Selective arylsulfonamide inhibitors of ADAM-17: Hit optimization and activity in ovarian cancer cell models

Article abstract of DOI:10.1021/jm4011753

Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in EGFR signaling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previously identified inhibitor 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound 21, which showed an IC ₅₀ of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays.

Full text of DOI:10.1021/jm4011753

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Article
Selective Arylsulfonamide Inhibitors of ADAM-17: Hit
Optimization and Activity in Ovarian Cancer Cell Models
Elisa Nuti, Francesca Casalini, salvatore Santamaria, Marina Fabbi, Grazia Carbotti,
Silvano Ferrini, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, Caterina
Camodeca, Elisabetta Orlandini, Susanna Nencetti, and Armando Rossello
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm4011753 • Publication Date (Web): 17 Sep 2013
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Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and
Activity in Ovarian Cancer Cell Models.
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Elisa Nuti, Francesca Casalini, Salvatore Santamaria, Marina Fabbi, Grazia Carbotti, Silvano
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Ferrini, Luciana Marinelli, Valeria La Pietra, Ettore Novellino, Caterina Camodeca,
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Elisabetta Orlandini, Susanna Nencetti, and Armando Rossello
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Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
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Dipartimento di Terapie Oncologiche Integrate, IRCCS AOU San MartinoꢀIST Istituto Nazionale
per la Ricerca sul Cancro, Largo R. Benzi 10, 16132 Genova, Italy
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Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Via
Domenico Montesano 49, 80131 Napoli, Italy
* To whom correspondence should be addressed. phone: +39 050 2219562; fax: +39 050 2219605;
eꢀmail: aros@farm.unipi.it.
†
Present address: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics,
Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3
7FY, United Kingdom
Abstract
Activated Leukocyte Cell Adhesion Molecule (ALCAM) is expressed at the surface of epithelial
ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAMꢀ17ꢀmediated
shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by
inhibitors of ADAMꢀ17. In addition, ADAMꢀ17 plays a key role in EGFR signalling and thus may
represent a useful target in anticancer therapy. Herein we report our hit optimization effort to
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identify potent and selective ADAMꢀ17 inhibitors, starting with previously identified inhibitor 1. A
new series of secondary sulfonamidoꢀbased hydroxamates was designed and synthesized. The
biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and
human EOC cell lines. The optimization process led to compound 21, which showed an IC50 of 1.9
nM on ADAMꢀ17 with greatly increased selectivity. This compound maintained good inhibitory
properties on sALCAM shedding in several in vitro assays.
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1. Introduction
ADAMꢀ17 or Tumor Necrosis Factorꢀα Converting Enzyme (TACE) is an integral plasma
membrane zincꢀdependent metalloprotease and member of the A Disintegrin And Metalloprotease
(ADAM) family of molecules. ADAMꢀ17 is produced as an inactive proenzyme of 120 kDa, which
is physiologically activated via stimulation of G protein–coupled receptors and furinꢀlike enzyme
cleavage of the ADAMꢀ17 prodomain leading to generation of the 100 kDa active enzyme. ADAMꢀ
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7 is a sheddase and/or activator of several biologically important membraneꢀanchored proteins,
1
including TNF, epithelial cell growth factors, and cell adhesion molecules. In recent years, we
focused our attention on studying interaction between ADAMꢀ17 and cell adhesion molecules
(CAMs) of the immunoglobulin superfamily. In particular, we have shown that Activated
Leukocyte Cell Adhesion Molecule (ALCAM or CD166) is expressed at the surface of epithelial
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ovarian cancer (EOC) cells, can be internalized following soluble ligand engagement and is
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released in a soluble form (sALCAM) by ADAMꢀ17ꢀmediated shedding. This process is relevant
to EOC cell motility, which is reduced by inhibitors of ADAMꢀ17. In addition, ADAMꢀ17 plays a
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key role in Epidermal Growth Factor Receptor (EGFR) signalling and thus may represent a useful
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target in anticancer therapy in EGFꢀdependent tumours. Recently, we have reported the synthesis
and biological evaluation of a series of arylsulfonamide hydroxamates as potent ADAMꢀ17
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inhibitors. Among these, compound 1 (Figure 1) showed a nanomolar activity for ADAMꢀ17
isolated enzyme. This compound proved to be also potent in inhibiting soluble ALCAM release in
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cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines. No toxicity for this
compound was detected on parallel cultures by MTT assay. In addition, it inhibited the EGFꢀ
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triggered invasive properties of ovarian cancer cells in vitro. These preliminary results allowed us
to validate ADAMꢀ17/ALCAM pathway as new target in anticancer therapy and prompted us to
undertake a structural optimization of 1 in order to find out more selective ADAMꢀ17 inhibitors. In
fact, compound 1 also inhibited other metalloproteases such as MMPꢀ2, MMPꢀ9 and MMPꢀ14 and
it is widely believed that some side effects that have been clinically observed with the use of broad
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spectrum MMP inhibitors, such as musculoskeletal syndrome (MSS), could be related to MMPꢀ
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/MMPꢀ14 inhibition. Moreover, a more targetꢀdirected inhibition could be helpful to discern the
actual ADAMꢀ17 biological activity from overlapping effects due to other metalloproteases and to
reduce toxicity.
FIGURE 1 HERE
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In the present paper, based on recent SAR data from our lab and others, we designed and
synthesized a series of secondary sulfonamidoꢀbased inhibitors, compounds 2-1310 (Table 1), with
bended P1’ substituents different from the highly exploited 4ꢀ(butꢀ2ꢀynyloxy)benzene group. In
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fact, as revealed by Xꢀray crystal structure of catalytic domain , ADAMꢀ17 is characterized by an
“Lꢀshaped” pocket with a polar access between S1’ and S3’, and this singular shape of the
specificity pocket has been largely used to design specific ADAMꢀ17 inhibitors by insertion of
bended substituents. Two examples of these selective inhibitors reported in literature for the
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treatment of inflammatory diseases are DPCꢀ333 from BristolꢀMyers Squibb (which entered
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clinical trials for rheumatoid arthritis) and WAYꢀ281418, developed by Wyeth researchers (Figure
2).
FIGURE 2 HERE
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Hydroxamates 2-13 were screened against recombinant human ADAMꢀ17 in order to select the P1’
substituent able to give the best results of selectivity for ADAMꢀ17 over MMPs. After the most
suitable and innovative P1’ substituent has been found, we sought to improve activity against
ADAMꢀ17 by introducing an amidic chain in the α position relative to the hydroxamate (P1),
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compounds 19-21 (Table 3). In fact, as previously shown, an α substituent in this
arylsulfonamidic scaffold could highly increase potency against ADAMꢀ17. The compounds which
gave the best results on isolated enzymes were finally tested on human EOC cell lines (A2774,
SKOV3ꢀluc and A2780), which express ADAMꢀ17 and its substrate ALCAM.
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. Chemistry.
14
Compound 2 (Table 1) has been synthesized as previously described. Benzyloxyꢀbenzene
derivatives 3-13 (Table 1) and 16 (Table 2) have been prepared as reported in Scheme 1.
SCHEME 1 HERE
Sulfonyl chlorides 33-43 were synthesized starting from sodium 4ꢀhydroxybenzenesulfonate
dihydrate, which was alkylated with the appropriate aryl bromides using sodium hydroxide as base.
Reaction of sodium salts 22-32 with oxalyl chloride in the presence of DMF in dichloromethane
afforded sulfonyl chlorides 33-43, which were coupled with glycine to give carboxylic acids 44-53
and
16.
Carboxylates
44-46
in
and
49-53
were
condensed
with
Oꢀ(tertꢀ
butyldimethylsilyl)hydroxylamine
presence
of
1ꢀ[3ꢀ(Dimethylamino)propyl]ꢀ3ꢀethyl
carbodiimide hydrochloride (EDC) to give silyl intermediates 54-61, which afforded hydroxamates
3-5 and 8-12 after acid cleavage with TFA. Alternatively, carboxylates 47, 48 and 16 were first
converted into protected hydroxamates 62-64 by condensation with Oꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀ
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yl)hydroxylamine (THPꢀhydroxylamine) in the presence of EDC and then hydrolyzed with 4 N HCl
to hydroxamates 6, 7 and 13, respectively.
