the synthesis of each of the trivalent compounds 27 and 29, res-
pectively, only 1.3 equivalents of amine per carboxylic acid unit For our planned examination of the multivalent compounds as
were used. With the aromatic tricarboxylic acid 26 as rigid selectin inhibitors, the O-sulfated derivatives were also
linker unit, the polarity of the final product is only moderate and required. Since the introduction of sulfate groups drastically
the reaction and purification proceeded perfectly. Starting from changes the physical and chemical properties of the molecules,
the aminopyran 1 the desired trivalent compound 27 was isolation of pure fully O-sulfated compounds continues to be a
Scheme 4: HATU-mediated synthesis of divalent amide 25 and trivalent amides 27 and 29. Conditions: a) HATU, Et3N, DMF, 24 h, rt.
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Beilstein J. Org. Chem. 2015, 11, 638–646.
Scheme 5: Polysulfations of amides 5 and 13. Conditions: a) 1) SO3∙DMF, DMF-d7, 1 d, rt; 2) 1 M NaOH, 0 °C; 3) dialysis, H2O.
great challenge. The polysulfation of the presented carbohy- agent were added and stirring was continued for another day;
drate mimetics proved to be the most demanding step of the this procedure was repeated until full conversion of the com-
synthesis requiring many attempts and optimizations to find a pound was observed. Unfortunately, with this protocol the
suitable and reasonably reproducible procedure. Since other O-sulfation and purification of the monovalent model com-
sulfation methods such as SO3∙pyridine [35] provided unsatis- pound 5 did not lead to a homogenous product (Scheme 5). In
factory results an excess of SO3∙DMF [13,36] was used as this case, we tried to follow the reaction progress by 1H NMR
sulfating agent and the resulting sulfuric acid monoesters (in a spectroscopy at 400 MHz which is apparently not sufficiently
mixture with an excess of the sulfating reagent) were directly sensitive. Hence product 31 was contaminated by other com-
converted into the corresponding sodium salts using a 1 M solu- pounds. Gratifyingly, the polysulfation of divalent amide 13
tion of sodium hydroxide. Subsequent purification by dialysis afforded the hexasulfated product 31 in 60% yield (full conver-
against water should afford the desired pure polysulfated com- sion already after one day as observed by 1H NMR spec-
pounds. We performed the sulfation reactions in deuterated troscopy at 700 MHz).
DMF as solvent in order to allow the direct reaction control by
1H NMR spectroscopy. When by 1H NMR control a mixture of A polysulfation reaction was also performed with amides
products was observed, additional equivalents of the sulfating derived from serinol (Scheme 6). The sulfation of compound 21
Scheme 6: Polysulfation of divalent amides 21 and 22 leading to tetrasulfated amides 32 and 33. Conditions: a) 1) SO3∙DMF, DMF-d7, 5 d (for 32),
1 d (for 33), rt; 2) 1 M NaOH, 0 °C; 3) dialysis, H2O.
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Beilstein J. Org. Chem. 2015, 11, 638–646.
was carried out using 3 equivalents of sulfating agent per added until pH 9 was reached and the mixture was filtrated
hydroxy group for five days. The desired polysulfated com- through a DOWEX® Na+ column. After purification, the
pound 32 could be isolated with a good yield. When the sulfa- desired sodium salt 34 was successfully obtained in excellent
tion reaction was performed using diamide 22, the reaction was yield (Scheme 7).
much faster and after one day a homogeneous product was
shown by 1H NMR spectroscopy. In this case no additional For the evaluation of the synthesized carbohydrate mimetics as
equivalents of the sulfating agent were added to the mixture and potential selectin inhibitors, surface plasmon resonance (SPR)
after dialysis the desired product 33 was isolated in very good spectroscopy [37] was applied. Following the same competitive
yield.
binding assay previously established for the test of such com-
pounds [38,39], only a few of the presented unsulfated or
The examples depicted in Scheme 5 and Scheme 6 were sulfated compounds could be screened as potential inhibitors.
