Water-compatible cycloadditions of oligonucleotide-conjugated strained allenes for dna-encoded library synthesis

Article abstract of DOI:10.1021/jacs.9b13186

DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with activated olefins, 1,3-dipoles, and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-barcoded compounds exhibit unprecedented ring and topographic features, related to elements found to be powerful in phenotypic screening.

Full text of DOI:10.1021/jacs.9b13186

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Article
Water-compatible Cycloadditions of Oligonucleotide-
conjugated Strained Allenes for DNA-encoded Library Synthesis
Matthias V. Westphal, Liam Hudson, Jeremy W. Mason, Johan
Pradeilles, Frederic J. Zecri, Karin Briner, and Stuart L. Schreiber
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13186 • Publication Date (Web): 08 Apr 2020
Downloaded from pubs.acs.org on April 9, 2020
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Water-compatible Cycloadditions of Oligonucleotide-conjugated
Strained Allenes for DNA-encoded Library Synthesis
Matthias V. Westphal,†,§ Liam Hudson,†,§ Jeremy W. Mason,†,§ Johan A. Pradeilles,†,§ Frédéric J.
Zécri,*,§ Karin Briner,*,§ Stuart L. Schreiber*,†,∥
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† Chemical Biology and Therapeutics Science Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA
§ Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA 02139, USA
∥ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA
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Supporting Information Placeholder
ABSTRACT: DNA-encoded libraries of small molecules are being explored extensively for the identification of binders in early drug-
discovery efforts. Combinatorial syntheses of such libraries require water- and DNA-compatible reactions, and the paucity of these reactions
currently limit the chemical features of resulting barcoded products. The present work introduces strain-promoted cycloadditions of cyclic
allenes under mild conditions to DNA-encoded library synthesis. Owing to distinct cycloaddition modes of these reactive intermediates with
activated olefins, 1,3-dipoles and dienes, the process generates diverse molecular architectures from a single precursor. The resulting DNA-
barcoded compounds exhibit unprecedented ring and topographic features—related to elements found to be powerful in phenotypic
screening.
published libraries. In response, recent work has expanded the
Introduction
toolbox of DEL chemists by identifying DNA-compatible
conditions for established off-DNA reactions. Examples for such
efforts include decarboxylative radical additions to Michael
acceptors,11,12 Ullmann-type N-arylations,13 maleimide Diels-Alder
reactions14a and intramolecular nitrone cycloadditions,14b and Ni/Ir
dual catalytic alkylations of aryl halides.15 The Brunschweiger
group has reported on DNA-compatible micellar catalysis16 and
introduced an approach in the solid phase towards hexathymidine-
conjugated heterocycles.17,18 In an alternative approach, two recent
reports describe DNA-immobilization on quaternary ammonium
resins to enable reactions under near anhydrous conditions
including decarboxylative sp2-sp3 cross couplings, electrochemical
aminations of aryl iodides, reductive aminations of ketones as well
as copper-mediated formation of heterocycles (tin amine protocol,
SnAP).19,20
The identification of small molecules that bind biological
macromolecules is a key step in early drug discovery. Target-
directed, binding-based approaches include high-throughput,
fragment, and in silico screening. While each of these techniques
has had significant impact on successful drug development
programs, they also have shortcomings. An additional approach
uses DNA-encoded libraries (DELs), which comprise collections
of compounds individually barcoded with DNA sequences that
report on the synthetic reactions leading to their formation.1 DELs
are typically prepared by split-and-pool synthesis from central
scaffolds and readily available building blocks as appendages. DEL
screens are commonly performed using immobilized proteins, and
barcode enrichment, as a surrogate for binding, is determined by
next-generation sequencing of PCR-amplified DNA. DELs are a
promising source of hit compounds with several examples having
advanced to clinical candidates.2 Beyond affinity-based screens,
recent work relying on spatial separation of individual library
members by microfluidics hint that DELs may become amenable
to activity-based screens.3,4 As for all hit-finding approaches,
compound libraries spanning diverse chemical space with features
well-suited for binding are considered most promising,5 especially
in the absence of known target binders.
