A Strategy for the Synthesis of Sulfonamides on DNA

Article abstract of DOI:10.1021/acs.orglett.9b03843

An efficient method is reported to synthesize sulfonamides on DNA from sulfinic acids or sodium sulfinates and amines in the presence of iodine under mild conditions. This method demonstrates a major expansion of scope of sulfonamide formation on DNA through the utilization of a novel sodium carbonate-sodium sulfinate bifunctional reagent class.

Full text of DOI:10.1021/acs.orglett.9b03843

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Strategy for the Synthesis of Sulfonamides on DNA
Wei Liu,† Wei Deng,† Saisai Sun,† Chunyan Yu,† Xubo Su,† Aliang Wu,† Youlang Yuan,† Zhonglin Ma,†
Ke Li,† Hongfang Yang,† Xuanjia Peng,*,† and Justin Dietrich*,‡
†WuXi AppTec (Shanghai) Co., Ltd. 288 Middle Fu Te Road, Shanghai 200131, China
‡Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States
S
* Supporting Information
ABSTRACT: An efficient method is reported to synthesize
sulfonamides on DNA from sulfinic acids or sodium sulfinates
and amines in the presence of iodine under mild conditions.
This method demonstrates a major expansion of scope of
sulfonamide formation on DNA through the utilization of a
novel sodium carbonate−sodium sulfinate bifunctional reagent
class.
ince the first report of DNA-encoded chemical libraries
(DELs) by Brenner and Lerner in 1992, there has been a
S
steady increase in attention from both the pharmaceutical and
academic sectors and has evolved into an extremely powerful
tool for medicinal chemists.1 Initial technology development
focused mostly on coding large peptide-like libraries; however,
reports by early adopters demonstrated that drug-like
molecules could be made on DNA and screening those
libraries could identify viable starting points that were
ultimately developed into clinical candidates.2 Today, almost
all pharmaceutical companies have incorporated encoded
library technologies (ELT) as part of their screening strategy
and many companies have been established that provide
support services to enable everything from synthesis to
screening of DELs.
Figure 1. Representative sulfonamide drugs.
Because of the limited stability of sulfonyl chlorides in water,
the reverse reaction where a sulfonyl chloride is conjugated to
DNA, HP-2N, and is then reacted with various amines to form
P-2 is beyond the scope of reported sulfonamide formation
reactions used to generate DELs. To improve the overall scope
of sulfonamide formation in the generation of DELs, we have
identified sulfinic acids and sodium sulfinates as water-soluble
and water-stable intermediates that can be readily converted to
sulfonamides in the presence of iodine. This methodology has
been utilized to design a novel sodium carbonate−sodium
sulfinate bifunctional reagent class that can be activated when
conjugated to ds-DNA, HP-2, to provide reverse sulfonamides
represented by P-2.
Considering the sensitivity of sulfonyl chlorides to water, our
efforts were focused on developing mild conditions that would
allow the sulfonylation to occur in water and under ambient
conditions. From the outset of study, we were encouraged by
the formation of sulfonamides promoted by iodine.7 It was
found that an amine attached to double-stranded DNA
(dsDNA), called headpiece 1 (see the structure in the
Supporting Information, SI),2a could undergo sulfonylation
One of the limitations of encoded library technologies
centers on the relatively small number of chemistry method-
ologies validated to encode small molecule synthesis on DNA.
