On the role of the vinylsulfoxide side chain of dirchromone towards its bioactivities

Article abstract of DOI:10.1039/d0ob01783c

Analogs of dirchromone were prepared to shed light on the pivotal role of its peculiar vinylsulfoxide side chain towards its cytotoxic and antimicrobial properties, especially dependant upon the presence and oxidation state of sulfur. The reaction of dirchromone with cysteamine revealed a surprising Michael acceptor behavior with elimination of the methylsulfinyl moiety and redox transformation of the sulfur atom that could be involved in the mode of action of dirchromone within cells.

Full text of DOI:10.1039/d0ob01783c

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
On the role of the vinylsulfoxide side chain of
dirchromone towards its bioactivities†
Cite this: DOI: 10.1039/d0ob01783c
Alexis St-Gelais,
André Pichette*
Jérôme Alsarraf, * Jean Legault, Mouadh Mihoub and
Analogs of dirchromone were prepared to shed light on the pivotal role of its peculiar vinylsulfoxide side
chain towards its cytotoxic and antimicrobial properties, especially dependant upon the presence and
oxidation state of sulfur. The reaction of dirchromone with cysteamine revealed a surprising Michael
acceptor behavior with elimination of the methylsulfinyl moiety and redox transformation of the sulfur
atom that could be involved in the mode of action of dirchromone within cells.
Received 27th August 2020,
Accepted 18th November 2020
DOI: 10.1039/d0ob01783c
rsc.li/obc
the salient structural originality of dirchromone, which is one
of the relatively rare examples of sulfur-bearing secondary
Introduction
Dirchromones are a group of unique sulfur-bearing com- metabolites in terrestrial plants outside the Alliaceae and
pounds found in minute amounts in the stem, bark and roots Brassicaceae families,4 and the first within the
of the North American shrub Dirca palustris L. Thymelaeaceae.1 It lends itself to several potential structural
(Thymelaeaceae). Depending on their aromatic substitution modifications in order to define its role in the biological
pattern, they exhibited various degrees of cytotoxic and Gram- activity of dirchromone (Chart 1).
positive antimicrobial activities in vitro.1 Their scarcity in the
Firstly, the chiral nature of the sulfoxide must be addressed.
plant, however, initially prevented any rational structure– The natural dirchromone 1 and its derivatives were isolated as
activity relationship studies. A synthetic route to gram-scale racemates. However, sulfoxide chirality regularly features a key
preparation of dirchromone (1) was therefore specifically impact on bioactivity: a relevant example is the affinity of the
devised2 as the inclusion of the vinylsulfoxide moiety as the sulfoxide (R)-modafinil for dopamine D2 receptors in rat brain
side chain of a chromone proved to be a challenging task. The tissues, whereas its (S) counterpart is virtually inactive.5
incorporation of the peculiar conjugated sulfur function relied Various pharmaceutically relevant sulfoxides are preferably
on an original Pummerer reaction where an alkyl sulfoxide was prepared as enantiomerically pure drugs.6 In other instances,
converted into a vinyl sulfide. A novel soft-enolization Baker– chirality is not as directly critical. Sulindac, a non-steroidal
Venkataraman rearrangement, inspired by the conditions anti-inflammatory drug, is produced as a racemic methyl-
developed by Lim et al. for mixed Claisen condensations,3 sulfoxide. The active compound in fact being its sulfide metab-
then enabled the construction of the chromone framework olite, both enantiomers can elicit activity; it is, however, worth
which bore this sensitive function. With this fruitful strategy
available, the ensuing step naturally was to define the relevant
features of the parent scaffold towards its cytotoxic and anti-
microbial activities.
The lateral chain of dirchromone 1 features a conjugated
stereogenic sulfoxide. This moiety naturally draws attention as
Chaire de recherche sur les agents anticancéreux d’origine naturelle, Laboratoire
d’analyse et de séparation des essences végétales (LASEVE), Département des
Sciences Fondamentales, Université du Québec à Chicoutimi, 555, boulevard de
l’Université, Chicoutimi, Québec, G7H 2B1, Canada.