A
: Spring-loaded reagents for bioconjugation
F
F
O
compatible with
water and
O
H
H
biopolymers
O
I
II
III
B
: Reported reactivity of heterocyclic allenes
highly versatile,
reactive intermediates
usually generated under
anhydrous conditions
X
Diversity-oriented synthesis (DOS) has been particularly
successful in generating structure-diverse, stereochemistry-rich
libraries that include many distinct, rigid ring skeletons that can
reduce the entropic cost of binding and effectively display
appendages in three-dimensional space.6 Often fueled by
advancements in reaction methodology, the application of DOS
principles has delivered numerous chemical probes and clinical
candidates.7 Merging the logic of DOS with DNA-barcoding holds
great promise for the identification of protein binders that can
function by novel mechanisms of action.8
N
Me
N
H
O
O
O
N
H
H
CbzN
O
CbzN
H
N
H
H
[2+2]
[4+2]
[3+2]
[3+2]
O
C
this work
)
: Strained allenes for DNA-encoded library synthesis (
Y
Z
X
OTf
CsF
allenophiles
SiEt3
R2
R2
H2O-DMSO, rt
N
N
The conventional solution-phase synthesis of DELs relies on
reactions that tolerate water (to keep DNA in solution) and
maintain barcode integrity.9,10 These constraints have limited the
range of transformations applicable to DEL construction and led to
an enrichment of sp2-rich structures and peptidomimetics in
R1
R1
rigid bi- and tricycles
structurally diverse
sp3-rich
Figure 1. A: Water-compatible reagents for bioorthogonal
chemistry. trans-Cyclooctene (I) rapidly undergoes inverse-
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electron-demand Diels-Alder reactions with tetrazines.
Figure 2. Preparation of on-DNA strained allene precursor 3 by
conjugation of rac-2 to DNA-headpiece (DNA-HP). For
experimental details, see SI, Section 4c.
Cyclooctyne derivatives (II, III) undergo strain-promoted azide-
alkyne cycloadditions. B: In situ generated heterocyclic allenes
exhibit distinct cycloaddition modes with activated olefins, dienes
and 1,3-dipoles (major diastereomers shown). C: Fluoride-induced
formation of DNA-conjugated heterocyclic allenes and trapping
with various allenophiles affords structurally diverse cycloaddition
products.
With this material in hand, on-DNA strained allene generation
was investigated. To this end, 3 was combined with varying
amounts of cesium fluoride and azomethine imine 5 in DMSO-
water mixtures (10 µL total volume) for defined time intervals
(Table 1). Following ethanol precipitation, reaction outcomes were
analyzed by UPLC-MS and quantified by integration of UV
absorption (260 nm), neglecting non-DNA species as judged by the
absence of signal in the total ion chromatogram. In these
experiments, water content emerged as a critical parameter
inversely correlating with the consumption of 3 (entries 1-3). After
24 h, significant conversion was observed only for the reaction with
the lowest water content (75% DMSO), resulting in efficient
formation of a new species, the deconvoluted mass of which agreed
with cycloaddition product 6. The slow conversion in presence of
water, presumably originating from fluoride ion hydration, could
be overcome by increasing the concentration of activating agent
(entries 4-7). With further reduced water content (90% DMSO),
full consumption of 3 was observed with as little as 125 equivalents
of cesium fluoride (ca. 6 mM final concentration) within 1 h
(entries 8 and 9). Importantly, throughout the series the only
detected DNA-species were 3 and 6, provided the concentration of
trapping agent 5 was sufficiently high (entries 10-12), indicating
the desired transformation to be highly selective.
Strain-promoted reactions have found widespread application in
chemical biology. Prominent examples are the copper-free [3+2]
cycloaddition of cyclooctyne-derivatives with organic azides21,22
and the inverse-electron-demand Diels-Alder reaction of trans-
cyclooctene with tetrazines (
Figure 1, A).23,24 Having significantly advanced the field of
bioconjugation chemistry, these and related reactions are
compatible with water and biopolymers by necessity.25 With only
one recent report on inverse-electron-demand Diels-Alder
reactions26 and reactions of cyclooctyne-DNA conjugates in the
solid phase,27,28 strain-promoted reactivity has not yet found
general application in the context of DELs.
