Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors

Article abstract of DOI:10.1021/jacs.9b06446

Rocaglates are a family of natural products isolated from the genus Aglaia which possess a highly substituted cyclopenta[b]benzofuran skeleton and inhibit cap-dependent protein synthesis. Rocaglates are attractive compounds due to their potential for inhibiting tumor cell maintenance in vivo by specifically targeting eukaryotic initiation factor 4A (eIF4A) and interfering with recruitment of ribosomes to mRNA. In this paper, we describe an intercepted retro-Nazarov reaction utilizing intramolecular tosyl migration to generate a reactive oxyallyl cation on the rocaglate skeleton. Trapping of the oxyallyl cation with a diverse range of nucleophiles has been used to generate over 50 novel amidino-rocaglate (ADR) and amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B.

Full text of DOI:10.1021/jacs.9b06446

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Article
Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate
Derivatives and Their Biological Evaluation as eIF4A Inhibitors
Wenhan Zhang, Jennifer Chu, Andrew M. Cyr, Han Yueh, Lauren
E. Brown, Tony T. Wang, Jerry Pelletier, and John A. Porco
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06446 • Publication Date (Web): 16 Jul 2019
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Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-
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ǂ
Wenhan Zhang,a Jennifer Chu,b Andrew M. Cyr,a Han Yueh,a Lauren E. Brown,a Tony T. Wang,c
Jerry Pelletier,b, d, e* and John A. Porco, Jr.a*
a Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA
02215, United States of America
b Department of Biochemistry, d Department of Oncology, e Rosalind & Morris Goodman Cancer Research Centre, McGill University,
Montreal, Quebec, Canada, H3G 1Y6
c Laboratory of Vector-borne Viral Diseases, Division of Viral Products, Center for Biologics Evaluation and Research, Food and
Drug Administration, Silver Spring, MD 20903, USA
ABSTRACT: Rocaglates are a family of natural products isolated from the genus Aglaia which possess a highly substituted
cyclopenta[b]benzofuran skeleton and inhibit cap-dependent protein synthesis. Rocaglates are attractive compounds due to
their potential for inhibiting tumor cell maintenance in vivo by specifically targeting eukaryotic initiation factor 4A (eIF4A)
and interfering with recruitment of ribosomes to mRNA. In this paper, we describe an intercepted retro-Nazarov reaction
utilizing intramolecular tosyl migration to generate a reactive oxyallyl cation on the rocaglate skeleton. Trapping of the oxy-
allyl cation with a diverse range of nucleophiles has been used to generate over fifty novel amidino-rocaglate (ADR) and
amino-rocaglate derivatives. Subsequently, these derivatives were evaluated for their ability to inhibit cap-dependent protein
synthesis where they were found to outperform previous lead compounds including the rocaglate hydroxamate CR-1-31-B.
INTRODUCTION
Aglaia Lour. is a genus of angiosperm plants containing
(2) bound to a human eIF4A1-polypurine RNA complex
which revealed, among several key interactions identified,
more than 120 species.1 In 1982, the first rocaglate was iso-
lated from dried roots and stems of Aglaia elliptifolia Merr.;2
since this time, over thirty natural products of the rocaglate
family have been discovered, all sharing a highly substituted
cyclopenta[b]benzofuran with five contiguous stereocen-
ters. In the past several decades, numerous syntheses of
rocaglates have been reported due to their intriguing struc-
tures.3 4 These natural products and synthetic derivatives
,
(Figure 1A) exhibit many interesting biological activities
through targeting of the eukaryotic translation apparatus.5,
6 For example, the congener silvestrol (1) was found to in-
hibit the eIF4F complex by interfering with the function of
the DEAD box RNA helicase eIF4A.7 Additionally, silvestrol
has antitumor activity in a variety of pre-clinical murine
cancer models including hematological and solid tumors.8
Rocaglamide (2), methyl rocaglate (3), and the synthetic de-
rivative RHT (4) have also displayed anticancer and other
biological properties.9
Chemical syntheses of cyclopenta[b]benzofuran natural
products and analogues have revealed structure-activity re-
lationships (SAR) for antineoplastic activity in cancer cell
lines (Figure SI1).10 In particular, SAR studies have defined
chemically allowable modifications for rocaglates leading to
improved activity.5, 6 In particular, the C8b tertiary hydroxyl
moiety (red) has been found to be critical which appears to
be related to its role as a hydrogen bond (H-bond) donor
(Figure 1B); alkylation of this tertiary hydroxyl completely
eliminates cytotoxic activity.5d Recently, Iwasaki and co-
workers reported the co-crystal structure of rocaglamide
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H-bonding between the C8b hydroxyl of 2 and N7 of a gua-
nine RNA base (Figure 1B).11 In order to further study this
critical interaction and improve biological activities of
rocaglates, we have considered replacing the C8b tertiary
hydroxyl with nitrogen substituents, which would allow for
additional attachment of functional groups and manipula-
tion of binding affinity to the eIF4A-RNA complex. Along
these lines, Désaubry and coworkers have reported acyla-
mino- and sulfonamino-substitution at the C8b position of
the epi-rocaglaol scaffold as potential bioisosteric replace-
ments; unfortunately, these derivatives were not cyto-
toxic.5g A comprehensive SAR study of C8b-amino-substitu-
tion was not performed which may be due to challenges in
chemically modifying this position on the rocaglate core.