Compounds 17 and 18 (Table 2), close analogues of 13, were synthesized according to the route
described in Scheme 2. 4ꢀ(3,5ꢀDibromobenzyloxy)benzeneꢀ1ꢀsulfonyl chloride 43 was converted
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into the sulfonamide 65 by reaction with glycine tertꢀbutyl ester hydrochloride in H O and dioxane
in the presence of TEA. This ester was successively converted by Pdꢀcatalyzed Suzuki coupling to
monoꢀsubstituted biaryl derivatives 66 and 67, which were hydrolyzed to carboxylic acids 68 and
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9 respectively. These carboxylates were finally converted to their corresponding hydroxamates 17
and 18 by condensation with Oꢀ(tertꢀbutyldimethylsilyl)hydroxylamine, followed by acid
hydrolysis with TFA.
SCHEME 2 HERE
NꢀMethyl derivative 15 (Table 2) and the αꢀsubstituted analogues of 13, compounds 19-21 (Table
3), were prepared as reported in Scheme 3. All these compounds were synthesized starting from 4ꢀ
(3,5ꢀDibromobenzyloxy)benzeneꢀ1ꢀsulfonyl chloride 43, obtained as described above. 43 was
converted into the corresponding Bocꢀsulfonamide 76 by reaction with ammonia, followed by
treatment with diꢀ(tertꢀbutyl)dicarbonate. Sulfonamide 76 underwent Mitsunobu reaction in the
presence of diisopropylazodicarboxylate (DIAD) and triphenylphophine with optically active
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alcohol 77 to give ester 78 of (R) configuration. Acid hydrolysis of 78 yielded the NHꢀsulfonamide
carboxylate 79, which was finally converted into the corresponding hydroxamate 19 by
condensation with THPꢀhydroxylamine in DMF and acid cleavage with 4 N HCl. The sulfonyl
chloride 43 was also made reacting with nonꢀnatural aminoacids such as sarcosine tertꢀbutyl ester
hydrochloride or DꢀCbzꢀornithine or Dꢀcarbamoylꢀornithine in the presence of TEA to give
sulfonamides 70, 72 and 73, respectively. Acid hydrolysis with TFA of tertꢀbutyl ester 70 afforded
carboxylate 71. Condensation of 71 and 72 with THPꢀhydroxylamine in the presence of EDC
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yielded tetrahydropyranyl intermediates 74 and 75 which, after mild hydrolysis with HCl 4N, gave
the corresponding hydroxamates 15 and 20. Finally, hydroxamic acid 21 was obtained from
carboxylate 73 by condensation with Oꢀ(tertꢀbutyldimethylsilyl)hydroxylamine, followed by acid
hydrolysis with TFA.
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SCHEME 3 HERE
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. Results and Discussion
Biological Activity on Isolated Enzymes.
The first series of hydroxamates, compounds 2-13, were tested in vitro for their ability to inhibit
human recombinant ADAMꢀ17, MMPꢀ1, ꢀ2, ꢀ9 and ꢀ14 by a fluorimetric assay, which uses a
15
16
fluorogenic peptide as the substrate (Table 1). Compound 14 , previously reported by Wyeth
researchers as ADAMꢀ17 inhibitor and bearing the highly exploited 4ꢀ(butꢀ2ꢀynyloxy)benzene
group in P1’, was taken as reference compound to evaluate the effect of the different R groups on
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the simple glycineꢀlike scaffold. On the basis of our previous results , we focused our attention on
secondary sulfonamides because the substitution of sulfonamide NH was seen to be detrimental to
ADAMꢀ17 inhibitory activity.
Among the substituted benzyloxy derivatives, the best results of activity were achieved by
compound 3, which resulted as potent as the reference compound 14 on ADAMꢀ17 (IC =16 nM).
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also against MMPꢀ2 and MMPꢀ9. The replacement of the bromine atom with a fluorine or a
trifluoromethoxy group in the paraꢀposition led to a drop of activity for ADAMꢀ17, with the 4ꢀ
phenyl derivative 6 being the worst of the series (IC50=640 nM). The introduction of the same
substituents in the metaꢀposition of the benzyl moiety resulted in a general improvement of ADAMꢀ
1
7 inhibitory activity with respect to the unsubstituted analogue 2, without any significant
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improvement in selectivity. Finally, the presence of a 4ꢀquinoline group as in 11 led to a decrease of
activity against all tested enzymes, probably due to an excessive bulkiness of the substituent.
At this point the introduction of a second halogen atom on the benzyl moiety was considered and
the 3,5ꢀdiꢀhalo substituted compounds 12 and 13 were synthesized. Both compounds had the same
activity towards ADAMꢀ17 with respect to their 3ꢀmono substituted analogues (7 and 8) but
presented an increased selectivity over the MMPs tested. In particular, the 3,5ꢀdibromobenzyloxy
derivative 13 resulted the most promising of this first series, with a good activity for ADAMꢀ17
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(IC50=105 nM) and the best selectivity profile obtained so far over MMPs (a > 500ꢀfold selectivity
over MMPꢀ9, ꢀ14 and ꢀ1), even compared to the reference compound 14. These data suggested that
the 3,5ꢀdibromobenzyloxybenzene group could be a valid alternative to the use of the 4ꢀ(butꢀ2ꢀ
ynyloxy)benzene group as P1’ substituent, and therefore 13 became the focus of additional efforts
to improve activity towards ADAMꢀ17.
TABLE 1 HERE
Compounds 15-18 (Table 2) were subsequently synthesized as close analogues of 13, introducing
some modifications on this promising scaffold. We first synthesized the Nꢀmethyl analogue of 13
(15), which showed a decrease of ADAMꢀ17 inhibitory activity compared to 13. Then we tested the
carboxylate analogue of 13, compound 16, in order to evaluate the effect of a different zincꢀbinding
group (ZBG) on this scaffold but this compound was completely devoid of activity for ADAMꢀ17.
This disappointing result discouraged us to change the ZBG at least at this point of the optimization
process. Finally, we replaced a bromine atom of 13 with a pyridinꢀ3ꢀyl moiety (18) or a 4ꢀ
methoxyphenyl group (17) in order to better explore the S1’ꢀS3’ pocket space. Both compounds
showed a reduced inhibitory activity against ADAMꢀ17, with 18 being 5ꢀfold less active than 13.
TABLE 2 HERE
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On the basis of these findings, in order to further increase activity on ADAMꢀ17 of this class of
inhibitors, we decided to keep the compound 13 scaffold unchanged and to introduce different
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amidic chains in P1. In fact, as previously shown, an α substituent in this arylsulfonamidic scaffold
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could highly increase potency against ADAMꢀ17. First, we chose to insert
a
benzyloxycarbonylaminoꢀethyl chain in P1 because this was the group originally present in our
previous compound 1. As expected, compound 19 (Table 3) resulted 2.5ꢀfold more active than its
unsubstituted analogue 13, showing an IC50=43 nM on ADAMꢀ17, without any loss in selectivity.
Encouraged by this data, we put a longer chain in P1 and synthesized compound 20 (Table 3) with a
benzyloxycarbonylaminoꢀpropyl chain. We thus obtained a further increase of ADAMꢀ17 inhibitory
potency (IC =11 nM) still maintaining a strong selectivity over MMPs, even compared to 19. In
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particular, the selectivity for ADAMꢀ17 over MMPꢀ2 progressively increased from 16ꢀfold for
compound 13 to 130ꢀfold for 20. Finally, as last step of our optimization process we tried to
improve the hydrophilicity of our inhibitor by replacing the benzyloxycarbonylamino (Cbz) moiety
of 20 with an ureidic group (compound 21, Table 3).