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When contained within 8-membered rings and smaller, cyclic
allenes show increased reactivity and readily undergo strain-
releasing reactions.29,30 Both carbo- and heterocyclic allenes have
been prepared under anhydrous conditions by the action of
alkyllithiums on dihalocyclopropane precursors (Doering–Moore–
Skattebøl rearrangement),31,32 by base-induced elimination of
vinylbromides,33 or more recently by fluoride-induced β-
elimination of silyl-vinyl-triflates.34–36 Importantly, strained
allenes exhibit distinct cycloaddition modes with olefins, 1,3-
dipoles, and furans/N-substituted pyrroles to undergo [2+2], [3+2]
and [4+2] reactions, respectively.36–38 The possibility to generate
diverse molecular architectures from a common precursor (
Table 1. Formation and trapping of a DNA-conjugated
strained allenes.a
N
H
O
N
N
OTf
N
N-
N+
SiEt3
Me
N
O
H
5
Figure 1, B) renders these intermediates particularly interesting
in the context of diversity-oriented synthesis. Motivated by a recent
report on azacyclic allene reactivity by the Garg group,37 we here
document the successful implementation of strain-promoted
cycloadditions for DNA-encoded library synthesis (
N
6
CsF
O
O
O
O
aq. DMSO
rt, time
H
H
N
N
3
O
O
Figure 1, C).
Results and Discussion
#
5 [mM]
15
CsF [mM]
50
%DMSO
25
t [h]
24
24
24
1
3 [%]
100
97
0
6 [%]
0
Our efforts commenced with the preparation of DNA-conjugated
allene precursor 3 designed to minimally perturb steric and
electronic factors of piperidine-derivative 4 used in Garg’s off-
DNA study.37 Racemic benzoic acid-derivative rac-2 was prepared
in four steps from 1 closely resembling the published synthetic
strategy towards 4 (see SI, Section 4c). rac-2 was elaborated into 3
by amide conjugation to a double stranded DNA-headpiece (DNA-
HP) developed by researchers at GlaxoSmithKline.39
1
2
3
4
5
6
7
8
9
15
50
50
3
15
50
75
100
98
100
100
100
100
15
1000
500
750
375
~6
50
2
50
1
28
1
72
75
1
99
75
1
28
0
72
OTf
OTf
OTf
SiEt3
Me
SiEt3
Me
90
1
100
73
SiEt3
Me
15
~3
90
1
27
0
DMTMM
DNA-HP
OMe
N
N
4 steps
N
SiEt3
10
11
12
a
2
50
90
12
12
12
100
95
CO2Bn
O
O
O
O
4
1
50
90
0
N
1
H
N
0.5
50
90
0
84
rac-2
3
CO2H
O
Reactions were performed at room temperature with 3
(0.5 nmol) in a total volume of 10 µL for the indicated time.
Following ethanol precipitation, residual 3 and newly formed 6
were detected by UPLC-MS and quantified (%AUC) by integration
of UV chromatograms (260 nm) considering DNA-species only.
The relative configuration of the two newly formed stereogenic
HO
O
P
O
O
O
O
OMe
TGACTCCC
ACTGAG
N
N
3
Cl-
N+
O
Me
N
OMe
O
HO P
O
P
O
HO
O
O
DMTMM
O
O
O
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centers in 6 indicates the expected major product as observed in
SI, Table S2); 3) water content critically influences the rate of
conversion (higher water content slows the reaction); 4) higher
fluoride concentrations increase the rate of conversion. Encouraged
by these results, the scope of the reaction was evaluated with a
variety of 1,3-dipoles, olefins and N-substituted pyrroles
(Figure 3). In order to attenuate potential reactivity differences,
building blocks were
off-DNA precedence.[37] For additional data, see SI, Table S1.