E-mail: jerome1_alsarraf@uqac.ca, andre_pichette@uqac.ca; Fax: +1-418-615-1203;
Tel: +1-418-545-5011
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, synthesis, and characterization of new compounds, 1H and 13C NMR
spectra of new compounds. See DOI: 10.1039/d0ob01783c
Chart 1 Structural modifications introduced to the lateral chain of dir-
chromone (1) in order to study their influence on bioactivity.
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
noting that the metabolization profiles of these enantiomers while simultaneously generating a suitable acyl chloride to
differ.7 In addition to chirality, the example of sulindac also obtain a phenone ester 11a. This intermediate was in turn sub-
points out the importance of verifying the impact of the oxi- mitted to a soft-enolization Baker–Venkataraman rearrange-
dation state of the sulfur atom in dirchromone. To complete ment enabled by the addition of magnesium bromide diethyl
this study of the sulfur moiety, the recurring bioisosteric re- etherate, and further dehydrated to the chromone to yield
placement between carbonyl, sulfoxide, and sulfone in medic- sulfide 2a. Racemic dirchromone 1 was produced by oxidation
inal chemistry has to be considered.8 Broadening this explora- with meta-chloroperbenzoic acid (mCPBA). Attempts at prepar-
tion, thiophene analogs, which were prepared previously9 but ing enantiopure sulfoxides from sulfide 2a using classical
apparently never tested for their cytotoxicity, have been Kagan oxidation conditions12 afforded equivocal results with
included in the structural study herein reported.
unpredictable enantiomeric excesses. Therefore, direct separ-
In addition of the side chain heteroatoms, its carbon back- ation of the enantiomers of dirchromone (−)-1 and (+)-1 by
bone must also be considered. On the one hand, the homolo- chiral preparative HPLC was achieved at milligram scale.
gation of the alkyl chain of the sulfoxide could have an impact. Sulfone 3 was prepared in good yield by oxidation of dirchro-
On the other hand, the role of the alkene should be clarified, mone 1 with an excess of hydrogen peroxide in acetic acid
as it induces extended conjugation of the chromone and sulf- (Scheme 2).
oxide. This could in turn, among others, produce a relevant
The same synthetic route was successfully applied to the
Michael acceptor. For instance, vinylsulfones were developed preparation of substituted compounds 5, 6, and 7 (see the
to irreversibly bind to cysteine proteases by such a mecha- ESI†). 3-(Ethylsulfinyl)propanoic acid 10b was obtained by first
nism.10 Michael acceptor properties are relevant both for reacting 3-mercaptopropionic acid with ethyl bromide13 to
desired biological effects and toxicity of drugs, for example obtain crude S-ethyl-3-mercaptopropionic acid and oxidizing
inducing binding to macromolecules (often via free cysteine the latter to sulfoxide. 2b was obtained from 3-mercaptopro-
thiols) or depleting glutathione (GSH) stocks in target cells to pionic acid in 11% yield over 6 steps following a published
increase susceptibility to other treatments. Modulation of this procedure;2 compound 5 was then prepared by oxidation in a
reactivity can be a helpful approach in tuning the activity of yield of 67%. Methacrylic acid was used as the starting
drug candidates.11 Therefore, the Michael acceptor nature of material towards compound 6 by reacting with S,S′-dimethyl
dirchromone was studied, and the products of this reaction dithiocarbonate in presence of aqueous potassium hydroxide14
were in part characterized.
