Fluorinated triazole-containing sphingosine analogues. Syntheses and in vitro evaluation as SPHK inhibitors

Article abstract of DOI:10.1039/c8ob01867g

Sphingosine analogues with a rigid triazole moiety in the aliphatic chain and systematic modifications in the polar head and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently ring opened in a regioselective manner in acidic medium. Up to 16 sphingosine analogues were prepared in a straightforward manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying comparable activity to that of DMS.

Full text of DOI:10.1039/c8ob01867g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Received 00th January
20xx,
Fluorinated triazole-containing sphingosine analogues. Syntheses
and in vitro evaluation as SPHK inhibitors.
Margarita Escudero-Casao,a Adrià Cardona,a Raúl Beltrán-Debón,b Yolanda Díaz,*a M. Isabel
Matheu,*a Sergio Castillón.a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Sphingosine analogues with a rigid triazole moiety at the aliphatic chain and systematic modifications at the polar head
and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine
key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently
ring opened in a regioselective way in acidic medium. Up to 16 sphinosine analogues were prepared in a straightforward
manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying
comparable
activity
to
that
of
DMS.
Cell death
Cell growth
Introduction
O
NH2
Sphingosine
Kinase (SPHK)
Ceramidase
NH C13H27
NH2
Sphingosine kinase (SPHK) is a key regulator of the sphingolipid
rheostat (Scheme 1),1 a dynamic balance between ceramide
(Cer) and sphingosine 1-phosphate (S1P) that guides the cell
toward either an apoptotic or a survival process (Scheme 1).2,3
SPHK catalyses the ATP-dependent phosphorylation of
sphingosine (Sph) to generate S1P4 and exist in two isoforms,
SPHK1 and SPHK2.5 The interest of SPHK inhibitors6 as
potential drugs stems from the fact that SPHK1 is usually up-
regulated in several forms of cancer and that its genetic
ablation leads to the sensitization of cancer cells to
chemotherapeutic agents and its implication in several
diseases.7 Similarly, different evidences support a role for
SPHK2 in cancer.8
C13H27
C13H27
C13H27
O
O
O
OH
P
O
OH
OH
OH
OH
Sphingosine
(Sph)
Sphingosine-1-phosphate
(S1P)
Ceramide
(Cer)
Scheme 1. Ceramide/Sphingosine-1-phosphate rheostat
out: safingol10 (saturated sphingosine analog with the unnatural
threo stereochemistry), N,N-dimethylsphingosine (DMS),11 short
-
chain sphinganine (C12) and 3-fluorosphingosine analogues,12 N-
derivatized analogues such phenethyl isothiocyanate derivative,13
guanidine analog LCL351,14 and N-methylated SK1-I,15 the aromatic
analogue SG-12,16 enigmol (where the 1-OH of Sph has been shifted
to position 5),17 phytosphingosine,18 FTY720,19 and its vinyl
phosphonate derivatives.20
There has been extensive focus on the development of
effective sphingosine kinase inhibitors (SKIs) during the recent
years and the progress in this area has been recently
reviewed.7a,9 Among the described SKIs derived from
sphingolipids (Figure 1) stand
Quite recently, the structures of SPHK1 in complexes with ADP, and
some inhibitors21 have been disclosed. The hydrophilic head group
of the sphingosine is situated at the cleft between two N- and C-
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obtained from alkynyl aldehydes by one-carbon
homologation.30
Here we report that enantioenriched alkynylaziridines can be
accessed by a proline organocatalyzed aziridination reaction of
α,β-unsaturated aldehydes followed by a homologation
reaction (Scheme 2). Regioselective ring opening of this
Figure 1. SPHK inhibitors derived from sphingolipids
domains, making hydrogen-bond interactions with Asp and Ser
residues. The hydrophobic alkyl chain is accommodated in a J-
shaped tunnel, lined by the side chains of mostly nonpolar
residues.
Figure 2. Structural modifications of sphingosine proposed in
this work.
Despite the wide array of compounds developed so far and the
recent breakthroughts22 in the structural and functional
characterization of SPHK, synthesis may provide new
architectures with whom to gain insight into the regulation of
the complex mechanism that govern SP1 metabolism. In this
context, the aim of this work is the syntheses of new lipidic
compounds as potential SKIs. The structures proposed for this
purpose retain the polar part of the parent compound,
sphingosine, mantaining the key aminodiol moiety. The
headgroup will be attached to a triazole core, mimicking the
trans double bond present in sphingosine23 and allowing
additional interactions (Figure 2). The triazole unit, in turn, will
be appended to
a modified lipophilic end to enhance
Scheme 2. Retrosynthetic proposal: organocatalyzed
hydrophobic interactions with the pocket of the SPHK1.