These initial experimental results allow for the following
conclusions: 1) DNA-conjugated strained allenes can be formed in
aqueous solution and exhibit considerable lifetime in the medium;
2) cycloadditions with azomethine imine 5 take place efficiently
and rapidly in aqueous mixtures of DMSO (for other solvents, see
Y
Z
X
OTf
1,3-dipole
or pyrrole
or olefin
SiEt3
Me
9
(180 mM)
N
3
N
10
11
12
13
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CsF (200 mM)
O
O
O
O
90% aq. DMSO
rt, 1 h
H
H
N
N
7–9
O
O
O-
N+
N
O-
N+
N
O-
N+
Et
O-
N+
R1
N
O
O-
N+
N
R2
O-
N+
S
Et
N
N
7
7a
92%
7b
>95%
7c
>95%
7d
>95%
7e
sluggish
7f
0%
[3+2]
O
NH2
NO2
CO2Me
O
N
N
N
HN
N
N
R1
R2
8a
>95%
8b
>95%
8c
8d
>95%
8i
57%
8j
48%
NH2
N
>95%
R3
CO2H
H2N
O2N
NH2
HO
N
8
N
N
N
N
[4+2]
N
N
8e
8f
8g
74%
8h
8k
8l
>95%
>95%
81%
25%
46%
N
HO
N
N
HN
HN
S
O
S
O
O
9a
9b
9c
9d
9q
9r
>95%
>95%
>95%
>95%
28%
DNA alkylation
NH2
N
O
S
O
O
N
O
O
N
S
N
N
N
H
N
H2N
N
R2
9e
93%
9f
95%
9g
9h
9s
9t
R1
>95%
91%
0%
DNA alkylation
N
O
O
O
9
O
P
O
O
PO(OEt)2
N
N
H
[2+2]
N
H
OH
OH
O
9i
9j
9k
9l
9u
9v
>95%
>95%
>95%
>95%
0%
0%
NH2
O
O
O
N
H
HN
N
9m
9n
9o
9p
>95%
9w
0%
9x
0%
>95%
>95%
>95%
Figure 3. Selected examples of building blocks used in strain-promoted cycloaddition reactions of DNA-conjugated allenes derived in situ
from 3. Product display (%AUC) was determined by integration of UV signals (260 nm) considering DNA-species only. For additional
examples of [2+2] reactions, see SI, Figure S5. For titration experiments with each type of cycloaddition partner, see SI, Figure S6.
used in excess (180 mM final concentration). Nitrones derived
from both aromatic and aliphatic aldehydes (7a-7d) participated in
the transformation to give the expected [3+2] cycloaddition
products of type 7 in high purity (>95 %AUC). Ketone-derived
nitrone 7e resulted in a sluggish reaction profile, presumably due
to higher steric hindrance of the dipole. Pivaldehyde-derived
nitrone 7f did not afford the expected product. Instead, a species
with an apparently missing tert-butyl group was detected. This
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result could be explained by fast cycloaddition of a competing
show signs of DNA alkylation. Although observed in 90% aq.
DMSO, these findings might have implications not only in the
context of DNA-encoded library synthesis, but for the field of
bioconjugate chemistry in general, where maleimides (EDMSO ≈ -
14) are often used, as well as for toxicological assessment of
electrophilic drugs.
nitrone formed from small quantities of formaldehyde present in
DMSO (see SI, Figure S1). [4+2] reactions of N-substituted
pyrroles (8a-8h) efficiently afforded bridged tricyclic compounds
of type 8 and tolerated the presence of numerous functional groups
(nitro, aniline, phenol, aldehyde, ester). The presence of carboxylic
acid 8k slowed the consumption of starting material and resulted in
formation of a species exhibiting a mass in agreement with either a
ketone originating from triflate hydrolysis and desilylation or an
allylic alcohol resulting from hydration of the intermediate allene
(req. m/z 5208 Da, found 5209 Da). A species with the same
retention time and mass spectral properties was formed in presence
of excess primary amine 8l. The slowed consumption of starting
material in the presence of acidic protons as in 8k appears to be a
general phenomenon (see SI, Table S3). The supposed fluoride
sequestration might be explained by hydrogen bond formation and
could be overcome by lowering the concentration of the acidic
building block, thereby increasing the ratio of fluoride to acid (see
SI, Table S4). Alternatively, fluoride sequestration may also be
overcome by the addition of basic buffer (see SI, Figure S2).
Unlike reagent classes such as boronic acids, aldehydes or
amines, the number of commercially available 1,3-dipoles is
limited. Thus, a combinatorial synthesis of such building blocks
ideally avoiding tedious purification would be highly desirable. We
therefore attempted the synthesis of a test set of azomethine imines
by simply combining 3-pyrazolidinone with various aldehydes in
ethanol. Incubation of the resulting mixtures at room temperature
overnight, removal of the volatiles and reconstitution of residual
material in DMSO afforded solutions for immediate use in on-DNA
reactions, notably without purification. Assuming quantitative
azomethine imine formation, on-DNA precursor 3 was combined
with 1,3-dipoles (15 mM final concentration) and cesium fluoride
(50 mM final concentration) in 90% aqueous DMSO. In this non-
optimized procedure, about half of the building block solutions thus
prepared validated (>80%AUC) to afford the expected DNA-
species as identified by UPLC-MS analysis following ethanol
precipitation (see SI, Figure S7).