RESULT AND DISCUSSION
Discovery of the Intercepted Retro-Nazarov Reaction.
We recently synthesized tosyl-enol rocaglate (6a) from
keto-rocaglate (5a) in an effort to access aglaroxin C ana-
logue 8 (Scheme 1).5i In this transformation, we expected
conjugate addition of benzamidine followed by a tosylate
extrusion to afford enamine 7 under basic conditions which
may further cyclize to pyrimidinone 8. When triethylamine
or 4-dimethylaminopyridine (DMAP) were employed as ba-
ses, a trace amount of 8 was generated. In contrast, use of
sodium hydride (NaH) as base produced an unknown prod-
uct which had the same molecular weight as 7 but did not
undergo subsequent pyrimidinone cyclization. NMR studies
were not sufficiently informative to characterize the struc-
ture due to the lack of proton signals on the cyclo-
penta[b]benzofuran core. Instead, X-ray crystal structure
analysis was used to confirm the new structure as the
amidino-rocaglate (ADR) 9a (Scheme 1). Notably, in the
solid-state structure the imidazoline N-H moiety resides on
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the nitrogen replacing the C8b hydroxyl, retaining the rela- 6a (Scheme 2A) to alkoxide 11 which may result in intra-
molecular tosyl migration16 to afford tosylate enolate 12.
Subsequent ionization of the tertiary tosylate facilitates for-
mation of the stabilized oxyallyl cation 13. Based on the re-
activity observed, generation of the oxyallyl cation occurs
during warming and is a fast process. We have found that
the rates of subsequent trapping of oxyallyl cation 13 vary
for different amidines (vide infra) which suggests that this
is the rate determining step for the process. After formation
of the C-N bond in adduct 14, a rapid cyclization completed
the transformation and constructed the hemiaminal of 9a.
To further probe the mechanism (Scheme 2B), we used en-
antioenriched (-)-6a (>98 % ee) as starting material, which
was synthesized using either asymmetric ESIPT-mediated
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tive stereochemistry of the cyclopenta[b]benzofuran core.
Generally speaking, the imidazoline N-H has a lower pKa
(26.7-30.7 in DMSO) than a hydroxyl (tBuO-H: 32.2-32.5 in
DMSO) and thus may serve as a suitable hydrogen-bond do-
nor for biological target engagement. 12 In addition, the
newly-formed C1 hemiaminal hydroxyl group is situated on
the face corresponding to the same stereochemistry of
the secondary alcohol in rocaglates 1-4. According to previ-
ous SAR studies of rocaglate analogues, the overall reten-
tion of functional group stereochemistry of the rocaglate
scaffold is important to maintain inhibition of eIF4A-de-
pendent protein synthesis.5, 6
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Proposed Mechanistic Pathway. Mechanistically, we
[3+2] photocycloaddition or biomimetic kinetic resolution
propose that the amidine substitution proceeds through an
of an aglain ketone precursor.17
Compound (-)-6a was
, 4n-o
intercepted retro-Nazarov reaction process (Scheme 2).13 14
,
,
then subjected to amination using NaH and benzylamine. In
the event, oxyallyl cation 13 was trapped with benzylamine
to afford the amino-rocaglate (-)-15h in 90% yield. As ex-
pected, complete retention of chirality for amino-rocaglate
15 A number of elegant studies have been reported outlining
construction of the cyclopenta[b]benzofuran core of the
rocaglates using Nazarov cyclization.4l-m, p-q According to our
reaction protocol, NaH deprotonates the tertiary alcohol of
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15h (>98% ee) demonstrated that the retro-Nazarov reac- C8b position which correlates well with the trapping of ox-
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tion was irreversible from dienone 10. Otherwise, loss of
enantiopurity of amino-rocaglate 15h would be observed.