TABLE 3 HERE
For 21 and its analogue 20, the physicoꢀchemical properties influencing metabolism, cell
permeation, and bioavailability were evaluated with QikProp software (Schrödinger, LLC New
York). As shown in Table 4, while 20 possesses an high MW, high number of Hꢀbond acceptors
and a logS which is quite far from ideal values, 21 has a lower MW, appropriate number of Hꢀbond
donors and acceptors, and a good logS. Thus, the replacement of the Cbz moiety in 20 with an
ureidic group (21) should lead to an improvement of the physicoꢀchemical properties of the
inhibitor.
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TABLE 4 HERE
Unpredictably, this ureidic derivative was optimal for this series exhibiting a 6ꢀfold increase in
inhibitory potency against ADAMꢀ17 (IC50=1.9 nM) with respect to 20 and a comparable
selectivity profile. In fact, 21 displayed a 126ꢀfold selectivity for ADAMꢀ17 over MMPꢀ2, a 860ꢀ
fold selectivity over MMPꢀ9, a 10000ꢀfold selectivity over MMPꢀ14 and no measurable inhibitory
activity toward MMPꢀ1 (IC >500 ꢁM). Table 5 shows a direct comparison between the selectivity
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profiles of 21 and of our previous compound 1. 21 resulted as potent as 1 on ADAMꢀ17 (with an
IC50=1.9 nM and 1.6, respectively) but showed a greatly improved selectivity over the tested
MMPs.
TABLE 5 HERE
All these P1ꢀsubstituted compounds (19-21) and their unsubstituted analogue 13 were also screened
against human recombinant ADAMꢀ10, which has the highest aminoacid sequence homology as
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compared to ADAMꢀ17 among all known MMPs. ADAMꢀ10 is not implicated in ALCAM
ectodomain shedding but is able to cleave another cellꢀcell adhesion molecule, desmoglein 2 (Dsgꢀ
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), together with ADAMꢀ17. Moreover, ADAMꢀ10 is considered a target in anticancer therapy
for its ability to shed the human epidermal growth factor receptorꢀ2 (HERꢀ2), a tyrosine kinase
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receptor that is associated with cancer proliferation. Among the tested compounds, 21 was found
to be the most active on this enzyme, with an IC =150 nM.
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Biological Activity on Ovarian Cancer Cell Lines.
The activity of compounds 1, 13, 19-21 was then evaluated in living cancer cells. As described
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before, modulation of soluble sALCAM release can be used as readꢀout test to score the inhibition
of ADAMꢀ17 activity in cells. Ovarian cancer cells (A2774, SKOV3ꢀluc and A2780) express high
cell surface levels of ALCAM, which is shed in soluble form constitutively and even more
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following tyrosine kinase receptor (e.g. EGFR) activation. sALCAM can be easily assessed by
3
ELISA of cell culture conditioned media. When assayed for inhibition of constitutive or EGFꢀ
induced sALCAM release, each compound was tested at 10 ꢀM, 1 ꢀM, 100 nM and 10 nM
concentrations with overnight incubation. Multiple tyrosine kinase activation can be mimicked by
treatment with pervanadate (PV), which is a general phosphotyrosine phosphatase inhibitor that
leads to metalloproteases activation. As controls, cultures treated with the corresponding amounts of
solvent (DMSO) were used. Cell morphology was monitored by microscopy and cell viability was
assed on parallel cultures by MTT assay (data not shown), which showed no significant toxic
effects on cells. As shown in Table 6, among the new derivatives with greatly increased selectivity
on isolated enzymes, compound 21 maintained good inhibitory properties on sALCAM shedding in
any condition, displaying a similar IC50 in the nanomolar range when PV was used as stimulus in
the three cell lines (a representative dose/response experiment is shown in Figure 3). Consistent
with data obtained on the ADAMꢀ17 isolated enzyme, compounds 1 and 21 showed comparable
IC50, while compounds 13, 19 and 20 showed higher IC50. Similar results were obtained using EGF
as stimulus, although the IC50 observed were in general higher. The different sensitivity of PVꢀ
versus EGFꢀinduced sALCAM release to the compounds studied may reflect the different levels of
tyrosine phosphorylation achieved with the two stimuli and the resulting levels of ADAMꢀ17
activation. Indeed, PV behaves as a stronger stimulus, achieved by its broad ability to block
phosphotyrosineꢀphosphatases, resulting in a maximal activation of ADAMꢀ17 and sALCAM
shedding in a short time frame (90 min of test). On the other hand, EGF is a more specific stimulus
acting on a single TKꢀreceptor, which requires a longer incubation time (18 h), during which
redundant and ADAMꢀ17ꢀindependent mechanisms of shedding may be operative.
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TABLE 6 HERE
FIGURE 3 HERE
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4
. Molecular Modeling
Docking Studies. To get an insight into the binding mode of 21 into the ADAMꢀ17 active site,
2
0
ensembleꢀdocking studies were performed by means of Glide 5.5 program . Five Xꢀray structures
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representative for the enzyme flexibility (PDB codes: 2DDF, 2I47, 2OI0, 3EDZ, 3EWJ) were used.
Docking of 21 in the 2DDF and 2I47 structures resulted in poorly ranked and not fully convincing
poses as the 3,5ꢀdibromobenzyloxy P1’ group did not occupy the S1’ pocket. This is not surprising
because in these two structures the S1’ loop is in a closed conformation with not enough room to
permit the allocation of such a bulky moiety. Otherwise, docking of 21 using 2OI0, 3EDZ and
3EWJ structures converged on similar and more convincing binding poses, where the P1’
substituent properly fits in the S1’ cavity. Particularly, as shown in Figure 4 (PDB code 2OI0), the
hydroxamate group chelates the zinc ion in a bidentate fashion, the phenyl ring stacks with the
H405 and interacts with V402 and L348 side chains, while the 3,5ꢀdibromobenzyloxy group is well
inserted in the S1’ pocket where multiple hydrophobic contacts are detected with V434, L401,
A439, V440, L401, N447 side chains and with E398 βꢀ and γꢀcarbons. Moreover, one sulfonamide
oxygen establishes the commonly found bifurcated Hꢀbond with L348 and Gly349 backbone NH.
The propylꢀurea moiety lies along the S1 pocket establishing hydrophobic contacts with the L350
and V314 side chains, while multiple Hꢀbonds are detected between the two urea NH and T347
hydroxyl group and between the urea carbonyl oxygen and the K315 side chain. Clearly, all these
interactions endowed 21 with a low nanomolar inhibitory activity toward ADAMꢀ17.
FIGURE 4 HERE
As regards the activity of 21 towards MMPs, it is well known that differential substitutions on the
P1’ group can be successfully used to design selective inhibitors for MMPs. Indeed, the analysis of
the MMPs Xꢀray structures reveals that the length of the S1’ pocket increases in the following
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order: MMPꢀ1 < MMPꢀ14 < MMPꢀ2 ≈ MMPꢀ9. The SAR herein presented (Table 1) corroborates
this consideration, in fact the activity on MMPꢀ1 drops abruptly by just introducing a bended P1’
group (2), while MMPꢀ14 can tolerate para and meta halogenated phenyl decorations (2, 3, 4, 8,
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2). On the contrary, MMPꢀ9 and ꢀ2 are able to allocate almost all the inhibitors synthesized except
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for 13 and its derivatives (15ꢀ21). Thus, docking studies of 21 into the aforementioned MMPs were
performed with the aim to better clarify the structural features responsible for the observed
2
1
22
inactivity towards these enzymes. Unsurprisingly, as regards MMPꢀ1 and ꢀ14 (1HFC and 3MA2,
respectively), the docking program is incapable to find a pose where the P1’ group is inserted into
the S1’ pocket, thus leaving the majority of 21 poses largely solvent exposed. Conversely, in the
2
3
24
lowest energy binding poses of 21 into the active sites of MMPꢀ2 and ꢀ9 (3AYU, 4H3X,
respectively), the 3,5ꢀdibromobenzyloxy group fits in the S1’ pocket and the hydroxamate group
chelates the zinc ion, although the sulfonamide geometry is gravely distorted. However, the bottom
part of the S1’ pocket of both enzymes is open and solvent exposed, with a predominance of
hydrophilic residues (T143, T145, K146, N147, R149 and S151 in MMPꢀ2; E132, R140, T142,
E143 and D150 in MMPꢀ9), consequently, it can be assumed that the large and hydrophobic 3,5ꢀ
dibromobenzyloxy moiety is not well tolerated in such a region thus accounting for the higher IC50
on MMPꢀ2 and ꢀ9 found for 21.