9
10
11
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[2+2] cycloadditions of commercial activated and non-activated
olefins were investigated next. Vinyl (hetero-)aromatics and
acrylamides including 1,1-disubstituted congeners performed very
reliably in the reaction (9a-9p). Interestingly, N-vinyl amide 9g
efficiently afforded the expected species while the analogous
process with enol ether derivative 9v resulted in no significant
product formation. This finding is in agreement with relative
estimated radical stabilization energies (RSE) of initial diradical
species, which are the presumed intermediates in this type of [2+2]
cycloaddition.30,40 The difference in RSE of relevant O- and N-
stabilized radicals was calculated to favor the latter by ca. 25 kJ/mol
(see SI, Figure S3).41
While DNA-conjugate 3 was shown to undergo fluoride-induced
elimination readily to form a highly reactive strained allene that
could be trapped even in aqueous media, it is amenable to one-step
diversification only—provided no additional functionalities are
introduced by virtue of the cycloaddition partners. To highlight the
promise of the described transformation in terms of combinatorial
DEL synthesis, a second-generation substrate (11) was prepared by
conjugating rac-10 to a PEG-linker extended version of DNA-HP
(AOP-HP) via amide bond formation. 11 exhibits a nosyl group on
nitrogen, the on-DNA deprotection of which has been described,43
and as such offers two points of diversification (strained allene
cycloaddition, N-capping). In addition, library synthesis should
benefit from spatial separation of the nucleophilic nitrogen and the
cycloaddition product appendages, providing more uniform
reactivity during N-capping reactions. Figure 4 shows four
examples of a synthetic sequence involving strain-promoted
cycloadditions/Ns-deprotection to afford intermediate piperidines,
which were subjected to N-sulfonylations using 2-
methylbenzenesulfonyl chloride as a representative N-capping
reaction (Figure 4, A). Final products 12-15 were derived in 79-
96 %AUC as evident from the UV chromatograms (Figure 4, B).
The reaction with vinyl sulfone 9r afforded several species that
could be only partially resolved chromatographically. Inspection of
mass spectra indicated formation of multiple adducts, most likely
arising from the desired [2+2] cycloaddition and additional DNA
alkylation reactions (up to seven events by mass spectrometry (see
SI, Figure S4). This finding prompted us to examine a variety of
acceptor-substituted olefins of varied electrophilicity on the Mayr
reactivity scale42 (see SI, Table S5). Qualitative correlation of the
reaction outcomes with the corresponding electrophilicity
parameters of building blocks revealed that electrophiles with
EDMSO > -19 tend to undergo DNA alkylation reactions under the
chosen conditions (90% aq. DMSO, 180 mM building block,
200 mM CsF, 1 h, rt). Less electrophilic building blocks did not
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A
N
N
N
O
MeO
or
N
N
N
O
OTf
N
SiEt3
OTf
DMTMM
AOP-HP
O
SiEt3
a, b
O
6
7
8
or
or
N
S
O
N
S
O
N
S
N
S
O
3
N
NH
O
O
O
O
3
N
CO2H
Ns
O
O
Ns
9
rac-10
11
12
13
14
15
10
11
12
13
14
15
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B
12
(96%)
13
(92%)
14
(79%)
15
(88%)
req. 5688 Da
found 5689 Da
req. 5652 Da
found 5653 Da
req. 5647 Da
found 5649 Da
req. 5654 Da
found 5655 Da
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
time [min]
time [min]
time [min]
time [min]
Figure 4. A: Synthesis of DNA-conjugated strained allene precursor 11 enables two-step diversification. Reagents and conditions: a) 11
(5 nmol), 1,3-dipole or styrene derivative (25 mM), CsF (23 mM), 90% aq. DMSO, rt, 1 h; then 4-methoxythiophenol (85 mM), carbonate
buffer (pH10), 60% aq. DMSO, 80 °C, 1 h. For UPLC-MS analysis of intermediate piperidines, see SI, Figure S8; b) 2-
Methylbenzenesulfonyl chloride (40 mM), phosphate buffer (pH8), 20% aq. MeCN, rt, 12 h. B: UPLC-MS analysis of N-sulfonylation
reactions following EtOH precipitation indicates efficient formation of compounds 12-15 (orange: UV (260 nm), blue: total ion
chromatogram). Figures in parentheses refer to %AUC of the corresponding species.