Additional SPHK1 affinity might be anticipated to be increased
through derivatization of the amino group.
aziridination and Corey-Fuchs reaction as the key steps.
Considering our experience in the field of the synthesis of
sphingoid bases,24 and aiming to explore new methodologies
for obtaining sphingosine derivatives, we envisioned the
synthesis of the proposed analogues by click reaction from a
common intermediate, obtained from an alkynyl aziridine
(Scheme 2).
common intermediate followed by triazole click chemistry with
the corresponding fatty alkyl azides furnishes a library of
sphingosine analogues bearing a triazole unit containing
oligofluorinated alkyl chains. This library may be extended by
selected derivatizations at the amino moiety.
Alkynyl aziridines are useful intermediates in many synthetic
process and they have been synthesized though a variety of
protocols.25 For some of them the asymmetric version has
been reported. Thus, enantioenriched alkynylaziridines have
been prepared from chiral alkynylamino alcohols by
intramolecular substitution reaction,26 by addition of
guanidium ylides to aldehydes,27 by catalyzed nitrene addition
to alkynyl olefins,28 and by catalyzed addition of carbenes to
imines.29 Yudin reported that alkynyl aziridines could be
Results and discussion
Starting
organocatalyzed aziridination reaction was first synthesized
α,β
-unsaturated aldehyde substrate 231 for
according to the literature via monoprotection of diol 1 as p-
methoxybenzyl ether32 and subsequent Swern oxidation in a
56% global yield (Scheme 3). The enantioselective
organocatalytic aziridination33 of the
aldehyde
catalyzed by TMS-protected diphenylprolinol (R)-3 34
α
,
β
-unsaturated
with O-tosyl-N-tert-butoxycarbonyl-hydroxylamine
provided
2
,
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the desired -formyl aziridine 4a in a 70% yield with 20:1 d.r.
ARTICLE
with sodium azide (Scheme 5). For practical reasons,39 azides 10c
and 10d were synthesized by Wittig reaction with the
corresponding azido aldehydes 13 and 14. All aldehydes were
obtained from the respective alcohols by Swern oxidation.
β
and 99 ee%. The enantiomeric excess was stablished via
formation of the corresponding vinyl derivative via Wittig
reaction (see Supporting Information).
With aldehyde 4a in hand, we set up one-carbon
homologation
Scheme 5. Synthesis of azides 10a-d
Scheme 3. Synthesis of ethynyl aziridine 7 from diol 1.
Scheme 4. Synthesis of intermediate 9 by aziridine ring opening.
Scheme 6. Azide-Alkyne Cycloaddition.
to render the alkyne moiety. When aldehyde 4a was treated
under Corey- Fuchs conditions35 with CBr4, triphenylphosphine
and zinc durst in dichloromethane the corresponding
Copper catalysed cycloaddition reaction of azides 10a-d with the
alkyne 9 previously prepared afforded triazoles 15a-d in yields
ranging from 66% to 86% (Scheme 6). With these protected
triazole-based sphingosine analogues in hand, the corresponding
modifications in the amine functionality were carried out. Thus, the
preparation of the non fluorinated N-monomethyl amine 18a was
accomplished by reduction of the carbamate group and ulterior p-
methoxybenzyl ether deprotection. Inverting the sequence of
events, as it was done for the fluorinated analogues (see below),
leads in this case to worse yields. For obtaining fluorinated N-
methyl derivatives 18b-d an additional double bond reduction step
dibromoalkene
the tribrominated alkene
yield). Product might result from bromide ring opening of
aziridine 4a 36
Gratifyingly, both products,
treatment led to the corresponding ethynylaziridine
metal-halogen exchange and ulterior
-elimination,37 and from
through an additional ring closing process in the basic media.
5
was obtained only in a 8% yield (Scheme 3),
6, being the main product (70 %
6
.
5
and
6, when submitted to LDA
7
via
α
6
Ring opening of aziridine 7 with acetic acid at room temperature,
followed by basic hydrolysis of the acetate group in 8 furnished the
N-protected amino alcohol 9 in excellent yield (Scheme 4). The was required. This transformation was performed from 15b-d with
observed regioselectivity can be rationalized considering the
selective nucleophilic attack at the propargylic position (see ref. 25
for a general review dealing with synthesis and opening of alkynyl
(and vinyl) aziridines). This effect has also been described in the
ring-opening reactions of vinyloxirane and activated vinylaziridine
Pd/C, H2, with concomitant PMB hydrogenolysis, and Boc group was
subsequently reduced (Scheme 7). Boc deprotection of compounds
17b-d led to free amino analogues 19b-d. Non fluorinated
aminodiol 19a, in turn, can be directly obtained from non
olefinated compound 15a by simultaneous Boc and PMB
deprotection with TFA.
derivatives.38
N,N-dimethyl derivatives 20a-d were synthesized from 19a-d
by reductive amination with p-formaldehyde (Scheme 7). The
synthesis of N-guanidine sphingosines was accomplished by
reaction of amines 19a-d with N,N’-di-Boc-1H-pyrazole-1-
carboxiamidine to afford N-Boc derivatives 21a-d, followed by
deprotections with a 1:1 mixture of TFA/CH2Cl2.