followed by oxidation to sulfoxide 10c. The 11-methylated
product 6 was subsequently prepared in an overall 18% yield
(7 steps from methacrylic acid). 12-Methyl-dirchromone 7 was
prepared by first performing a Michael addition on methyl cro-
tonate using S-methyl-isothiourea,15 hydrolyzing the ester and
oxidizing the obtained sulfide-bearing acid to prepare crude 3-
(methylsulfinyl)-butanoic acid 10d. The presence of a methyl
group α to the sulfoxide apparently interfered with the ensuing
Pummerer rearrangement, with roughly equivalent quantities
of the sulfur-bearing ester and of the crotonate ester of 2′-
hydroxy-acetophenone being obtained as an inseparable
mixture. These were thus submitted as is to the soft-enoliza-
tion Baker–Venkataraman rearrangement and acidic methano-
lic dehydration providing a mixture of the expected chromone
and 2-(2-methoxypropyl)-chromone. Nevertheless, with the oxi-
dation of the sulfide, the desired product 7 could be obtained
separately albeit in low overall yield (6% from methyl croto-
nate, over 5 steps). The bioisosteric replacement of the sulfox-
ide by a ketone to obtain compound 4 was carried through the
synthesis of (E)-2-but-1-en-1-ylchromone 14 (Scheme 3).
Results and discussion
Preparation of dirchromone analogs
Dirchromone 1 and its deoxy counterpart 2a were obtained
from the dirchromone preparation described earlier2
(Scheme 1). Briefly, commercial 3-methylthiopropionic acid
was quantitatively oxidized into the corresponding sulfoxide
10a, which then underwent an uncommon Pummerer
rearrangement transferring the oxidation to the carbon chain
Scheme 1 Synthetic route to dirchromone analogs. i: Oxalyl chloride (2
equiv.), cat. DMF DCM, 1 h, rt; ii: 2’-hydroxyacetophenone (4 equiv.),
KOH (4 equiv.), DMF, 5 min, rt; iii: MgBr2·Et2O (2.5 equiv.), diisopropyl-
ethylamine (3 equiv.), DCM, 24 h, rt; iv: HCl 37%, MeOH, 24 h, rt; v:
mCPBA (1 equiv.), DCM, 24 h, rt.
Scheme 2 Oxidation of dirchromone 1 to sulfone 3.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Organic & Biomolecular Chemistry
Paper
Effect of structural modifications on bioactivities
Synthesized compounds were screened for their cytotoxicity
using two malignant (DLD-1 colorectal adenocarcinoma and
A-549 pulmonary adenocarcinoma) and one healthy (WS1 skin
fibroblasts) human cell lines (Table 1). The results are
expressed as half-maximal inhibitory concentration (IC50)
using etoposide as a positive control. Overall, it is of interest to
note that DLD-1 cells appeared to be more affected than the
other cell lines by dirchromone and its analogs. It could be of
interest to pursue experiments towards other colorectal malig-
nant cells.
No relevant difference in cytotoxic activities was recorded
between the two enantiomers of dirchromone (−)-1 and (+)-1.
Although this structural feature could have relevance for other
aspects of the biological interactions of dirchromone in vivo,
such as systemic toxicity and metabolization, this result estab-
lished that further in vitro screening efforts could proceed with
racemic sulfoxides like those initially isolated from
D. palustris. Other sulfoxide analogs 5–7 were therefore tested
as racemates.
Modifications to the sulfur heteroatom generally reduced
cytotoxicity. The sulfide 2a was much less active, even exerting
no effect (IC50 > 100 µM) on healthy WS1 cells. Thiophenes
8–9 also featured greatly diminished potency. Bioisosteric re-
placement of the sulfoxide by a carbonyl in compound 4 had a
detrimental effect on activity, especially for DLD-1 and WS1
cells. Sulfone 3 was slightly less active than dirchromone 1 on
these lines, but not as clearly affected as the sulfide 2a and car-
bonyl 4. This demonstrates that the sulfur atom is an advan-
tageous feature to exert the biological response, and that the
S–O bond is pivotal in that regard at least for DLD-1 and WS1
cell lines. Methylation in compound 7 only slightly increased
activity on A-549, while in compounds 5 and 6, the increment
affected both DLD-1 and A-549. Although the effects are
modest, this suggests that alkylation with longer carbon
chains could be explored to obtain more active analogs.