5. Conclusions
Starting with our previously published molecule 1, we carried out a systematic SAR investigation of
the P1’ substituent in order to find out a moiety different from the highly exploited 4ꢀ(butꢀ2ꢀ
ynyloxy)benzene group able to improve the selectivity for ADAMꢀ17 over MMPs. Optimization of
the benzyloxyꢀphenyl portion led to the identification of the 3,5ꢀdibromobenzyloxyꢀphenyl group,
which afforded improved ADAMꢀ17 selectivity (compound 13). Furthermore, introduction of an
amidic chain in the α position relative to the hydroxamate (P1 group) greatly increased potency
against ADAMꢀ17 (compounds 19-21). In particular, the ureidic derivative 21 resulted the best of
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the series being as potent as 1 on ADAMꢀ17 (IC =1.9 nM) and showing a greatly improved
5
0
selectivity over the tested MMPs. In fact, 21 displayed a 126ꢀfold selectivity for ADAMꢀ17 over
MMPꢀ2, a 860ꢀfold selectivity over MMPꢀ9, a 10000ꢀfold selectivity over MMPꢀ14 and no
measurable inhibitory activity toward MMPꢀ1 (IC50>500 ꢁM). Finally, the compounds, which
gave the best results on isolated enzymes (13, 19-21), were tested on human EOC cell lines (A2774,
SKOV3ꢀluc and A2780), which express ADAMꢀ17 and its substrate ALCAM. 21 maintained good
inhibitory properties on sALCAM shedding in any condition, displaying a similar IC50 in the
nanomolar range when PV was used as stimulus in the three cell lines. Consistent with data
obtained on the ADAMꢀ17 isolated enzyme, compounds 1 and 21 showed comparable IC50 also on
living cancer cells, suggesting that selective inhibition of ADAMꢀ17 activity might be sufficient to
block sALCAM release in cells. Further investigations are necessary to assess the effect of the
improved ADAMꢀ17 selectivity in ovarian cancer models in vivo.
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6. Experimental Section
1
Chemistry. Melting points were determined on a Kofler hotstage apparatus and are uncorrected. H
13
and C NMR spectra were determined with a Varian Gemini 200 MHz spectrometer. Chemical
shifts (δ) are reported in parts per million downfield from tetramethylsilane and referenced from
1
3
solvent references. Coupling constants J are reported in hertz; C NMR spectra were fully
decoupled. The following abbreviations are used: singlet (s), doublet (d), triplet (t), doubleꢀdoublet
(dd), broad (br) and multiplet (m). Where indicated, the elemental compositions of the compounds
agreed to within ±0.4% of the calculated value. Chromatographic separations were performed on
silica gel columns by flash column chromatography (Kieselgel 40, 0.040–0.063 mm; Merck) or
using ISOLUTE Flash Si II cartridges (Biotage). Reactions were followed by thinꢀlayer
chromatography (TLC) on Merck aluminum silica gel (60 F254) sheets that were visualized under a
3
UV lamp and hydroxamic acids were visualized with FeCl aqueous solution. Evaporation was
performed in vacuo (rotating evaporator). Sodium sulfate was always used as the drying agent. Dꢀ
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Cbzꢀornithine (HꢀDꢀOrn(Z)ꢀOH) and Dꢀcarbamoylꢀornithine (HꢀDꢀCitꢀOH) were purchased from
Bachem (Switzerland). 3,5ꢀDibromobenzyl bromide and 4ꢀbromomethylbiphenyl were purchased
from ABCR (Germany). 1ꢀ(bromomethyl)ꢀ3ꢀ(trifluoromethoxy)benzene, 1ꢀ(bromomethyl)ꢀ4ꢀ
fluorobenzene,
1ꢀ(bromomethyl)ꢀ4ꢀ(trifluoromethoxy)benzene,
1ꢀ(bromomethyl)ꢀ3,5ꢀ
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difluorobenzene, and 8ꢀ(bromomethyl)quinoline were purchased from Maybridge (UK). All other
commercially available chemicals were purchased from SigmaꢀAldrich.
The purity of the final compounds was determined by reverseꢀphase HPLC on a Merck Hitachi Dꢀ
7
000 liquid chromatograph. HPLC purity was determined to be >95% for all final products using a
Discovery C18 column (250 mm × 4.6 mm, 5 ꢁm, Supelco), with a mobile phase of 40%
water/60% methanol at a flow rate of 1.4 mL/min, with UV monitoring at the fixed wavelength of
2
56 nm. See the Supporting Information for compound purity analysis data for final compounds.
General procedure for the synthesis of benzyloxy-benzene sodium salts 22-32. To a suspension
of sodium 4ꢀhydroxybenzenesulfonate dihydrate (1.3 g, 5.6 mmol) in isopropanol (25 mL),
containing 5.6 mL of NaOH 1N freshly prepared, the appropriate substituted benzylbromide (11.2
mmol) was added. The reaction was refluxed (70 °C) overnight. Isopropanol was evaporated and
the precipitate was collected by filtration and washed with isopropanol. The solid was dried in
vacuo.
Sodium 4-(4-bromobenzyloxy)benzenesulfonate (22). The title compound was prepared from 4ꢀ
1
bromobenzyl bromide following the general procedure. White solid (79% yield). HꢀNMR (DMSOꢀ
6
d ) δ: 5.10 (s, 2H); 7.38ꢀ7.42 (m, 4H); 7.49ꢀ7.60 (m, 4H).
Sodium 4-(4-fluorobenzyloxy)benzenesulfonate (23). The title compound was prepared from 1ꢀ
1
(
bromomethyl)ꢀ4ꢀfluorobenzene following the general procedure. White solid (74% yield). Hꢀ
6
NMR (DMSOꢀd ) δ: 5.08 (s, 2H); 6.90ꢀ6.96 (m, 2H); 7.18ꢀ7.26 (m, 2H); 7.37ꢀ7.52 (m, 4H).
Sodium 4-(4-(trifluoromethoxy)benzyloxy)benzenesulfonate (24). The title compound was
prepared from 1ꢀ(bromomethyl)ꢀ4ꢀ(trifluoromethoxy)benzene following the general procedure.
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White solid (69% yield). HꢀNMR (DMSOꢀd ) δ: 5.14 (s, 2H); 7.36ꢀ7.42 (m, 4H); 7.50ꢀ7.59 (m,
6
4
H).
Sodium 4-(biphenyl-4-ylmethoxy)benzenesulfonate (25). The title compound was prepared from
1
4
ꢀbromomethylbiphenyl following the general procedure. White solid (70% yield). HꢀNMR
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18
19
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21
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(
6
DMSOꢀd ) δ: 5.17 (s, 2H); 6.94ꢀ6.98 (m, 2H); 7.38ꢀ7.47 (m, 6H); 7.51ꢀ7.55 (m, 5H).
Sodium 4-(3-bromobenzyloxy)benzenesulfonate (26). The title compound was prepared from 1ꢀ
1
bromoꢀ3ꢀ(bromomethyl)benzene following the general procedure. White solid (76% yield). Hꢀ
NMR (DMSOꢀd
6
) δ: 5.13 (s, 2H); 6.91ꢀ6.96 (m, 2H); 7.35ꢀ7.39 (m, 1H); 7.42ꢀ7.43 (m, 1H); 7.47ꢀ
7
.54 (m, 3H); 7.65ꢀ7.66 (m, 1H).