To improve the structural diversity and chemical space
coverage of DNA-encoded libraries, there is an imminent
need to expand the number of compatible reactions in the
presence of double stranded DNA.3 More specifically,
methodologies must not alter DNA and should be compatible
with water, or aqueous solutions, within a pH range of 4−14.2h
The sulfonamide functional group has been incorporated
into a number of drugs (Figure 1) and is associated with a
multitude of biological activities. Because of the ability of
sulfonamides to interact with metals, amino acids, and nucleic
acids, sulfonamide formation is an important component of a
medicinal chemist’s toolbox of reactions.4 Typically, the most
common method to construct sulfonamides is the sulfonylation
of amines with sulfonyl chlorides in various organic solvents.5
Extending this methodology to sulfonamide formation of an
amine intermediate that is attached to DNA, HP-1, to form
DNA-conjugated sulfonamide, P-1, required the optimization
of aqueous buffer conditions and is now a well-established
methodology that is utilized primarily in sulfonamide capping
designs for DNA-encoded library generation (Scheme 1).3b,6
Received: October 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03843
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Letter
Scheme 1. Previous Work vs Current Work of On-DNA
Sulfonylation
Table 1. Optimization of Sulfonylation via DNA 1 and
a
Sodium Benzenesulfinate
H2O/Buffer
solution (pH)
Oxidant: PhSO2Na Conversion
Entry Oxidant
(equiv)
(%)
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
H2O
7.0
8.5
9.5
12.0
9.5
9.5
9.5
9.5
9.5
9.5
9.5
9.5
9.5
9.5
100:200
100:200
100:200
100:200
100:200
100:100
50:100
25:50
50:100
50:100
50:100
50:100
0:50
13
11
40
89
65
30
88
60
79
80
78
0
9
NCS
NBS
NIS
NaClO
−
10
11
12
13
14
15
0
91
93
b
c
I2
I2
50:100
50:100
a
Reaction conditions: Headpiece 1 solution (1 equiv, 5 μL, 1 mM in
H2O; 1 mM in 250 mM, pH 7.0/8.5/12.0 phosphate buffer solution;
1 mM in 250 mM, pH 9.5 borate buffer solution), PhSO2Na (200
mM in H2O), I2 (400 mM in EtOH)/ NCS, NBS, NIS (400 mM in
b
DMA)/NaClO (400 mM in H2O), 25 °C for 16 h. A dsDNA of
with sodium benzenesulfinate aa in the presence of iodine to
form DNA-conjugated benzenesulfonamide 1aa in 13% yield
when reacted in water (Table 1, entry 1). Optimization of this
reaction first focused on modulating the pH by incorporating
various buffer solutions ranging from pH 7.0 to 12.0 (Table 1,
entries 2−5). The optimal pH was found to be pH = 9.5 (entry
4) and provided an increase in yield to 89%. Next we looked at
lowering the ratio of iodine to sodium benzenesulfinate from
2:1 to 1:1 at the optimal pH of 9.5 (entry 6). A ratio of 1:1 was
less favorable and provided only a 30% yield. Lowering the
overall equivalents of reagents to 50 equiv of sodium
benzenesulfinate and 100 equiv of iodine did not adversely
affect the overall yield (entry 7); however, further reduction to
25 and 50 equiv respectively decreased conversion to the
desired product. Finally, several other oxidants were tested to
replace iodine. NCS, NBS, and NIS gave very similar results.
No product was detected when NaClO was utilized or no
oxidant. Because there was no advantage identified in using
other oxidants, iodine was the oxidant of choice. To
summarize, entry 7 represents the optimal conditions identified
in this study. Due to the extra small scale of reaction on DNA
synthesis, it is hard to perform characterization by NMR. So
the reaction conditions were applied to synthesize sulfona-
mides from small molecules (sulfinate and amine), and the
products were characterized by 1H and 13C NMR (see SI).We
also conducted the sulfonylation by dsDNA of different
sequence or longer sequence, and comparable conversions
were obtained (entries 14 and 15). Considering possible
suroxidation of nucleobases in the condition, the chemo-
selectivity of the sulfonylation was tested. When using a new
DNA compound in which the amino group was blocked by
amidation of benzoic acid, about 1% suroxidation of
nucleobases was observed.
c
different sequence was used. dsDNA of longer sequence 41 was used
(see the structure in SI).
(Table 2, ab−ad). The results showed that both electron-
deficient (ab) and electron-rich (ac, ad) sodium sulfinates
underwent efficient sulfonylation with headpiece 1, giving high
conversions over 80%. Further investigation focused on
evaluating whether there was an increase in overall scope in
comparison to sulfonyl chlorides by identifying 14 sulfonyl
chlorides (average yield = 17%) that performed poorly
(conversion <40%) in sulfonamide formations in previous
DEL monomer validation studies. The respective sodium
sulfinates were synthesized (see SI), and then their reactivity
was evaluated under our optimal conditions with headpiece 1.