Additionally, when weak nucleophiles or no nucleophile
were used in the reaction, retro-Nazarov products 10 were
obtained (cf. red arrows, Scheme 2B).18 We also used oxy-
gen-based nucleophiles, including water and methanol, to
trap oxyallyl cation 13 to afford keto-rocaglate 5a and O-
methyl-rocaglate 5b.10 Alternative enol protection reagents,
including mesyl chloride, triflic anhydride,19 sulfonyl chlo-
ride,4g, 5g and diphenyl phosphoryl chloride20 were investi-
gated to generate oxyallyl cation precursors. Unfortunately,
only retro-Nazarov products were generated during enol
protection except when using mesyl chloride. However, the
corresponding mesyl-enol rocaglate10 failed to migrate and
generate product 9a under standard amidine addition con-
ditions (cf. Table 1) but instead afforded N-(methyl-
sulfonyl)benzenecarboximidamien and keto-rocaglate 5a.10
yallyl cation 13 with amidines from the convex face.
Syntheses of Amidino-Rocaglates. The intercepted
retro-Nazarov reaction was found to tolerate a wide range
of amidine and guanidine reaction partners (Table 1).
Rocaglates with various carbonyl substitutions were also
found to be workable. Generally, the intercepted retro-
Nazarov reaction was robust and operationally simple;
overall, 29 amidino-rocaglates were synthesized in good
yields. A general issue for this reaction was found with hy-
groscopic amidine salts which introduced trace amounts of
water competing with amidine nucleophiles to afford keto-
rocaglate 5a. The water content of amidines varies from
batches and vendors, so we did not optimize reaction con-
ditions for each substrate. However, simple azeotropic dry-
ing of the amidine salts using benzene was found to improve
product yields (e.g. 9e from 47% to 79%; 9g from 29% to
94%). Additionally, several amidine salts were found to
have poor solubility in reactions leading to recovery of 6. In
these cases, 25 mol% of NaHMDS (1M in THF) was used as
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To further understand the stereoselectivity of the inter-
cepted retro-Nazarov reaction, we performed a DFT analy-
sis of 13 at the B3LYP/6-31G** level21 which has been ex-
a proton shuttle (9e-g, 9m).
tensively used for computational studies of oxyallyl cation
After having initial success using benzamidine to gener-
ate 9a (88% yield), we next evaluated use of aliphatic ami-
dines. With increasing steric size of amidine substitution
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intermediates.
Interestingly, the DFT model of 13
(Scheme 2B) shows a trigonal, pyramidal carbocation at the
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(e.g. from methyl to t-butyl), we observed decreasing reac-
method enabled rapid access to a diverse collection of 29
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tion rates. Use of acetamidine afforded the corresponding
adduct 9b in 81% yield, whereas the highly hygroscopic bu-
tylamidine and pentylamidine afforded products 9c and 9d
in lower yields (54% and 61%, respectively). Likewise,
when a benzylamidine reagent was used, a 79% yield of ad-
duct 9e was obtained. Bulkier amidines such as neo-pen-
tylamidine and iso-butanamidine resulted in excellent
yields of the desired products 9f and 9g (88% and 94%, re-
spectively). Similarly, the cyclohexyl-substituted product 9i
was formed in 88% yield. Interestingly, the parent amidine,
guanidine, successfully generated compound 9j in a 70%
yield. We employed 2-methoxyl- and 2-chloroacetamidine
to access ADR’s with modification handles in excellent 9k
(90%) and 9l (92%) yields. Additionally, strained cyclopro-
pyl and cyclobutyl amidines were also tolerated in the reac-
tion affording derivatives 9m and 9n in 81% and 92%
yields, respectively. Unsymmetrical amidines generated 9o
and 9p in excellent yields (90% and 73%). Of note, 9o and
9p were formed as the major regioisomers, whereas the mi-
nor regioisomers were also formed through trapping by the
exocyclic nitrogen atom of the amidine reagents.10
amidino-rocaglate (ADR) derivatives.