Scheme 3 Synthesis of compounds 4, 8 and 9. (a) (COCl)2 (1.5 equiv.),
cat. DMF, DCM, rt., 1 h; (b) 2’-hydroxyacetophenone (4 equiv.), KOH (4
equiv.), DMF, rt.,
5 min; (c) MgBr2·Et2O (2.5 equiv.), diisopropyl-
ethylamine (3 equiv.), rt., 24 h; (d) HCl 37%, MeOH, rt., 24 h; (e) Pd(OH)2/
C (0.05 equiv.), K2CO3 (0.25 equiv.), t-BuOOH (10 equiv.), DCM, rt., 48 h.
Esterification of (E)-pent-2-enoic acid 12 via its acyl chloride
and 2′-hydroxyacetophenone afforded ester 13 in 64% yield.
Chromone 14 was then prepared in 27% yield over two steps
by the soft-enolization Baker–Venkataraman rearrangement
and cyclization sequence used for other derivatives. The mod-
erate yield could be explained by partial loss of 14 via the acid-
catalyzed methoxylation of the 11,12-alkene during chromone
cyclization in methanol. Classical Riley oxidation conditions16
using SeO2 failed to oxidize the allylic methylene of chromone
14, but a Pd(OH)2/K2CO3/tert-butyl hydroperoxide system17
afforded ketone 4 albeit in a modest 27% oxidation yield.
The soft-enolization Baker–Venkataraman rearrangement
was also efficiently extended to the preparation of thiophenes
8 and 9 from commercial thiophenecarboxylic acids 15 and 17
(Scheme 3). Preparation of their sulfone analogs was
attempted, but the molecules either resisted oxidation or
entirely degraded, depending on the amount of mCPBA used.
To complete this study, the preparation of the deconjugated
sulfoxide 2-(2-(methylsulfinyl)ethyl)chromone was attempted
by successive treatment of 2-(2-mercaptoethy)chromone2 with
aqueous dimethylsulfate in the presence of a base and
immediate oxidation to the sulfoxide, but the prevalence of
byproducts (notably 2-vinylchromone) prevented isolation of a
sufficient amount to proceed to testing. Chances are the
product was fundamentally unstable.
Table 1 Cytotoxicity and anti-Gram-positive activities of compounds
1–9
IC50 a (µM)
DLD-1
MIC90 a (µM)
Compound
A-549
WS1
S. aureus
1
2.8 0.2
2.5 0.3
2.8 0.4
13
14
17
62
28
22
1
3.1 0.1
2.8 0.2
3.8 0.5
>100
12
22
16
>100
2.9 0.4
>100
1
2
2
(−)-1
(+)-1
2a
3
1
1
7
2
1
36
6.2 0.3
13
7
6.1 0.1
4
2
12
1
5
6
7
8
1.4 0.1
1.7 0.2
2.8 0.2
7.2 0.9
6.7 0.5
3.3 0.1
1.5 0.1
3.1 0.4
>100
>100
46 12
37
83
>100
>100
>100
3
4
5
1
53
2
84 10
93
2.0 0.3
9
>100
3.0 0.4
8
Etoposide
Gentamycin
0.072 0.006
a Values SD (n = 3) are representative of three different experiments.