In accord with off-DNA precedence,38,44,45 we note that the here-
described on-DNA transformations are expected to form
diastereoisomeric mixtures of varying ratios. Indeed, the
corresponding UV chromatograms regularly show split peaks (see
Figure 4, B and SI) sharing the same mass spectral properties. We
acknowledge that this property of the presented on-DNA process
may complicate off-DNA hit validation following a library
screening campaign but advocate for its widespread use given the
unprecedented nature of the formed products. In this context, a
substructure search of cores 7-9 in the ChEMBL database returned
zero hits,46 supporting the notion that derivatives of these structures
are indeed covering uncharted chemical space.
The present work describes a rare example of a DNA-compatible
process allowing the synthesis of highly structurally diverse, rigid
core structures of high sp3-content from a single precursor.
Extension of the concept to other strained allene precursors
including bicyclic and seven-membered systems may further
expand the scope of unprecedented structures that can be
incorporated into DNA-encoded libraries. Given the convenient
reaction setup, the remarkably efficient and selective reaction
profiles and the number of commercially available or easily
prepared building blocks, strain-promoted cycloaddition reactions
should find widespread use in the field of DNA-encoded library
synthesis.
In an additional experiment, aliquots of the intermediate
piperidine-DNA conjugates, isolated and purified by standard
ethanol precipitation, were subjected to T4 DNA ligase-mediated
ligation reactions with a 23-basepair primer sequence. The success
of these ligations was confirmed by gel electrophoretic analysis
(see SI, Figure S9). Furthermore, real-time polymerase chain
reaction (qPCR) studies were performed to assess the extent of
potential DNA degradation during the reaction.[9] To this end, a
full-length DNA-encoded library was subjected to conditions with
varied DMSO and cesium fluoride content (see SI, Figure S10).
Subsequent quantification of amplifiable material did not indicate
any DNA degradation in samples treated with CsF (100 mM) in
85% aq. DMSO. Samples incubated with very high fluoride
concentrations (4 M CsF in 50% aq. DMSO or 3 M CsF in 75% aq.
DMSO) showed ca. 80% remaining amplifiable material. Notably,
all test conditions in this degradation study used substantially more
activating agent than needed for efficient allene formation (see
Table 1 and SI, Table S1). In conclusion, the successful outcome
of enzymatic ligation reactions with samples that underwent strain-
promoted cycloadditions along with negligible DNA degradation
warrants a promising integration of the described transformation
into existing DEL synthesis workflows.47
ASSOCIATED CONTENT
Supporting Information
Supplementary tables and figures, detailed experimental
procedures (off and on-DNA work), and analytical data.
AUTHOR INFORMATION
Corresponding Authors
*stuart_schreiber@harvard.edu
*karin.briner@novartis.com
*frederic.zecri@novartis.com
ORCID
Matthias V. Westphal: 0000-0003-0693-0789
Stuart L. Schreiber: 0000-0003-1922-7558
Notes
The authors declare the following competing financial interests:
S.L.S. serves on the Board of Directors of the Genomics Institute
of the Novartis Research Foundation (“GNF”); is a shareholder and
serves on the Board of Directors of Jnana Therapeutics; is a
shareholder of Forma Therapeutics; is a shareholder and advises
Conclusion
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Catalyzed DNA-Encoded Library Synthesis. J. Am. Chem. Soc. 2019, 141,
3723–3732.
Kojin Therapeutics, Kisbee Therapeutics, Decibel Therapeutics
and Eikonizo Therapeutics; serves on the Scientific Advisory
Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo
Therapeutics, and F-Prime Capital Partners; and is a Novartis
Faculty Scholar.
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ACKNOWLEDGMENT
John Capece, Jennifer Poirier, Philip Michaels, Carmelina Rakiec,
Thomas Dice and Ritesh Tichkule are gratefully acknowledged for
excellent technical and analytical support. Bruce Hua and Drs.
Christopher Gerry, Wenyu Wang, Christian Gampe, Simone
Bonazzi, Nichola Smith and Frédéric Berst are gratefully
acknowledged for general support, fruitful discussions and
valuable feedback during preparation of this manuscript. The
research was supported in part by the National Institute of General
Medical Sciences (R35GM127045 awarded to S.L.S.) and by the
NIBR Scholar’s Program.
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Supporting Information.
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OTf
H
N
SiEt3
O
N
N
Ns
Ns
5
on-DNA strain-promoted cycloadditions
6
7
R
R'
R
N
N
R
structural diversity
O
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or
or
rigid, sp3-rich scaffolds
water- & DNA-compatible
N
N
N
Ns
Ns
Ns
[2+2]
[3+2]
[4+2]
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