selected from quite a number of experiments. Often these trans- The unsulfated amides 14, 21 and 22 were not soluble in water
formations were not well reproducible due to purification prob- and therefore not applicable for testing. The soluble divalent
lems. Although the reason for this irreproducibility was not compound 23 (Table 2) did not show any inhibition even at the
clear, it was noted that during neutralization even addition of tested maximum concentration of 1 mM. These negative results
small amounts of 1 M sodium hydroxide solution to the reac- are similar to those with the related unsulfated amine deriva-
tion mixture did not allow accurate pH control. The resulting tives previously reported [24]. We expected that all polysul-
highly basic conditions could lead to decomposition or regener- fated amides are water soluble at concentrations suitable for the
ation of the hydroxy groups leading to inhomogeneous SPR assay, but disappointingly amides 31 and 33 (Scheme 5
mixtures. A better pH control could be achieved using 0.5 M and Scheme 6) were not sufficiently soluble and therefore no
sodium hydroxide solution and hence the pH could be stopped tests could be performed with these compounds. At least diva-
close to neutrality. Additionally, the obtained mixture was lent amide 32 and trivalent amide 34 showed inhibitory activity
filtrated through an ion exchange DOWEX® Na+ (50WX8-200) as L-selectin ligands in the 1 μmolar range (Figure 1). In a
column to assure that all sulfuric acid monoesters as well as the qualitative test compound 34 also inhibited P-selectin, a result
excess of the sulfating agent were converted into the corres- to be confirmed in quantitative studies. Quite surprisingly, the
ponding sodium salts. After this filtration a dialysis of the mix- flexible divalent serinol derivative 32 showed a good inhibitory
ture generally afforded pure products. The modified procedure potential with an IC50 value of 1 μM. The rigid trivalent com-
was applied to the O-sulfation of amide 27 and the reaction was pound 34 has a slightly inferior activity with an IC50 value of
complete after 3 days. Sodium hydroxide solution (0.5 M) was 2 μM, but is still a fairly good inhibitor.
Scheme 7: Conversion of trivalent compound 27 into nonasulfated carbohydrate mimetic 34. Conditions: a) 1) SO3∙DMF, DMF-d7, 3 d, rt;
2) 0.5 M NaOH, 0 °C, DOWEX® Na+; 3) dialysis, H2O.
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Beilstein J. Org. Chem. 2015, 11, 638–646.
Figure 1: Structures of O-sulfated divalent amide 32 and trivalent amide 34 and their respective IC50 values for L-selectin as determined by SPR.
When comparing the two O-sulfated amides 32 and 34 a multi-
Supporting Information
valency effect is not evident and a sound structure–activity
discussion is not feasible as the two compounds have different
Supporting Information File 1
end groups and different flexibilities. A series of related com-
pounds is required to have a better understanding of struc-
ture–property relationships and the influence of multivalency.
Unfortunately, only a few of our prepared compounds were
sufficiently soluble in water to be suitable for the SPR test.
However, a series of other multivalent conjugates was synthe-
sized by using click chemistry with the azide derived from
aminopyran 1 and results will be published in due time [40].
General information, experimental procedures and
analytical data as well as copies of NMR spectra of all
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-72-S1.pdf]
Acknowledgements
This work was generously supported by the Deutsche For-
schungsgemeinschaft (SFB 765) and by Bayer HealthCare. We
acknowledge Dr. T. Ngo for providing the azo compound 9,
C. Kühne for valuable discussions and Dr. R. Zimmer and
Dr. M. Kandziora for their help during preparation of the
manuscript.
Conclusion
In this article we disclose the preparation of divalent and triva-
lent carbohydrate mimetics with end groups derived from
aminopyran 1 and serinol (2). The units were connected by
amide bonds that were either formed by Schotten–Baumann
reaction using the corresponding acid chlorides or by a coupling
of the amines to carboxylic acids using HATU as reagent. The
subsequent O-sulfation of the obtained compounds with
SO3∙DMF was optimized with the help of 1H NMR spectro-
scopic control (700 MHz). A crucial detail is also the neutral-
ization step which works reliable only with 0.5 M sodium
hydroxide solution. By these methods a few oligovalent
O-sulfated carbohydrate mimetics could be prepared and tested
as L-selectin inhibitors by SPR. The divalent amide 32 and
trivalent amide 34 showed surprisingly good activities with
IC50 values in the micromolar range. Further studies are
required to reveal a multivalency effect and to understand struc-
ture–property relationships of compounds of this type.
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