The average yield of all 14 sodium sulfinates in comparison to
sulfonyl chlorides was improved to 77% from 17%. The results
showed that, under the optimal conditions, the heterocycle-
subsituted sodium sulfinates improved the conversion greatly.
The disubstituted sulfinates were also active, while the more
hindered 2, 5-difluorobenzenesulfinate was less reactive.
Besides, a variety of sodium sulfinates containing pyridine
and quinoline were also studied, and it was found that they
could effectively react with headpiece 1 to provide the desired
product with mild to high conversion. Moreover, the oxidized
condition also tolerated nitrile, Boc, and carboxylic acid
groups. Neither sodium sulfinate nor sulfonyl chloride with
substituted pyrimidine could provide the corresponding
product probably due to their sluggish reactivity.
For the next part of our study, we evaluated the scope of the
amine component in this reaction (Table 3). To this end, 29
unnatural amino acids appended to headpiece 1 provided 8
alkyl primary amines, 14 alkyl secondary amines, 6 aromatic
primary amines, and 1 aromatic secondary amine. The results
showed that all aliphatic amines, whether primary or
To determine the scope of the reaction, three commercially
available para-substituted sodium sulfinates were evaluated
B
DOI: 10.1021/acs.orglett.9b03843
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Table 2. Substrate Scope of the Sulfonamide Formation
Table 3. Substrate Scope of the Sulfonamide Formation
from Different DNA-Conjugated Amine and Sodium
from DNA-Conjugated Amines and Sodium
a
a
Sulfinate
Benzenesulfinate
a
Reaction conditions: Headpiece 1 solution (1 equiv, 5 μL, 1 mM in
250 mM, pH 9.5 borate buffer solution), RSO2Na (100 equiv, 200
mM in H2O), I2 (50 equiv, 400 mM in EtOH), 25 °C for 16 h. The
conversion by using sulfonyl chloride is in parentheses.
a
Reaction conditions: Headpiece 2−30 solution (1 equiv, 5 μL, 1
mM in 250 mM, pH 9.5 borate buffer solution), PhSO2Na (100
equiv, 200 mM in H2O), I2 (50 equiv, 400 mM in EtOH), 25 °C for
16 h.
secondary, gave good to excellent conversion (average 89%).
Most anilines also gave excellent yields, except for hetero-
aromatic amines (28, 29, and 30) and sterically blocked
anthranilamide 26.
Scheme 2. Preparation and Stability Study for DNA-
Next, we aimed at employing this methodology to convert a
DNA conjugated sulfinic acid, or sodium sulfinate, to
sulfonamide. In Table 2, au was presented, which has a
sodium carboxylate para to the sodium sulfinate. In this
methodology development, the sodium sulfinate portion could
be activated in the presence of a free carboxylate. For this
study, we postulated that we could also orthogonally activate
the sodium carboxylate. To this end, we first reacted the
bifunctional sodium carboxylate-sodium sulfinate reagent with
HCl solution to remove the sodium salt and then activated the
sodium carboxylate with HATU in the presence of DIPEA in
pH 9.45 buffer (Scheme 2). With this method, we were able to
form the DNA conjugated benzene sulfinate in 99% yield. The
DNA conjugated benzene sulfinic acid was kept open to air in
buffer to investigate its stability. After 2 weeks, no oxidized
product 31-ox was detected; however, when 2 equiv of iodine
were added to 31, a 97% conversion of 31-ox was observed. In
order to limit the formation of 31-ox, the order of addition and
equivalents was explored. It was found that first adding 600
equiv of amine and then 10 equiv of iodine resulted in the
optimal conversion to the desired sulfonamide product.