Syntheses of Amino-Rocaglates. Inspired by mechanis-
tic considerations, we also sought to synthesize amino-
rocaglates utilizing amines as nucleophiles to trap oxyallyl
cation intermediate 13. Accordingly, we explored substrate
scope for the synthesis of amino-rocaglates5g under the
same conditions (Table 2). Our initial attempts employed
several primary amine derivatives to generate amino-
rocaglates in good yields (86% for 15a; 90% for 15b; 75%
for 15c). Of note, the use of N-methyl ethylenediamine (for
15c) reinforced that the oxyallyl cation intermediate pre-
fers to be trapped by the less hindered primary amine moi-
ety. The secondary amine residue in 15c may also be uti-
lized to introduce biological probes. Moreover, use of an al-
lyl amine reaction partner afforded 15d in 79% yield; pro-
pargylamide was also used to form alkynylated derivative
15e in 59% yield which may serve as a click-chemistry han-
dle. Likewise, we introduced an additional functionalized
side chain using butylamine dimethyl acetal to access com-
pound 15f in 73% yield. The acetal may eventually be con-
verted into a pendant aldehyde as a handle for further func-
tionalization. In addition to amines with useful modification
handles, we also investigated the steric effect of amines.
From methyl to adamantyl amine (15g to 15k), we ob-
served a slight decrease in yields for the desired amino-
rocaglates from (88% to 44%) and an increased trend of
retro-Nazarov products generation. Interestingly, the weak
nucleophile, aniline, was also able to trap the oxyallyl cation
affording 15l (70%). We found that tethered heterocycles
were also workable for amino-rocaglate synthesis. For ex-
ample, a tetrahydropyranyl amine was a successful trap-
ping reagent affording amino-rocaglate 15m (43%), while
N-morpholinyl ethyleneamine provided 15n with a remote
morpholine functional group in a moderate yield (60%).
Nevertheless, introduction of thiazole and imidazole heter-
In addition, we found that heteroaryl and aryl amidines
with various electronic properties provided the desired ad-
ducts in reasonable yields (75% for 9q; 55% for 9r; 93% for
9s; 84% for 9t; 62% for 9u; 72% for 9v). Moreover, both
Boc-protected piperidinyl and N-morpholinyl amidines
were used to generate adducts 9v and 9w in 67% yields. We
also tested a variety of rocaglate derivatives in reactions
with acetamidine. To this end, tosyl-enol rocaglamide 6z
yielded 9z in 83% yield, and tosyl-enol RHT 6aa led to com-
pound 9aa in 79% yield. To our delight, we found that the
amidine addition could also tolerate ketone (9ab, 92%) and
aldehyde functional groups on the rocaglate skeleton. Inter-
estingly, the aldehyde product subsequently underwent de-
hydration yielding the α,β-unsaturated aldehyde 9y (not
shown).10 Overall, this powerful late-stage functionalization
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ping method. In particular, we obtained a 25% yield of 15o
bearing the thiazole functional group, whereas use of an im-
idazole-tethered amine afforded product 15p in 49% yield.
To our delight, 3-picolylamine underwent the desired reac-
tion to afford a 70% yield of amino-rocaglate 15q. In addi-
tion, use of secondary amine such as diethylamine led to a
27% yield of 15r along with significant yield of retro-Naza-
rov products as the major product, highlighting limitations
with use of hindered amines. Finally, dimethyl hydrazine
broadened the scope of the intercepted retro-Nazarov reac-
tion to afford rocaglate hydrazine derivative 15s in 75%
yield.
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Late-Stage Functionalization of Amino-Rocaglates.