In order to perform click triazole syntheses, azides 10a-d were
synthesized. 1-Azidododecane 10a was obtained quantitatively
from 1- bromododecane by treatment with sodium azide in a 1:1
mixture of refluxing EtOH: H2O. Azide 10b was synthesized from 9-
bromononanal 11 via Wittig reaction with the corresponding
trifluorinated phosphorous ylide and ulterior bromide displacement
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Although purification of guanidine derivatives was performed
under basic conditions, and despite an ulterior treatment with
aqueous NaOH had been carried out, compounds 22b-d were
obtained as the trifluoroacetate salts.
The half maximal inhibitory concentration (IC50) of each
compound was determined using an in vitro time-resolved
fluorescence energy transfer (TR-FRET) analysis (Table 1 and
Figures 1 and 2 of Supporting Information). This experiment
was performed independently for each kinase and dimethyl
sphingosine was used as a reference.
None of the compounds showed a higher inhibitory activity
than the reference DMS, but two of them showed an IC50 value
close to DMS. Thus, the non-fluorinated guanidine derivative
22a showed an IC50 = 7.9 µM for SPHK2 and the pentafluoro N-
monomethy compound 18c an IC50 = 30.0 µM for SPHK1.
However, these activities were not selective and these
compounds showed also inhibitory activity against the other
kinase.
More interestingly, some compounds actually showed modest
but selective inhibitory activity for SPHK2 (free amino
trifluoromethyl and heptafluoro compounds 19b and 19d as
well as N,N-dimethylamino fluorinated derivatives 20b, 20c
and
Scheme 7
.
Last steps and N-derivatization for the syntheses of
target triazole analogues.
20d). As a general trend, the family of compounds constituted
by heptafluoroderivatives (18d 19d 20d and 22d) showed a
,
,
good and selective inhibitory activity against SPHK2, being the
N,N-dimethyl derivative 22d the best compound in these
series in terms of activity/selectivity.
The presence of polyfluorinated alkyl fragments in
a
compound is known to affect the lipophilicity and
conformational rigidity of the parent molecule along with
other effects.40 In our case, the terminal heptafluoropropyl
unit can confer a lower conformational mobility to these
family of sphingolipid analogues, which might difficult a proper
fitting of the alkylic chain into the J-shaped tunnel of SPHK1.
This fact could explain the observed selective inhibitory
activity against SPHK2 if the cavity of this kinase was more
straight than that of the SPHK 1. However, the cristal structure
of SPHK2 has not been elucidated yet, so this hypothesis can
not be confirmed. Nonetheless, these results postulate
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heptafluoroderivatization as a starting point for future SPHK2
selective inhibitors.
Acknowledgements
We thank the Spanish Government (CTQ2014-58664-R and
CTQ2017-89750-R) for financial support. A.C. thanks
Universitat Rovira i Virgili for a Research Fellowship.
Table 1. IC50 values of compounds 18a-d, 19a-d, 20a-d, 22a-d and
the reference, DMS, for each Sphingosine kinase.
N
N
N
N
NH
NH2
N
N
R1
R1
HO
HO
OH
18a R1: C12H25
18b R1: C11H22CF3
OH
19a R1: C12H25
19b R1: C11H22CF3
19c R1: C10H20CF2CF3
Notes and references
18c R1: C10H20CF2CF3
1
2
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19d
R : C H18CF2CF2CF3
18d R1: C9H18CF2CF2CF3
1
9
.
NH
N
N
N
N
N
H2N
HO
NH
N
R1
N
R1
HO
OH
OH
22a R1: C12H25
22b R1: C11H22CF3
3
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HO
(DMS)
OH
Inhibitor SPHK1 SPHK2 Inhibitor SPHK1 SPHK2
7
18a
18b
18c
61.5
48.9
30.0
51.6
97.1
-
22.9
41.9
39.5
10.7
25.6
40.5
-
20a
20b
20c
20d
22a
22b
22c
22d
110.2
22.2
56.8
70.8
15.6
7.9
-
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8
9
18d
19a
19b
19c
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41.9
-
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28.5
3.8
5, 184; L.U.
27.3
2, e129.
1
,
Values are expressed as concentrations (µM), and no value (“-“) means low
or no inhibitory activity detected.
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Conflicts of interest
There are no conflicts to declare.
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