Conjugated Benzene Sulfinic Acid
Similar to our studies in Table 3 for the generation of
sulfonamides from DNA-conjugated amines, the scope of
amines by employing ammonium hydroxide, primary alkyl
amines, secondary alkyl amines, and primary aryl amines were
C
DOI: 10.1021/acs.orglett.9b03843
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explored (Table 4). In all cases, good to excellent conversions
were observed, except for electron-deficient anilines bp and bs
Table 5. Substrate Scope of the Sulfonamide Formation
from DNA-Conjugated Sulfinic Acids and Morpholine
a
Table 4. Substrate Scope of the Sulfonamide Formation
from DNA-Conjugated Benzenesulfinic Acid and Amines
a
a
Reaction conditions: Headpiece 31−40 solution (1 equiv, 5 μL, 1
mM in H2O), morpholine (600 equiv, 200 mM in NMP), I2 (10
equiv, 10 mM in EtOH), 25 °C for 1 h.
electron-withdrawing and electron-donating groups were
incorporated (32−35) on the phenyl sulfinic acid. Moreover,
the sulfonylation occurred with moderate to good yields when
DNA-conjugated heterocyclic sulfinic acids, such as furanyl 38,
pyridyl 39, and quinolyl 40, were employed.
To provide further evidence that our two protocols are
compatible with DEL synthesis, we evaluated the DNA ligation
efficiency of the attached DNA oligomers. For this study, a
dsDNA amine headpiece was used to form conjugated
sulfonamides 41aa and 43bi by utilizing the reaction
methodologies presented in Table 2 and Table 4, respectively
(Scheme 3). The products were purified by ethanol
precipitation at each chemical step. Subsequently, the two
DNA-conjugated sulfonamides were ligated to another dsDNA
to produce longer DNA products 42 and 44. The mass spectra
after ligation displayed the corresponding molecule weight,
indicating that ligation was successful. Further qPCR showed
Scheme 3. DNA-Compatible Chemistry Validation Process
a
Reaction conditions: Headpiece 31 solution (1 equiv, 5 μL, 1 mM in
H2O), amine (600 equiv, 200 mM in NMP), I2 (10 equiv, 10 mM in
b
EtOH), 25 °C for 1 h. Ammonium hydroxide (600 equiv, 200 mM
in H2O). The conversion was determinded after enzymatic digestion
of reaction solution.
as well as heterocyclic aromatic amines cd and ce. For the
cases of low conversion to sulfonamides, the conversion of
oxidized byproduct 31-ox was increased. In a future study, how
to improve the quality and diveristy of sulfonamide library will
be further investigated. In the amine monomer set that we
explored, we incorporated boc-diamines cj, ck, cl, cm, and cn
as well as prop-2-yn-1-amine bb that have the potential to be
utilized in subsequent reactions.
Finally, 10 different DNA-conjugated sulfinic acids 31−40
were prepared by acylation (Table 5). All desired sulfonamides
were observed by employing optimized condition with
morpholine. High conversions were achieved when both
D
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In conlusion, two distinct methodologies to construct
sulfonamides in the generation of DELs have been presented.
We have expanded the scope of sulfonamide formation for
DEL synthesis by expanding the scope and types of amines and
sulfonamide diversity that can achieve acceptable levels of
prevalidation and presented a way to form sulfonamides from
DNA conjugated sulfinic acids. This methodology provides
reagents that are not only stable in water in comparison to
sulfonyl chlorides but also can even be stored in water for
weeks providing more robust reproducibility and improved
operational simplicity. Future library generation with this
methodology relies on the availability of large sets of
monofunctional, bifunctional, and trifunctional sulfinic acids
and/or sodium sulfinates. Even though this method has
expanded the scope of aryl sulfonamide formation, the
formation of alkyl sulfonamides remains problematic. Our
future studies will aim at solving this limitation as well as
utilizing these methods in library production.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03843.
General procedures for synthesis and characterization
data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: peng_xuanjia@wuxiapptec.com.
*E-mail: justin.dietrich@abbvie.com.
ORCID
Xuanjia Peng: 0000-0001-6067-0311
Notes
The authors declare no competing financial interest.
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