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Antimicrobial activity is reported on Gram-positive of reports of Michael additions to unsaturated sulfoxides even
Staphylococcus aureus whereas the analogs were not active on though they could be suitable substrates.18 Conversely, one
Gram-negative bacteria, as found with natural dirchromones.1 could envision that the 2-vinylchromone motif, independently
Here again, chirality of the sulfoxide had a limited effect. of the sulfoxide, could be a thia-Michael acceptor. This type of
Several of the structural modifications abolish activity: thio- structure has seemingly not been studied extensively in that
phenes 8–9, sulfide 2a, carbonyl 4 and methylated dirchro- regard as only two studies reporting Michael addition of
mones 6 and 7 were inactive (>100 µM), or nearly so. amines and nitrilimines to 2-styrylchromone derivatives could
Homologation of the sulfoxide in compound 5 did not affect be retrieved,19,20 nevertheless showing some potential for this
the antimicrobial effect much. The most interesting obser- hypothesis. Since thia-Michael addition mechanisms are
vation is, however, that sulfone 3 is consistently more active known to be involved in several biological trapping agents,
than dirchromone 1. Since this modification also decreased dirchromone was submitted to the cysteamine adduct NMR
cytotoxicity, it provides perspective to design analogs that test proposed by Avonto et al.22 Addition of 2 equiv. of cystea-
would be less toxic and more potent against Gram-positive bac- mine to a solution of dirchromone 1 in deuterated dimethyl-
teria. Finally, there does not appear to be a relationship sulfoxide clearly led, within minutes, to disappearance of the
between cytotoxicity and antibacterial potential, implying that original alkene signals11,21 (Fig. 1, zones A and B) in an irre-
the mechanisms underlying both activities are possibly dis- versible fashion (based on the CDCl3 dilution reversibility
tinct and not merely arising from generic toxicity. Future test, data not shown). However, this transformation led to the
investigations should thus not only seek increased cytotoxicity, formation of several products with the 1H NMR spectrum of
but also identification of less toxic analogs expressing antibac- the mixture progressively evolving over the course of
terial potential.
45 minutes (zones C and D) with loss of the methylsulfinyl
signal (zone E). When the experiment was repeated with 4
equiv. of cysteamine, the process immediately proceeded
Dirchromone as a peculiar Michael acceptor
As these results highlighted the importance of the vinylsulfox- towards a cleaner mixture, but in no cases did a single com-
ide side chain of dirchromone 1 towards its cytotoxicity, the pound form. Under the same conditions, S-oxodirchromone 3
possibility that dirchromone might act as a thia-Michael featured a similar behavior, with loss of the alkene and
acceptor was then examined. Vinyl sulfoxides, to the best of S-methyl signals and emergence of new NMR peaks (see
our awareness, have not been commonly considered as useful ESI†). The bioisosteric ketone 4 also reacted as an irreversible
Michael acceptors; Nicponski and Marchi also noted scarcity Michael acceptor, but the terminal methyl signal remained as
Fig. 1 1H NMR experiments of the cysteamine adduct test of Avonto et al. for dirchromone, with all spectra locked on DMSO-d6 residual peak.
Spectrum (1) shows pure dirchromone, spectrum (2) its reaction with 2 equiv. cysteamine after 10 min, spectrum (3) its reaction with 2 equiv. cystea-
mine after 45 min, and spectrum (4) its reaction with 4 equiv. cysteamine (which was stable over time). Zones A and B indicate the original side chain
olefinic signals; zone C the C-3 signals; zone D evolving side chain signals; zone E the methylsulfoxide singlet.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Organic & Biomolecular Chemistry
Paper
a more shielded signal, setting it apart from sulfur-bearing
compounds.
Some reaction products of 0.5 mmol dirchromone and 4
equiv. cysteamine in DMSO were isolated by flash chromato-
graphy. This allowed identification of part of the products as
compounds 19–21 (Chart 2). Since Michael addition occurred
at position 12, 2-vinylchromone could be the driving Michael
acceptor moiety. The methylsulfinyl moiety was then effectively
locking the adduct in place. Interestingly, a similar elimination
of methylsulfoxide (as methanesulfenic acid) was already
reported for the reaction of GSH with aromatic S-oxides of
agrochemicals derivatives such as terbutryn sulfoxide.23
Furthermore, the presence of disulfide bridges in compounds
19 and 21 and the incorporation (after reduction) of at least
some of the methylsulfur released by dirchromone in structure
19 further indicated redox transformations driven by the
sulfur atom. Such a phenomenon may be relevant in biological
activities, since many natural sulfur-bearing molecules exert
part of their action via redox reactions: for example, the thio-
sulfinate generated enzymatically from alliin in Allium sp.,
allicin, can in turn mobilize four equiv. of thiol to yield
disulfides, which may effectively disrupt microbial biochemi-
cal integrity and could depress GSH stocks in mammalian
cells.24
In perspective, these findings could rationalize why sulfox-
ides and the sulfone were more efficient than the other deriva-
tives in the cytotoxic assays: carbonyl 4, for which the terminal
methyl remains, would not undergo the elimination step.