The derived amino-rocaglates 15 possess a higher oxida-
tion state than the natural rocaglates as silvestrol (1),
rocaglamide (2) and rocaglaol (not shown).5c-d, 4f, h To com-
pare the biological activity of amino-rocaglates with natural
rocaglates, we explored late-stage functionalization of
amino-rocaglate scaffold 15a (Scheme 3). Additionally, we
targeted modification of the methyl ester, as rocaglamide (2)
and RHT (4) display greater cytotoxicity than methyl
rocaglate (3) against several cancer cell lines.5, 6 Amide ex-
change of 15a generated amino-keto-rocaglamide 17 as a
useful synthetic intermediate. Subsequent reduction of 17
using borane dimethyl sulfide complex generated amino-
rocaglamide 18 (31%). Compound 15a was also converted
to amino-aglaroxin derivative 16 in 63% yield.5i On the
other hand, DMAP facilitated decarboxylation of 15a to af-
ford amino ketone 19 which was further reduced with
NaBH4 to afford amino-rocaglaol 20 in 71% yield in which
case syn-stereochemistry between the amine and alcohol
groups was observed. Additionally, oxime 21 was synthe-
sized using hydroxyl amine and triethylamine which was
followed by reduction with LiAlH4 to afford diamino-
rocaglate 22.
RNA base (Figure 1B).11 A correlated trend of IC50’s was ob-
served for carbonyl substitution (X = N(OMe)Me ≥ NMe2 >
OMe > Me), where 9aa and 9z showed excellent IC50’s of 59
BIOLOGICAL STUDIES
Structure-Activity Relationships. With amidino-
rocaglates and amino-rocaglates in hand, we evaluated
their inhibition of eIF4A-dependent translation using an in
vitro assay (Table 3A), wherein a bicistronic reporter mRNA
was designed for translation in Krebs-2 cell free extracts.23
In particular, translation of Firefly luciferase (FF) is cap-de-
pendent and depends on eIF4A activity; in contrast, transla-
tion of Renilla luciferase (REN) utilizes the HCV internal ri-
bosome entry site (IRES) which functions independently of
eIF4A. Relative IC50’s were determined by the inhibition of
FF obtained in the presence of compound relative to vehicle
controls and normalized to REN as an internal control. Our
previous enantioenriched lead compound, (-)-CR-1-31-B
(23), exhibited an IC50 of 272 nM in the bicistronic reporter
assay. As expected, amidino-rocaglates generally showed an
overall improvement in IC50; representative compounds are
shown for a preliminary discussion of SAR (Table 3B). In ac-
cordance with the eIF4A-RNA-rocaglamide (2) co-crystallo-
graphic analysis (Figure 1), the amide carbonyl of 2 inter-
acts with Gln195 of eIF4A as a H-bond acceptor, while the
tertiary hydroxyl of 2 serves as a H-bond donor to a guanine
and 63 nM, respectively. In contrast, the ester (9b, IC50
=
189 nM) and ketone (9ab, IC50 = 418 nM) were found to be
less potent supporting that the amide carbonyl of 9aa and
9z are more optimal H-bond donors to Gln195 of eIF4A. Ac-
cording to our previous findings, alkylation of the tertiary
hydroxyl of RHT (4) and rocaglamide (2) eliminated the
translation inhibition5c-d which was likely caused by disa-
bling their ability as H-bond donors. To further verify this
hypothesis, amidino-rocaglates (pKa of N-H 26.7 - 30.7 in
DMSO, strong H-bond donors)12b and amino-rocaglates
(pKa of N-H 36 to 44 in DMSO, weak H-bond donors)24
were next evaluated. Unfortunately, no translation inhibi-
tion by amino-rocaglates 15 and their derivatives 18, 20,
and 22 were observed.10 Preliminary SAR for ADR’s showed
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that the less sterically demanding alkyl amidines slightly in- priate formulation and drug-delivery strategies. Interest-
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creased potency for translation inhibition ranging from IC50
= 187 nM for the butyl derivative (9d) to IC50 = 267 nM for
the tert-butyl derivative (9f). Interestingly, aryl amidines
(e.g. 9a) were found to have dramatically decreased activity
(IC50 = 2500 nM) which may be caused by conformational
restrictions. Conversely, benzyl amidine 9e had IC50 = 60
nM, whereas the methylene tether may allow conforma-
tional adjustment to avoid rigid repulsion in the binding
pocket. Moreover, the guanidine-type structure (9j) as well
as methoxyl amidine (9k) also retained potent translation
inhibition (IC50 = 125 and 64 nM, respectively).10
ingly, we also noticed reduced cytotoxicity of the unnatural
enantiomer (+)-9aa (IC50 = 76 nM). To evaluate possible off-
target inhibition of ADRs, we also tested (-)-9aa and (+)-
9aa using the eIF4A1em1jp cell line, a CRISPR-modified
NIH3T3 line containing the F163L mutation within eIF4A1,
which exhibits rescue of the eIF4A1-dependent translation
inhibition of silvestrol (1).7c We found that the eIF4A1em1jp
cells were less sensitive to (-)-9aa and (+)-9aa in compari-
son to wild type NIH3T3 cells (Figure SI2) which indicates
that the cytotoxicity of (+)-9aa and (-)-9aa are eIF4A1 de-
pendent.10 In eIF4A1em1jp cells, the cytotoxicity observed
may be related to the remaining wild-type eIF4A2 paralog.