Sodium 4-(3-fluorobenzyloxy)benzenesulfonate (27). The title compound was prepared from 1ꢀ
1
(bromomethyl)ꢀ3ꢀfluorobenzene following the general procedure. White solid (65% yield). Hꢀ
NMR (DMSOꢀd ) δ: 5.14 (s, 2H); 6.92ꢀ6.96 (m, 2H); 7.11ꢀ7.20 (m, 1H); 7.26ꢀ7.30 (m, 2H); 7.38ꢀ
6
7
.46 (m, 1H); 7.50ꢀ7.54 (m, 2H).
Sodium 4-(3-(trifluoromethoxy)benzyloxy)benzenesulfonate (28). The title compound was
prepared from 1ꢀ(bromomethyl)ꢀ3ꢀ(trifluoromethoxy)benzene following the general procedure.
1
White solid (61% yield). HꢀNMR (DMSOꢀd ) δ: 5.18 (s, 2H); 6.92ꢀ6.96 (m, 2H); 7.31ꢀ7.34 (m,
6
1
H); 7.44ꢀ7.54 (m, 5H).
Sodium 4-(biphenyl-3-ylmethoxy)benzenesulfonate (29). The title compound was prepared from
1
3ꢀ(bromomethyl)biphenyl following the general procedure. White solid (62% yield). HꢀNMR
6
(DMSOꢀd ) δ: 5.19 (s, 2H); 6.95ꢀ6.99 (m, 2H); 7.34ꢀ7.55 (m, 7H); 7.61ꢀ7.74 (m, 4H).
Sodium 4-(quinolin-8-ylmethoxy)benzenesulfonate (30). The title compound was prepared from
1
8
ꢀ(bromomethyl)quinoline following the general procedure. Yellow solid (80% yield). HꢀNMR
(MeODꢀd
6
) δ: 5.79 (s, 2H); 7.75ꢀ8.16 (m, 5H); 8.88ꢀ8.96 (m, 1H); 9.01ꢀ9.09 (m, 1H).
Sodium 4-(3,5-difluorobenzyloxy)benzenesulfonate (31). The title compound was prepared from
1
ꢀ(bromomethyl)ꢀ3,5ꢀdifluorobenzene following the general procedure. White solid (69% yield).
1
HꢀNMR (DMSOꢀd ) δ: 5.15 (s, 2H); 6.92ꢀ6.96 (m, 2H); 7.15ꢀ7.19 (m, 3H); 7.50ꢀ7.54 (m, 2H).
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Sodium 4-(3,5-dibromobenzyloxy)benzenesulfonate (32). The title compound was prepared from
1
3
,5ꢀdibromobenzyl bromide following the general procedure. White solid (84% yield). HꢀNMR
6
(DMSOꢀd ) δ: 5.13 (s, 2H); 6.92ꢀ6.96 (m, 2H); 7.50ꢀ7.54 (m, 2H); 7.67ꢀ7.68 (m, 2H); 7.80ꢀ7.81 (m,
2
H).
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General procedure for the synthesis of benzyloxy-benzene sulfonyl chlorides 33-43. To a 0 °C
solution of oxalyl chloride (1.3 mL, 15.3 mmol) in dry CH Cl (5.1 mL) under Ar atmosphere,
2
2
DMF was added dropwise (1.2 mL, 15.3 mmol) followed by the appropriate benzyloxyꢀbenzene
sodium salt 22-32 (5.11 mmol). The reaction was stirred at 0 °C for 10 min. and then at rt for 2
days. The crude was poured into ice and the product was extracted with EtOAc. Organic layers
2 4
were washed with water, dried over Na SO and concentrated in vacuo to give sulfonyl chlorides
3
4
3-43.
-(4-Bromobenzyloxy)benzene-1-sulfonyl chloride (33). The title compound was prepared from
benzyloxyꢀbenzene sodium salt 22 following the general procedure. The crude product was purified
by flash chromatography (nꢀhexane/EtOAc 14:1) using a Isolute Flash Si II cartridge to give 33 as a
1
white solid (32% yield). HꢀNMR (CDCl
3
) δ: 5.10 (s, 2H); 7.06ꢀ7.10 (m, 2H); 7.26ꢀ7.30 (m, 2H);
7
.51ꢀ7.55 (m, 2H); 7.94ꢀ7.98 (m, 2H).
-(4-Fluorobenzyloxy)benzene-1-sulfonyl chloride (34). The title compound was prepared from
4
benzyloxyꢀbenzene sodium salt 23 following the general procedure. The crude product was purified
by flash chromatography (nꢀhexane/EtOAc 3:1) using a Isolute Flash Si II cartridge to give 34 as a
1
white solid (68% yield). HꢀNMR (CDCl
3
) δ: 5.13 (s, 2H); 7.07ꢀ7.15 (m, 4H); 7.37ꢀ7.44 (m, 2H);
7
.95ꢀ8.02 (m, 2H).
4
-(4-(Trifluoromethoxy)benzyloxy)benzene-1-sulfonyl chloride (35). The title compound was
prepared from benzyloxyꢀbenzene sodium salt 24 following the general procedure. White solid
1
(65% yield). HꢀNMR (CDCl
3
) δ: 5.17 (s, 2H); 7.09ꢀ7.14 (m, 2H); 7.26ꢀ7.29 (m, 2H); 7.45ꢀ7.49 (m,
2
H); 7.98ꢀ8.02 (m, 2H).
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4-(Biphenyl-4-ylmethoxy)benzene-1-sulfonyl chloride (36). The title compound was prepared
from benzyloxyꢀbenzene sodium salt 25 following the general procedure. White Solid (70% yield).
1
3
HꢀNMR (CDCl ) δ: 5.22 (s, 2H); 6.98ꢀ7.02 (m, 2H); 7.12ꢀ7.16 (m, 2H); 7.37ꢀ7.52 (m, 4H); 7.58ꢀ
7
.67 (m, 3H); 7.93ꢀ8.02 (m, 2H).
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4
-(3-Bromobenzyloxy)benzene-1-sulfonyl chloride (37). The title compound was prepared from
1
benzyloxyꢀbenzene sodium salt 26 following the general procedure. Yellow oil (76% yield). Hꢀ
NMR (CDCl ) δ: 5.14 (s, 2H); 7.09ꢀ7.14 (m, 2H); 7.28ꢀ7.37 (m, 2H); 7.49ꢀ7.53 (m, 1H); 7.59ꢀ7.60
3
(m, 1H); 7.97ꢀ8.01 (m, 2H).
4
-(3-Fluorobenzyloxy)benzene-1-sulfonyl chloride (38). The title compound was prepared from
1
benzyloxyꢀbenzene sodium salt 27 following the general procedure. White solid (92% yield). Hꢀ
NMR (CDCl ) δ: 5.17 (s, 2H); 6.97ꢀ7.25 (m, 5H); 7.34ꢀ7.44 (m, 1H); 7.91ꢀ8.01 (m, 2H).
3
4
-(3-(Trifluoromethoxy)benzyloxy)benzene-1-sulfonyl chloride (39). The title compound was
prepared from benzyloxyꢀbenzene sodium salt 28 following the general procedure. White solid
1
(86% yield). HꢀNMR (CDCl
3
) δ: 5.19 (s, 2H); 7.10ꢀ7.14 (m, 2H); 7.22ꢀ7.50 (m, 4H); 7.98ꢀ8.02 (m,
2H).
-(Biphenyl-3-ylmethoxy)benzene-1-sulfonyl chloride (40). The title compound was prepared
4
from benzyloxyꢀbenzene sodium salt 29 following the general procedure. Yellow oil (98% yield).
1
HꢀNMR (CDCl
3
) δ: 5.23 (s, 2H); 6.97ꢀ7.02 (m, 2H); 7.11ꢀ7.17 (m, 2H); 7.37ꢀ7.64 (m, 8H); 7.91ꢀ
8.01 (m, 2H).
