Vicinal difluorination as a C=C surrogate: An analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

Article abstract of DOI:10.3762/BJOC.16.216

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

Full text of DOI:10.3762/BJOC.16.216

Vicinal difluorination as a C=C surrogate: an analog of
piperine with enhanced solubility, photostability, and
acetylcholinesterase inhibitory activity
Yuvixza Lizarme-Salas1, Alexandra Daryl Ariawan1, Ranjala Ratnayake2,
Hendrik Luesch2, Angela Finch3 and Luke Hunter*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2663–2670.
1School of Chemistry, University of New South Wales (UNSW),
Sydney NSW 2052, Australia, 2Department of Medicinal Chemistry
and Center for Natural Products, Drug Discovery and Development
(CNPD3), University of Florida, Gainesville FL 32610, United States
and 3School of Medical Sciences, University of New South Wales
(UNSW), Sydney NSW 2052, Australia
https://doi.org/10.3762/bjoc.16.216
Received: 12 August 2020
Accepted: 16 October 2020
Published: 28 October 2020
This article is part of the thematic issue "Organo-fluorine chemistry V".
Guest Editor: D. O'Hagan
Email:
Luke Hunter* - l.hunter@unsw.edu.au
* Corresponding author
© 2020 Lizarme-Salas et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Alzheimer's disease; bioisostere; conformational analysis; gauche
effect; stereoselective synthesis
Abstract
Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound
for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility
and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated
hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior
physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase.
This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.
Introduction
Piperine (1, Figure 1) is a well-known natural product that is (BACE-1), which suggests that 1 could hold promise as a dual
derived from peppercorns [1-3]. Many biological studies of 1 mechanism-of-action treatment for Alzheimer’s disease [4,10-
have been carried out, and these studies have led to a diverse 13].
array of biological activities being claimed for this compound
[4-9]. For example, 1 is reported to exhibit inhibitory activity However, piperine (1) has some limitations as a drug lead. For
towards both acetylcholinesterase (AChE) and β-secretase example, it has poor solubility, and it is susceptible to photo-
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Figure 1: The natural product piperine (1) is the inspiration for this work; the crystal structure is shown [14]. In this work, a hypothetical analog 2 was
designed to mimic parent compound 1. The predicted low-energy rotamers of 2 about the F–C–C–F and F–C–C=O bonds are shown; rotamers I and
IV give the best mimicry of 1.
isomerization of the conjugated system [15-17]. This prompted positioning of the F–C–C–F and F–C–C=O moieties within the
us to consider whether there was another structural motif that same molecule (2) means that these moieties would not func-
could (i) mimic the extended geometry of an E-alkene, (ii) tion independently, but rather would likely influence one
impart better solubility, and (iii) be more stable in the presence another, adding another layer of complexity. Finally, it is inter-
of UV light. Such a C=C surrogate might offer an improved esting to consider whether the microenvironment of a protein
lead compound for the development of drugs to treat binding site could also change the relative energies of the
Alzheimer’s disease.
various F–C–C–F and F–C–C=O rotamers, offering the possi-
bility that analog 2 might be an effective conformational mimic
Stereoselective fluorination is an emerging strategy for control- of 1 in some environments but not in others.
ling the conformations of organic molecules. The highly polar-
ized C–F bond tends to align in predictable ways with adjacent Herein, we describe the optimisation of a synthetic route to
functional groups, due to a combination of hyperconjugative compound 2, the conformational analysis of this molecule by
and/or dipolar interactions [18-21]. This knowledge led us to NMR and molecular modelling studies, a comparison of the
propose the hypothetical analog 2 (Figure 1) as a potential photostabilities of parent compound 1 vs derivative 2, and a
mimic of 1. The analog 2 contains a saturated alkyl chain with comparison of the inhibitory activities of 1 vs 2 towards both
two vicinal C–F bonds in the α/β positions relative to the amide AChE and BACE-1.
moiety. The presence of a vicinal difluoride moiety within an
Results and Discussion
alkyl chain is known to favour rotamers in which the C–F bonds
align gauche (I and II, Figure 1) [22]. Separately, the presence Synthesis
of fluorine on the α-carbon of a tertiary amide is known to Jacobsen and co-workers have recently described a method for
restrict the Cα–C(O) bond to a small set of low-energy rotamers the one-step, diastereoselective 1,2-difluorination of alkenes,
(III–V, Figure 1) [23]. Intriguingly, studies of simple molecules mediated by a hypervalent iodine catalyst [24]. The substrate
containing either F–C–C–F or F–C–C=O motifs have shown scope of the Jacobsen method has certain constraints but their
that the rotamer populations can change, depending on the original report did include some examples of α,β-unsaturated
polarity of the solvent [22,23]. The rotamers I and IV (Figure 1, amides, and so we were motivated to investigate the method in
boxed) would appear to provide the closest structural match this work, using compound 3 [25] as the substrate (Scheme 1).