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To further characterize the effect of amidino-rocaglate
chirality on translation inhibition, we synthesized enanti-
oenriched analogues (-)-9b, (-)-9n, (-)-9z, (-)-9aa and (+)-
9aa. As expected, only the natural (-)-enantiomers inhibited
in vitro eIF4A-dependent translation with an IC50 of 34 nM,
which is an approximately 9-fold increase in potency to our
previous lead-compound (-)-23 (Table 4). On the other
hand, the unnatural enantiomer (+)-9aa showed minimal
activity.
7c
However, for (+)-9aa further studies are needed to rule
out unrelated mechanisms.
CONCLUSION
In summary, we have discovered an intercepted retro-
Nazarov reaction providing an oxyallyl cation precursor for
late-stage modification of rocaglate natural products.
Through formal substitution of the rocaglate C8b hydroxyl
group, we synthesized a library of more than fifty amidino-
and amino-rocaglates as novel modified natural product de-
rivatives. Subsequent biological evaluation of the modified
rocaglate derivatives revealed preliminary SAR for the inhi-
bition of eIF4A-dependent translation, which identified
amidino-rocaglate (-)-9aa having a 9-fold increase in po-
tency in comparison to (-)-CR-1-31-B (23). In agreement
with the recently reported X-ray crystallographic analysis of
eIF4A-RocA-polypurine RNA,11 we demonstrated that the
lower pKa of the amidine N-H vs the original tertiary O-H
moiety likely contributes to improved translation inhibition.
Meanwhile, the amide carbonyls of 9z and 9aa serve as H-
bond acceptors likely facilitating interactions with Gln195
of eIF4A, although this aspect awaits structural confirma-
tion. SRB assays in MDA-MB-231 cells demonstrated that
amidino-rocaglates may serve as valuable cancer chemo-
therapeutic agents. Our studies further illustrate the power
of chemical synthesis enabling structural and biological im-
provement of complex natural products using targeted
modifications. Additional biological studies of amidino-,
amino-rocaglates, and related compounds including RNA
binding studies, in vivo activity as translation inhibitors, and
anti-neoplastic activity in mouse cancer models are cur-
rently in progress and will be reported in due course.