4
-(Quinolin-8-ylmethoxy)benzene-1-sulfonyl chloride (41). The title compound was prepared
from benzyloxyꢀbenzene sodium salt 30 following the general procedure. The crude product was
purified by flash chromatography on silica gel (nꢀhexane/EtOAc 14:1) to give 41 as a white solid
1
(15% yield). HꢀNMR (CDCl
3
) δ: 5.96 (s, 2H); 7.22ꢀ7.26 (m, 2H); 7.46ꢀ7.63 (m, 2H); 7.83ꢀ7.89 (m,
2H); 7.95ꢀ7.99 (m, 2H); 8.20ꢀ8.25 (m, 1H); 8.95ꢀ8.98 (m, 1H).
-(3,5-Difluorobenzyloxy)benzene-1-sulfonyl chloride (42). The title compound was prepared
4
from benzyloxyꢀbenzene sodium salt 31 following the general procedure. White solid (68% yield).
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HꢀNMR (CDCl ) δ: 5.15 (s, 2H); 6.77ꢀ6.85 (m, 1H); 6.94ꢀ6.97 (m, 2H); 7.08ꢀ7.13 (m, 2H); 7.97ꢀ
3
8
.02 (m, 2H).
4
-(3,5-Dibromobenzyloxy)benzene-1-sulfonyl chloride (43). The title compound was prepared
from benzyloxyꢀbenzene sodium salt 32 following the general procedure. Yellow oil (82% yield).
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9
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HꢀNMR (CDCl
3
) δ: 5.11 (s, 2H); 7.08ꢀ7.12 (m, 2H); 7.51ꢀ7.52 (m, 2H); 7.67ꢀ7.69 (m, 2H); 7.98ꢀ
8.02 (m, 2H).
General procedure for the synthesis of carboxylic acids 44-53 and 16. To a solution of glycine
68.61 mg, 0.91 mmol), in H O (0.9 mL) and dioxane (0.9 mL) containing TEA (0.25 mL, 1.828
(
2
mmol), the appropriate sulfonyl chloride (1.83 mmol) was added. The mixture was stirred at RT
overnight, dioxane was evaporated and the residue was treated with EtOAc, washed with HCl 1N,
brine and with a saturated solution of NaHCO . Aqueous basic phases were then acidified with HCl
3
1
N until pH=4 and the product was extracted with EtOAc. Organic layers were collected, dried over
Na SO and concentrated in vacuo.
2
4
2
-(4-(4-Bromobenzyloxy)phenylsulfonamido)acetic acid (44). The title compound was prepared
1
from sulfonyl chloride 33 following the general procedure. White solid (88% yield). HꢀNMR
(DMSOꢀd ) δ: 3.53 (d, J=5.86 Hz, 2H); 5.18 (s, 2H); 7.15ꢀ7.19 (m, 2H); 7.41ꢀ7.45 (m, 2H); 7.60ꢀ
6
7
.64 (m, 2H); 7.71ꢀ7.75 (m, 2H); 7.89 (t, J=5.86 Hz, 1H).
2
-(4-(4-Fluorobenzyloxy)phenylsulfonamido)acetic acid (45). The title compound was prepared
1
from sulfonyl chloride 34 following the general procedure. White solid (73% yield). HꢀNMR
(DMSOꢀd
6
) δ: 3.53 (d, J=6.04 Hz, 2H); 5.16 (s, 2H); 7.14ꢀ7.18 (m, 2H); 7.24ꢀ7.28 (m, 2H); 7.49ꢀ
.56 (m, 2H); 7.70ꢀ7.74 (m, 2H); 7.89 (t, J=6.04 Hz, 1H).
-(4-(4-(Trifluoromethoxy)benzyloxy)phenylsulfonamido)acetic acid (46). The title compound
7
2
was prepared from sulfonyl chloride 35 following the general procedure. White solid (80% yield).
1
6
HꢀNMR (DMSOꢀd ) δ: 3.53 (d, J=5.67 Hz, 2H); 5.22 (s, 2H); 7.15ꢀ7.19 (m, 2H); 7.39ꢀ7.43 (m,
2
H); 7.58ꢀ7.62 (m, 2H); 7.71ꢀ7.75 (m, 2H); 7.89 (t, J=5.67 Hz, 1H).
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2-(4-(Biphenyl-4-ylmethoxy)phenylsulfonamido)acetic acid (47). The title compound was
1
prepared from sulfonyl chloride 36 following the general procedure. Pinkish solid (45% yield). Hꢀ
NMR (DMSOꢀd
6
) δ: 3.54 (d, J=6.02 Hz, 2H); 5.24 (s, 2H); 7.18ꢀ7.22 (m, 2H); 7.37ꢀ7.57 (m, 5H);
7
.66ꢀ7.76 (m, 6H); 7.89 (t, J=6.02 Hz, 1H).
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49
50
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58
59
60
2
-(4-(3-Bromobenzyloxy)phenylsulfonamido)acetic acid (48). The title compound was prepared
1
from sulfonyl chloride 37 following the general procedure. White solid (81% yield). HꢀNMR
(DMSOꢀd ) δ: 3.54 (d, J=6.02 Hz, 2H); 5.19 (s, 2H); 7.16ꢀ7.20 (m, 2H); 7.33ꢀ7.58 (m, 3H); 7.68ꢀ
6
7
.72 (m, 2H); 7.75ꢀ7.76 (m, 1H); 7.89 (t, J=6.02 Hz, 1H).
2
-(4-(3-Fluorobenzyloxy)phenylsulfonamido)acetic acid (49). The title compound was prepared
1
from sulfonyl chloride 38 following the general procedure. White solid (76% yield). HꢀNMR
(MeODꢀd ) δ: 3.67 (s, 2H); 5.1 (s, 2H); 7.03ꢀ7.29 (m, 5H); 7.35ꢀ7.46 (m, 1H); 7.78ꢀ7.82 (m, 2H).
6
2
-(4-(3-(Trifluoromethoxy)benzyloxy)phenylsulfonamido)acetic acid (50). The title compound
was prepared from sulfonyl chloride 39 following the general procedure. White solid (75%
1
yield). HꢀNMR (DMSOꢀd
6
) δ: 3.53 (d, J=6.04 Hz, 2H); 5.25 (s, 2H); 7.16ꢀ7.20 (m, 2H); 7.34ꢀ7.37
(m, 1H); 7.49ꢀ7.60 (m, 3H); 7.71ꢀ7.75 (m, 2H); 7.89 (t, J=6.04 Hz, 1H).
2
-(4-(Biphenyl-3-ylmethoxy)phenylsulfonamido)acetic acid (51). The title compound was
1
prepared from sulfonyl chloride 40 following the general procedure. White solid (60% yield). Hꢀ
NMR (MeODꢀd
6
) δ: 3.64 (s, 2H); 5.17 (s, 2H); 7.15ꢀ7.19 (m, 2H); 7.29ꢀ7.48 (m, 6H); 7.58ꢀ7.65 (m,
3H); 7.70 (s, 1H); 7.79ꢀ7.83 (m, 2H).
2
-(4-(Quinolin-8-ylmethoxy)phenylsulfonamido)acetic acid (52). The title compound was
1
prepared from sulfonyl chloride 41 following the general procedure. White solid (72% yield). Hꢀ
NMR (Acetoneꢀd ) δ: 3.65 (s, 2H); 5.84 (s, 2H); 7.18ꢀ7.22 (m, 2H); 7.57ꢀ7.67 (m, 2H); 7.77ꢀ7.81
6
(m, 2H); 7.92ꢀ7.97 (m, 2H); 8.40ꢀ8.45 (m, 1H); 8.93ꢀ8.95 (m, 1H).
2-(4-(3,5-Difluorobenzyloxy)phenylsulfonamido)acetic acid (53). The title compound was
1
prepared from sulfonyl chloride 42 following the general procedure. White solid (81% yield). Hꢀ
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NMR (DMSOꢀd ) δ: 3.53 (d, J=5.13 Hz, 2H); 5.22 (s, 2H); 7.16ꢀ7.22 (m, 5H); 7.72ꢀ7.75 (m, 2H);
6
7
.89 (t, J=5.13 Hz, 1H).