with compound 1, but in a highly polar medium the more polar We recognized that the product of this reaction would most
rotamers II and V might predominate. Of course, the contiguous likely be the unwanted erythro-isomer 6 but we nevertheless
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Scheme 1: The attempted synthesis of 6 (a diastereoisomer of 2) via a one-step 1,2-difluorination reaction [24]. Py = pyridine; m-CPBA = m-chloro-
perbenzoic acid, DCM = dichloromethane.
deemed it a worthwhile preliminary investigation. Disappoint- sulfate 9, which was ring-opened using TBAF to furnish the
ingly, the treatment of the precursor 3 with pyridine·HF and fluorohydrin 10. A Mosher ester analysis of the fluorohydrin 10
either catalyst 4 or 5 at room temperature for two days gave no suggested that the earlier dihydroxylation reaction had
discernible reaction, and the starting material 3 was recovered proceeded with 90% ee. The deoxyfluorination of 10 was then
intact. Warming the reaction mixture to 50 °C caused the disap- attempted using several reagents including DeoxoFluor, Deoxo-
pearance of 3 but the formation of an intractable mixture of Fluor in combination with TMS-morpholine [29], and PyFluor
products. We were forced to conclude that the rather complex [30]. The optimal yield of the threo-difluoroalkane 11 was ob-
structure of 3 was incompatible with the Jacobsen catalytic tained with DeoxoFluor at elevated temperature (Scheme 2). A
system.
side-product in this fluorination reaction was the tricyclic com-
pound 12, which presumably formed through an electrophilic
Since the one-step difluorination method (Scheme 1) was un- aromatic substitution reaction of the activated alcohol interme-
successful, we decided to pursue a stepwise fluorination ap- diate. The inclusion of TMS-morpholine [29] reduced the for-
proach [26,27] (Scheme 2). Thus, the allylic alcohol 7 [28] was mation of this side-product but did not lead to an overall
protected as the benzyl ether then subjected to a Sharpless increase in the yield of 11. Despite the modest optimised yield
asymmetric dihydroxylation reaction to furnish the diol 8 in of the difluoroalkane 11, a sufficient quantity of this material
modest yield. The diol 8 was then converted into the cyclic was secured to continue with the synthesis. The hydrogenolysis
Scheme 2: The attempted synthesis of 2 via a stepwise fluorination approach (ether series). THF = tetrahydrofuran, AD-mix-α = commercially avail-
able asymmetric dihydroxylation reagent, TBAF = tetrabutylammonium fluoride, DeoxoFluor = bis(2-methoxyethyl)aminosulfur trifluoride.
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of the benzyl ether of 11 provided the primary alcohol 13, Gaussian software, using the M06-2X level of theory with the
which only needed to be oxidised to the carboxylic acid 14 then 6-311+G(d,p) basis set, parameters similar to those employed
coupled to piperidine in order to deliver the target compound, 2. by Linclau and co-workers for their studies of vicinal difluoro
However, the oxidation of 13 proved to be unexpectedly trou- systems [22]. A set of starting structures of 2 was generated by
blesome. Mild oxidising agents caused incomplete consump- systematically rotating three bonds (i.e., F–C–C–F, F–C–C=O,
tion of 13, while vigorous conditions led to the oxidation not and O=C–N–C) in 120° increments and the starting structures
only of the primary alcohol of 13 but also of the electron-rich were then geometry optimised and their energies calculated. To
aryl moiety (see Supporting Information File 1).
enable benchmarking against experiment, NMR spin–spin cou-
pling constants were calculated for the lowest-energy final
In order to circumvent the troublesome oxidation reaction (i.e., structures of 2 using the GIAO method with the B3LYP/6-
13→14, Scheme 2), and to seek higher enantiopurity of the 311+G(d,p) level of theory. Chloroform was used as the sol-
target, we modified the synthetic plan to include an ester moiety vent for both the NMR experiments and the SMD calculations.