Acknowledging that cysteamine is not the only biologically
relevant substrate that could react with dirchromone, reaction
of the latter with excess cysteine or GSH in aqueous media was
tested. All attempts similarly led to quick and complete trans-
formation of compound 1 into polar products, which could
not be isolated but illustrated that this sequence of events was
reasonably not limited to cysteamine and could take place
with other biomolecules. It is noteworthy that in pure aceto-
nitrile, no reaction between dirchromone and cysteamine took
place in over 48 h, at which point addition of water triggered
the conversion within seconds. The presence of either water or
DMSO appears to be necessary to the reaction.
Fig. 2 A-549 cells monolayer incubated with (A) 4’,6-diaminido-2-phe-
nylindole (DAPI) nucleus stain and (B) 10 µM dirchromone 1 for 4 h, both
excited at 377 nm and monitored at 447 nm.
This offers an intriguing overall picture, where dirchromone
combines three distinct reactivity mechanisms (Michael
addition, concomitant elimination of the methylsuflinyl
moiety, and redox capabilities) to generate a structurally orig-
inal series of reaction products. How this sequence of reac-
tions concretely takes place and precisely contribute to bioac-
tivity is currently unknown, but the contribution is plausible:
it could for example deplete the GSH stocks of the cells, gene-
rate toxic amounts of small sulfur-bearing compounds, disable
enzymes or proteins, or generate metabolites related to 19–21
that in turn exert the activity. Further research is warranted to
describe the reactivity of dirchromone and its sulfone analog
in more detail, with a variety of thiols or amines and in
different reaction conditions.
Notwithstanding, empirical observations suggest that this
reaction was likely to take place within cells cytosol. None of
the synthesized dirchromone derivatives exhibited fluo-
rescence when exposed to 365 nm UV light, to the exception of
sulfide 2a which emitted a blue color. Compounds 19 and 21
(but not 20) shared this property with the sulfide. Treatment of
A-549 cells with dirchromone 1 at the IC50 concentration gave
rise to a clear blue fluorescence in the cytoplasm upon
exposure to 377 nm UV light (Fig. 2). Dirchromone could
therefore serve as its own fluorescent probe to confirm that the
Michael addition/sulfur elimination/redox sequence took place
within the cells.
Conclusions
The versatile strategy established for the total synthesis of dir-
chromone 1 granted a straightforward access to various
analogs, thus enabling the exploration of the relevant features
of the side chain of dirchromone towards its biological pro-
perties. This study showed that its peculiar vinylsulfoxide func-
tion played a pivotal role to exert cytotoxicity. Chirality of the
sulfoxide did not influence these activities, but the S–O bond
Chart 2 Characterized products 19–21 from the reaction of dirchro-
mone 1 with an excess of cysteamine in DMSO.
This journal is © The Royal Society of Chemistry 2020
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
presence was critical to induce them. Homologation of the
alkylsulfoxide slightly increased cytotoxicity. Methylation of
the olefin also had a mild increasing effect on this activity, but
these modifications disabled antibacterial potential. On the
other hand, sulfone 3 displayed reduced cytotoxicity and
improved activity against S. aureus, making sulfone analogs of
dirchromones a relevant class of compounds to be explored for
antimicrobial properties. In presence of cysteamine, dirchro-
mone acted as a Michael acceptor, followed by elimination of
the sulfoxide moiety and redox reactions to generate a series of
structurally original compounds, some of which exhibiting
fluorescence. Therefore, dirchromone could probe such trans-
4 I. D. Nwachukwu, A. J. Slusarenko and M. C. H. Gruhlke,
Nat. Prod. Commun., 2012, 7, 395–400.
5 P. Seeman, H. C. Guan and H. Hirbec, Synapse, 2009, 63,
698–704.