2
-(4-(3,5-Dibromobenzyloxy)phenylsulfonamido)acetic acid (16). The title compound was
prepared from sulfonyl chloride 43 following the general procedure. Pale pink solid (79% yield).
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8
9
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8
9
0
1
6
HꢀNMR (DMSOꢀd ) δ: 3.54 (d, J=6.02 Hz, 2H); 5.20 (s, 2H); 7.16ꢀ7.20 (m, 2H); 7.70ꢀ7.71 (m,
13
2H); 7.72ꢀ7.76 (m, 2H); 7.83ꢀ7.85 (m, 1H); 7.90 (t, J=6.02 Hz, 1H). CꢀNMR (CDCl ) δ: 44.58;
3
6
9.079; 115.801; 123.521; 130.021; 130.185; 134.009; 142.275; 162.213; 170.207.
General procedure for the synthesis of Benzyloxy-phenylsulfonamido N-(tert-
butyldimethylsilyloxy)acetamides 54-61. Carboxylates 44-46 and 49-53 (0.32 mmol) were
2 2
suspended in dry CH Cl (8.5 mL) and Oꢀ(tertꢀbutyldimethylsilyl)hydroxylamine (47.9 mg 0.32
mmol) and EDC (93.5 mg, 0.48 mmol) were added. After stirring at RT overnight, the mixture was
washed with water and the organic phases were dried and evaporated in vacuo.
2
-(4-(4-Bromobenzyloxy)phenylsulfonamido)-N-(tert-butyldimethylsilyloxy)acetamide
(54).
The title compound was prepared from carboxylic acid 44 following the general procedure. The
crude product was purified by flash chromatography (nꢀhexane/EtOAc 2:1) using a Isolute Flash Si
1
II cartridge to give 54 as a white solid (43% yield). HꢀNMR (CDCl ) δ: 0.15 (s, 6H); 0.94 (s, 9H);
3
3
.57 (br s, 1H); 3.77 (br s, 1H); 5.01 (s, 2H); 5.24 (br s, 1H); 7.01ꢀ7.05 (m, 2H); 7.27ꢀ7.31 (m, 2H);
.51ꢀ7.55 (m, 2H); 7.77ꢀ7.81 (m, 2H); 8.43 (br s, 1H).
7
N-(tert-Butyldimethylsilyloxy)-2-(4-(4-fluorobenzyloxy)phenylsulfonamido)acetamide
(55).
The title compound was prepared from carboxylic acid 45 following the general procedure. The
crude product was purified by flash chromatography (nꢀhexane/EtOAc 2:1) using a Isolute Flash Si
1
II cartridge to give 55 as a white solid (26% yield). HꢀNMR (CDCl ) δ: 0.15 (s, 6H); 0.94 (s, 9H);
3
3
.57 (br s, 1H); 3.79 (br s, 1H); 5.08 (s, 2H); 5.28 (br s, 1H); 7.02ꢀ7.14 (m, 4H); 7.37ꢀ7.43 (m, 2H);
7.77ꢀ7.82 (m, 2H); 8.43 (br s, 1H).
N-(tert-Butyldimethylsilyloxy)-2-(4-(4-
(trifluoromethoxy)benzyloxy)phenylsulfonamido)acetamide (56). The title compound was
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prepared from carboxylic acid 46 following the general procedure. The crude product was purified
by flash chromatography (nꢀhexane/EtOAc 2:1) using a Isolute Flash Si II cartridge to give 56 as a
1
white solid (52% yield). HꢀNMR (CDCl
3
) δ:0.15 (s, 6H); 0.94 (s, 9H); 3.58 (br s, 1H); 3.79 (br s,
1
H); 5.11 (s, 2H); 7.03ꢀ7.07 (m, 2H); 7.24ꢀ7.27 (m, 2H); 7.44ꢀ7.48 (m, 2H); 7.78ꢀ7.82 (m, 2H);
.41 (br s, 1H).
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32
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36
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39
40
41
42
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44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
N-(tert-Butyldimethylsilyloxy)-2-(4-(3-fluorobenzyloxy)phenylsulfonamido)acetamide
(57).
The title compound was prepared from carboxylic acid 49 following the general procedure. The
crude product was purified by flash chromatography (nꢀhexane/EtOAc 3:1) using a Isolute Flash Si
1
II cartridge to give 57 as a white solid (57% yield). HꢀNMR (CDCl
3
) δ:0.14 (s, 6H); 0.94 (s, 9H);
3.57 (br s, 1H); 3.79 (br s, 1H); 5.12 (s, 2H); 5.28 (br s, 1H); 7.02ꢀ7.20 (m, 5H); 7.32ꢀ7.43 (m, 1H);
.77ꢀ7.82 (m, 2H), 8.53 (br s, 1H).
N-(tert-Butyldimethylsilyloxy)-2-(4-(3-
trifluoromethoxy)benzyloxy)phenylsulfonamido)acetamide (58). The title compound was
7
(
prepared from carboxylic acid 50 following the general procedure. The crude product was purified
by flash chromatography (nꢀhexane/EtOAc 2:1) using a Isolute Flash Si II cartridge to give 58 as a
1
colorless oil (41% yield). HꢀNMR (CDCl ) δ: 0.15 (s, 6H); 0.94 (s, 9H); 3.57 (br s, 1H); 3.77 (br s,
3
1
H); 5.13 (s, 2H); 7.03ꢀ7.07 (m, 2H); 7.20ꢀ7.48 (m, 4H); 7.79ꢀ7.83 (m, 2H); 8.44 (brs, 1H).
2
-(4-(Biphenyl-3-ylmethoxy)phenylsulfonamido)-N-(tert-butyldimethylsilyloxy)acetamide (59).
The title compound was prepared from carboxylic acid 51 following the general procedure. The
crude product was purified by flash chromatography (nꢀhexane/EtOAc 3:1) using a Isolute Flash Si
1
II cartridge to give 59 as a colorless oil (21% yield). HꢀNMR (CDCl ) δ: 0.14 (s, 6H); 0.93 (s, 9H);
3
3
.58 (br s, 1H); 3.78 (br s, 1H); 5.17 (s, 2H); 5.61 (br s, 1H); 7.05ꢀ7.09 (m, 2H); 7.36ꢀ7.51 (m, 5H);
.57ꢀ7.64 (m, 4H); 7.77ꢀ7.81 (m, 2H);8.84 (br s, 1H).
7
N-(tert-Butyldimethylsilyloxy)-2-(4-(quinolin-8-ylmethoxy)phenylsulfonamido)acetamide (60).
The title compound was prepared from carboxylic acid 52 following the general procedure. The
crude product was purified by flash chromatography (nꢀhexane/EtOAc 1:1) using a Isolute Flash Si
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5
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6
1
II cartridge to give 60 as a colorless oil (15% yield). HꢀNMR (CDCl ) δ: 0.14 (s, 6H); 0.92 (s, 9H);
3
3
7
.56 (br s, 1H); 3.80 (br s, 1H); 5.55 (br s, 1H); 5.88 (s, 2H); 7.13ꢀ7.17 (m, 2H); 7.43ꢀ7.60 (m, 2H);
.75ꢀ7.88 (m, 2H); 8.17ꢀ8.22 (m, 1H); 8.85 (br s, 1H); 8.92ꢀ8.95 (m, 1H).
N-(tert-Butyldimethylsilyloxy)-2-(4-(3,5-difluorobenzyloxy)phenylsulfonamido)acetamide (61).
The title compound was prepared from carboxylic acid 53 following the general procedure. The
0
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8
9
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7
8
9
0
crude product was purified by flash chromatography (nꢀhexane/EtOAc 2:1) using a Isolute Flash Si
1
II cartridge to give 61 as a white solid (53% yield). HꢀNMR (CDCl ) δ: 0.15 (s, 6H); 0.94 (s, 9H);
3
3
.59 (br s, 1H); 3.79 (br s, 1H); 5.10 (s, 2H); 5.23 (br s, 1H); 6.74ꢀ6.83 (m, 1H); 6.94ꢀ7.06 (m, 4H);
.79ꢀ7.83 (m, 2H); 8.41 (br s, 1H).