Amidino-Rocaglates are Cytotoxic Towards Cancer
Cells. We next evaluated amidino-rocaglates in a sulforho-
damine B (SRB) assay using MDA-MB-231 breast cancer
cells for a cellular readout of cytotoxicity (Figure 2). In par-
ticular, (-)-9k, (-)-9z, (-)-9aa, and (+)-9aa were compared
with rocaglate hydroxamate (-)-23. We found excellent cy-
totoxicity of the ADR (-)-9aa with an IC50 = 0.97 nM with a
nearly 2-fold increase in potency over the previous lead-
compound (-)-23 (IC50 = 1.9 nM). In addition, the IC50 of di-
methylamide (-)-9z and methyl ester (-)-9k were deter-
mined to be 1.2 and 3.6 nM, respectively, showing a similar
overall trend as we have observed in the FF/HCV/REN as-
say (Table 3). The inspiring high-potency of amidino-
rocaglates (ADR) underscores their utility as promising
agents for anticancer treatment combined with the appro-
ASSOCIATED CONTENT
Supporting Information. Experimental details, characterization
data, and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*porco@bu.edu
*jerry.pelletier@mcgill.ca
Current Address
7
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ǂDepartment of Hematology and Oncology, Beth Israel Dea-
coness Medical Center, Boston, MA 02215, USA
(Boston University) for X-ray crystal structure analyses, Mi-
1
2
3
4
5
6
7
8
chael Smith (Boston University) for assistance plotting the X-
ray crystal structures, Dr. Aaron B. Beeler for suggesting DFT
calculations, and Dr. Xiao Wang (Merck & Co., Inc., Kenilworth,
NJ) for suggestions regarding NMR experiments and structure
elucidation of 9ac. NMR (CHE-0619339) and MS
(CHE0443618) facilities at Boston University are supported by
the NSF. Research at the BU-CMD was supported by NIH grant
GM-067041. We also thank Dr. Kyle Reichl (Amgen, Inc.) for
proofreading the manuscript.
Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
ACKNOWLEDGMENT
We thank the National Institutes of Health (R01 DK088787 and
R35 GM-118173) and the Canadian Institutes of Health Re-
search (FDN-148366) for research support, Dr. Jeffrey Bacon
9
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12, 5506. (c) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Anto-
line, J. E.; Hsung, R. P. Stereoselectivity in Oxyallyl–Furan (4
+ 3) Cycloadditions: Control of Intermediate Conformations
and Dispersive Stabilization in Cycloadditions Involving Ox-
azolidinone Auxiliaries. Chem. Sci. 2010, 1, 387. (d) Anto-
line, J. E.; Krenske, E. H.; Lohse, A. G.; Houk, K. N.; Hsung, R.
P. Stereoselectivities and Regioselectivities of (4 + 3) Cy-
cloadditions Between Allenamide-Derived Chiral Oxazoli-
dinone-Stabilized Oxyallyls and Furans: Experiment and
Theory. J. Am. Chem. Soc. 2011, 133, 14443.
16 For an O- to O-1,4-tosyl shift, see: (a) Zagorevskii, V. A.;
Kirsanova, Z. D. Migration of the Tosyl Group in 7-O-To-
sylesculetins. Khim. Geterots. Soedin. 1970, 6, 309; Chem.
Heterocycl. Compd. 1970, 6, 288. For N- to N-1,3-tosyl shift,
see (b) Mertens, M. D.; Pietsch, M.; Schnakenburg, G.; Gü-
tschow, M. Regioselective Sulfonylation and N- to O-Sulfonyl
Migration of Quinazolin-4(3H)-ones and Analogous Thieno-
pyrimidin-4(3H)-ones. J. Org. Chem. 2013, 78, 8966 and ref-
erence therein. For O- to N-1,4-tosyl shift, see (c) Andersen,
K. K.; Gowda, G.; Jewell, L.; McGraw, P.; Phillips, B. T. Substi-
tution at Tetracoordinate Sulfur(VI). Rearrangement of 2-
Aminoaryl Arenesulfonates to N-(2-Hydroxyaryl)arenesul-
fonamides. J. Org. Chem. 1982, 47, 1884.
23 Novac, O.; Guenier, A. S.; Pelletier, J. Inhibitors of Protein
Synthesis Identified by a High Throughput Multiplexed
Translation Screen. Nucleic Acids Res. 2004, 32, 902.
24 (a) Bordwell, F. G.; Drucker, G. E.; Fried, H. E. Acidities of
Carbon and Nitrogen Acids: the Aromaticity of the Cyclo-
pentadienyl Anion. J. Org. Chem. 1981, 46, 632. (b) Bordwell,
F. G. Equilibrium Acidities in Dimethyl Sulfoxide Solution.
Acc. Chem. Res. 1988, 21, 456.
17 For asymmetric [3+2]-photocycloadditions using ESIPT,
see: (a) Xia, B.; Gerard, B.; Solano, D. M.; Wan, J.; Jones, G.;
Porco, J. A., Jr. ESIPT-Mediated Photocycloadditions of 3-Hy-
droxyquinolinones: Development of
a
Fluorescence
Quenching Assay for Reaction Screening. Org. Lett. 2011, 13,
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