6 E. Wojaczyńska and J. Wojaczyński, Chem. Rev., 2010, 110,
4303–4356.
7 D. Brunell, D. Sagher, S. Kesaraju, N. Brot and
H. Weissbach, Drug Metab. Dispos., 2011, 39, 1014–1021.
8 G. A. Patani and E. J. LaVoie, Chem. Rev., 1996, 96, 3147–
3176.
9 X. F. Wu, H. Neumann and M. Beller, Chem. – Eur. J., 2012,
18, 12595–12598.
formations within cells. These initial findings not only stress 10 J. T. Palmer, D. Rasnick, J. L. Klaus and D. Brömme, J. Med.
the uniqueness of reactivity of dirchromone, but also calls for Chem., 1995, 38, 3193–3196.
future detailed investigation of the Michael acceptor properties 11 M. H. Johansson, Mini-Rev. Med. Chem., 2012, 12, 1330–
and mechanism of action of dirchromone within cells.
1344.
12 H. B. Kagan, Phosphorus Sulfur Silicon Relat. Elem., 1986,
27, 127–132.
13 M. J. P. Vaismaa, S. M. Yliniemelä and M. K. Lajunen, Z.
Naturforsch., B: J. Chem. Sci., 2007, 62, 1317–1323.
14 S. Cadamuro, I. Degani, R. Fochi and V. Regondi, Synthesis,
1986, 12, 1070–1074.
Conflicts of interest
There are no conflicts to declare.
15 Y. Zhao, Z. M. Ge, T. M. Cheng and R. T. Li, Synlett, 2007,
1529–1532.
16 L. Kürti and B. Czakó, Strategic applications of named reac-
tions in organic synthesis, Elsevier Academic Press,
Burlington, MA, 2005.
Acknowledgements
The authors acknowledge the Chaire de Recherche sur les
Agents Anticancéreux d’Origine Naturelle for funding. This
work was supported by the Canadian Institutes of Health 17 J. Q. Yu and E. J. Corey, J. Am. Chem. Soc., 2003, 125, 3232–
Research (CIHR, operating grants 311906 and 326083 to 3233.
A. P. and J. L.). A. S. G. thanks NSERC for PhD 18 D. Nicponski and J. Marchi, Synthesis, 2014, 46, 1725–1730.
scholarship. C. Dussault (UQAC) is gratefully acknowledged for 19 H. M. Hassaneen, S. M. S. Atta, N. M. Fawzy, F. A. Ahmed,
a
biological assays, and A. Ardaillou for additional NMR experi-
ments over the course of manuscript revision.
A. G. Hegazi, F. A. Abdalla and A. H. Abd El Rahman, Arch.
Pharm., 2002, 335, 251–261.
20 A. Bouchama, R. Hassaine, O. Talhi, N. Taibi,
R. F. Mendes, F. A. Almeida Paz, K. Bachari and
A. M. S. Silva, Synlett, 2018, 29, 885–889.
References
21 S. Amslinger, ChemMedChem, 2010, 5, 351–356.
1 A. St-Gelais, J. Legault, V. Mshvildadze and A. Pichette, 22 C. Avonto, O. Taglialatela-Scafati, F. Pollastro, A. Minassi,
J. Nat. Prod., 2015, 78, 1904–1909.
V. Di-Marzo, L. De-Petrocellis and G. Appendino, Angew.
Chem., Int. Ed., 2011, 50, 467–471.
23 J. K. Huwe, V. J. Feil, J. E. Bakke and D. J. Mulford,
Xenobiotica, 1991, 21, 179–191.
2 A. St-Gelais, J. Alsarraf, J. Legault, C. Gauthier and
A. Pichette, Org. Lett., 2018, 20, 7424–7428.
3 D. Lim, F. Fang, G. Zhou and D. M. Coltart, Org. Lett., 2007,
9, 4139–4142.
24 C. Jacob, Nat. Prod. Rep., 2006, 23, 851–863.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2020