throughout (Scheme 3). Thus, the α,β-unsaturated ester 15 [25]
was carried through a similar sequence to that previously de- The three lowest-energy structures to emerge from the computa-
scribed, i.e., dihydroxylation, cyclic sulfate formation, ring- tional analysis (i.e., 2a–c) are shown in Figure 2. The global
opening with TBAF (although note the regioselectivity [31]), minimum structure 2a has a F–C–C–F dihedral angle of 73°,
deoxyfluorination, and deprotection to deliver the difluorinated giving an extended zigzag carbon chain. This approximates
acid 20. Finally, coupling of the acid 20 with piperidine rotamer I (Figure 1) and in this regard 2a is a good conforma-
afforded the target compound 2 in moderate yield (Scheme 3). tional mimic of 1. However, 2a has a F–C–C=O dihedral angle
The enantiopurity of 2 was investigated using chiral HPLC. of 152°, approximating rotamer III (Figure 1) and in this regard
From a spectroscopically pure sample of 2, two HPLC peaks 2a is a poorer conformational mimic of 1. The next-higher
were observed, with an integral ratio of 99:1. It is assumed that energy structure (2b, Figure 2) is related to 2a through a ring-
the two peaks correspond to the two enantiomers of 2 and, if flip of the piperidine moiety (equivalent to a 180° rotation of
that assumption is true, then the optical purity of this sample is the amide bond). The structures 2a,b are close in energy,
98% ee.
suggesting that both puckers of the piperidine moiety would be
substantially populated in solution. A similar situation occurs
for piperine itself; an indirect evidence for this comes from the
Conformational analysis
Having completed the synthesis of the target molecule 2, the crystal structure of 1 (Figure 1), where there is a second mole-
next task was to investigate the conformational behavior of this cule in the unit cell (not shown) that has the alternative ring
molecule. This was achieved by performing a DFT study in the pucker [14]. The next-higher energy calculated structure of 2
Scheme 3: Synthesis of compound 2 via a stepwise fluorination approach (ester series). DIC = diisopropylcarbodiimide, HOBt = hydroxybenzotri-
azole, DMF = N,N-dimethylformamide.
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Figure 2: Conformational analysis of 2 by DFT and NMR. The numbering scheme for NMR spins is given on structure 2a.
(i.e., 2c, Figure 2) has a F–C–C–F dihedral angle of −52°. This bears a close resemblance to the solid-state conformation of
approximates rotamer II (Figure 1), giving a bent carbon chain piperine (1, Figure 1). The structure 2f has a F–C–C–F dihedral
that contrasts with the extended chains of 2a,b. The structure 2c angle of 57° and a F–C–C=O dihedral angle of –133°. These
has a F–C–C=O dihedral angle of −118°; this approximates angles approximate rotamers I and IV, respectively (Figure 1).
rotamer IV (Figure 1). Together, the structures 2a–c seem to The unexpectedly high relative energy that was calculated for
dominate the conformer population distribution of 2 in chloro- compound 2f might be partially attributable to the fact that it
form solution, because the weight-averaged calculated J-values features only a single F···H contact within 2.50 Å. The calcula-
of 2a–c match the experimentally-measured J-values quite well tions suggest that the conformer 2f is not significantly popu-
(Figure 2). But none of the structures 2a–c are a close confor- lated in chloroform solution but it was not possible to verify this
mational match with piperine (1).
by NMR measurements, because 2f is essentially superimpos-
able with 2a,b within the fluoroalkyl segment. In more polar
A noteworthy feature of structures 2a,b (Figure 2) is that both, solvents such as water, the intramolecular F···H interactions
the α-fluorine and the β-fluorine atoms of each structure make would be expected to decrease in significance [32] and this
close contacts with the hydrogen atoms on the piperidine ring might increase the accessibility of conformer 2f. We reasoned
(2.08–2.34 Å). This manifests in the observation of a through- that comparing the biological activities of 1 vs 2 might shed
space coupling (J = 1.9 Hz) between the α-fluorine and a piperi- light on this possibility (vide infra).
dine hydrogen in the experimental NMR spectrum of 2 (i.e.,
spins 6/7, Figure 2). The attractive F···H interactions might Photostability
explain why the amide bond is twisted by 11–20° from planarity A limitation of piperine (1) as a drug lead is its instability under
in 2a,b. In structure 2c, only the α-fluorine makes close contacts UV light. The conjugated system of 1 is well-known to undergo
with hydrogens on the piperidine ring, and the amide is twisted facile E/Z isomerization upon the absorption of UV photons,
to a lesser degree in that case (8° away from planarity). It is leading rapidly to a mixture of all four possible geometric
interesting that in the crystal structure of piperine itself (1, isomers of 1 [15-17]. In the present work, this phenomenon was
Figure 1) [14], the amide bond is also twisted by 15° away from confirmed by exposing an ethanolic solution of 1 to sunlight for
planarity. In this case the distortion might be attributable to a 2.5 h (Figure 3). The analysis of the product by 1H NMR spec-
H···H clash (1.99 Å).
troscopy revealed a multitude of new signals in the alkenyl
region. In contrast, the analog 2 lacks conjugation in the central
Structure 2f (Figure 2), which was among the higher-energy portion of the molecule and was therefore expected to be more
calculated conformers of 2 (see Supporting Information File 1), stable to UV light. Indeed, the exposure of 2 to sunlight in an
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nol as a co-solvent, was a major problem in this assay. We ob-
served cloudiness or the appearance of a precipitate at higher
concentrations of 1, which affected the reproducibility of the
assay, and prevented complete inhibition from being achieved
(Figure 4a). The estimated IC50 of 1 was >1,000 μM. In
contrast, analog 2 posed no solubility problems in this assay,
generating a reproducible curve all the way to complete inhibi-
tion and returning an IC50 value of 51.7 μM. Thus, the replace-
ment of the C=C fragment in 1 with a threo-difluoroalkane
motif in 2 appears to preserve or enhance the AChE-binding
ability, while simultaneously offering the advantage of im-
proved aqueous solubility.
The inhibition of BACE-1 was measured using a fluorogenic
peptide substrate according to an established method
(Figure 4b) [34]. Intriguingly, the relative activities of 1 vs 2
were reversed in comparison with the AChE assay. The lead
compound 1 achieved the complete inhibition of BACE-1 under
the conditions of the assay, giving an IC50 value of 59.2 μM. In
contrast, analog 2 was a much weaker inhibitor of BACE-1,
Figure 3: Analog 2 has greater stability to UV light than does piperine
(1).
identical manner to that described for 1 led to no detectable de- failing to achieve complete inhibition, and giving an estimated
composition (Figure 3, Supporting Information File 1).
IC50 value of >1,000 μM.
Biological activity and solubility
The biological activities of piperine (1) and the analog 2 were relative activities of 1 vs 2 in the AChE vs BACE-1 assays. One
compared using two different assays, namely the inhibition of possibility is that analog 2 is induced to adopt the “correct” con-
There are several conceivable explanations for the reversed
either acetylcholinesterase (AChE) or β-secretase (BACE-1).
formation when binding to both targets (i.e., 2f, Figure 2), and
this structure fits well within the AChE active site but poorly
The inhibition of AChE was measured using a modification of a within the BACE-1 active site, perhaps due to unfavourable
previously described colorimetric assay (Figure 4a) [33]. It interactions of the fluorine substituents of 2 with BACE-1
quickly became apparent that the limited solubility of piperine active site residues. A second possibility is that 2 adopts an
(1) in 50 mM Tris-HCl buffer, even in the presence of metha- “incorrect” conformation upon binding to both targets (e.g., 2a,
Figure 4: Biological activity of piperine (1) and derivative 2. (a) Inihbition of AChE by 1 (IC50 >1000 μM) and 2 (IC50 = 51.7 μM) and (b) inhibition of
BACE-1 by 1 (IC50 = 59.2 μM) and 2 (IC50 > 1000 μM).
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Figure 2), and this novel molecular shape is readily accommo-
dated by AChE [35] but not by BACE-1, perhaps due to differ-
ent levels of flexibility within the enzyme active sites. A third
possibility is that the analog 2 adopts different conformations
upon binding to AChE vs BACE-1, since the microenviron-
ments within the enzymes’ active sites could be different (e.g.,
more/less polar), the “correct” binding geometry of 2 might be
favoured in AChE but not in BACE-1. These possibilities all
remain speculative in the absence of high-resolution structural
data of the enzyme–ligand complexes.
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint: https://doi.org/10.3762/bxiv.2020.93.v1
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ORCID® iDs
Yuvixza Lizarme-Salas - https://orcid.org/0000-0001-6964-8129
Ranjala Ratnayake - https://orcid.org/0000-0002-5980-2070
Angela Finch - https://orcid.org/0000-0002-4598-6745
Luke Hunter - https://orcid.org/0000-0002-8678-3602
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