7
General procedure for the synthesis of Benzyloxy-phenylsulfonamido N-(tetrahydro-2H-
pyran-2-yloxy)acetamides 62-64. Carboxylic acids 47, 48 and 16 (0.46 mmol) were dissolved in
dry DMF (1 mL) and Oꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)hydroxylamine (166.7 mg, 1.42 mmol), Nꢀ
methylmorpholine redistilled (0.15 mL, 1.38 mmol), HOBT (74.6 mg, 0.55 mmol), and EDC (123.5
2
mg, 0.64 mmol) were added under N atmosphere. After stirring for 2 h, the reaction mixture was
3
diluted with EtOAc and washed with water, saturated solution of NaHCO , and brine. The organic
phase was dried over Na SO , filtered and concentrated in vacuo.
2
4
2
-(4-(Biphenyl-4-ylmethoxy)phenylsulfonamido)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide
(
62). The title compound was prepared from carboxylic acid 47 following the general procedure.
The crude product was purified by flash chromatography (nꢀhexane/EtOAc 1:1) using a Isolute
1
Flash Si II cartridge to give 62 as a colorless oil (61% yield). HꢀNMR (CDCl
3
) δ: 1.67ꢀ1.81 (m,
6
H); 3.62 (s, 2H); 3.81ꢀ3.99 (m, 2H); 4.81ꢀ4.92 (m, 1H); 5.16 (s, 2H); 7.06ꢀ7.10 (m, 2H); 7.36ꢀ7.51
(
m, 5H); 7.57ꢀ7.66 (m, 4H); 7.79ꢀ7.83 (m, 2H); 8.91 (br s, 1H).
2-(4-(3-Bromobenzyloxy)phenylsulfonamido)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide
(63). The title compound was prepared from carboxylic acid 48 following the general procedure.
The crude product was purified by flash chromatography (nꢀhexane/EtOAc 1:1) using a Isolute
1
Flash Si II cartridge to give 63 as a colorless oil (86% yield). HꢀNMR (CDCl ) δ: 1.68ꢀ1.82 (m,
3
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6H); 3.62 (s, 2H); 3.75ꢀ3.93 (m, 2H); 4.81ꢀ4.89 (m, 1H); 5.08 (s, 2H); 5.40 (br s, 1H); 7.01ꢀ7.05 (m,
2
H); 7.29ꢀ7.35 (m, 2H); 7.46ꢀ7.49 (m, 1H); 7.56ꢀ7.57 (m, 1H); 7.78ꢀ7.82 (m, 2H); 9.13 (br s, 1H).
2
-(4-(3,5-Dibromobenzyloxy)phenylsulfonamido)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide
(64). The title compound was prepared from carboxylic acid 16 following the general procedure.
10
11
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13
14
15
16
17
18
19
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22
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The crude product was purified by flash chromatography (nꢀhexane/EtOAc 1:1) using a Isolute
1
Flash Si II cartridge to give 64 a colorless oil (82% yield). HꢀNMR (CDCl ) δ: 1.67ꢀ1.81 (m, 6H);
3
3
.64 (s, 2H); 3.61ꢀ3.99 (m, 2H); 4.79ꢀ4.91 (m, 1H); 5.05 (s, 2H); 5.27 (br s, 1H); 7.01ꢀ7.05 (m, 2H);
.51ꢀ7.52 (m, 2H); 7.65ꢀ7.66 (m, 1H); 7.80ꢀ7.84 (m, 2H); 8.98 (br s, 1H).
7
General procedure for the synthesis of Benzyloxy-phenylesulfonamido N-hydroxy acetamides
3-5, 8-12. Silyl precursors (0.05 mmol) were dissolved in dry CH Cl (0.4 mL) and TFA (0.22 mL,
.8 mmol) was added dropwise at 0 °C. After 5h stirring, TFA was evaporated. The crude products
were purified by trituration with nꢀhexane/Et O to give the desired hydroxamates 3-5 and 8-12.
2
2
2
2
2
-(4-(4-Bromobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide (3). The title compound was
prepared from Oꢀsilylate derivative 54 following the general procedure. White solid (85% yield).
1
Mp: 135ꢀ137 °C; HꢀNMR (DMSOꢀd
6
) δ: 3.27 (d, J=5.31 Hz, 2H); 5.18 (s, 2H); 7.15ꢀ7.19 (m, 2H);
13
7
.41ꢀ7.45 (m, 2H); 7.59ꢀ7.63 (m, 2H); 7.71ꢀ7.75 (m, 2H); 8.86 (br s, 1H); 10.53 (br s, 1H). Cꢀ
NMR (DMSOꢀd ) δ: 43.11, 68.78, 114.98, 121.15, 128.70, 129.91, 131.38, 132.18, 135.77, 160.93,
6
1
64.28. Elemental Analysis for C15
Found %C, 43.54; %H, 3.81; %N, 6.56.
-(4-(4-Fluorobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide (4). The title compound was
2 5
H15BrN O S. Calculated: %C, 43.39; %H, 3.64; %N, 6.75;
2
prepared from Oꢀsilylate derivative 55 following the general procedure. The crude product was
purified by flash chromatography (nꢀhexane/EtOAc 2:3) using a Isolute Flash Si II cartridge to give
1
4
as a white solid (36% yield); mp: 128ꢀ130°C; HꢀNMR (DMSOꢀd
6
) δ: 3.27 (d, J=5.9 Hz, 2H);
5.17 (s, 2H); 7.15ꢀ7.19 (m, 2H); 7.24ꢀ7.28 (m, 2H); 7.49ꢀ7.56(m, 2H); 7.71ꢀ7.75 (m, 2H); 7.81 (t,
1
3
J=5.9 Hz, 1H); 8.87 (br s, 1H); 10.53 (br s, 1H). CꢀNMR (DMSOꢀd
6
) δ: 40.71, 70.83, 114.61,
1
15.73, 128.34, 128.75, 132.09, 136.84, 161.82, 163.74, 166.68. Elemental Analysis for
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
C H FN O S. Calculated: %C, 50.84; %H, 4.27; %N, 7.91; Found %C, 50.97; %H, 4.31; %N,
15
15
2
5
7
.77.
N-Hydroxy-2-(4-(4-(trifluoromethoxy)benzyloxy)phenylsulfonamido)acetamide (5). The title
compound was prepared from Oꢀsilylate derivative 56 following the general procedure. White solid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(
87% yield); mp: 114ꢀ116 °C; HꢀNMR (DMSOꢀd
6
) δ: 3.28 (d, J=6.04 Hz, 2H); 5.23 (s, 2H); 7.16ꢀ
7.20 (m, 2H); 7.39ꢀ7.43 (m, 2H); 7.59ꢀ7.63 (m, 2H); 7.72ꢀ7.76 (m, 2H); 7.82 (t, J=6.04 Hz, 1H);
1
3
8
.88 (br s, 1H); 10.54 (br s, 1H). CꢀNMR (DMSOꢀd ) δ: 43.11, 68.65, 114.94, 121.06, 128.72,
6
1
15 3 2 6
29.69, 132.22, 135.82, 147.90, 160.95, 164.28. Elemental Analysis for C16H F N O S.
Calculated: %C, 45.72; %H, 3.60; %N, 6.66; Found %C, 45.83; %H, 3.81; %N, 6.30.
2-(4-(3-Fluorobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide (8). The title compound was
prepared from Oꢀsilylate derivative 57 following the general procedure. The crude product was
purified by flash chromatography (nꢀhexane/EtOAc 2:3) using a Isolute Flash Si II cartridge to give
1
8
as a yellow solid (45% yield); mp: 98ꢀ100 °C; HꢀNMR (DMSOꢀd
6
) δ: 3.27 (s, 2H); 5.21 (s, 2H);
1
3
7
.16ꢀ7.20 (m, 3H); 7.29ꢀ7.32 (m, 2H); 7.41ꢀ7.51 (m, 1H); 7.72ꢀ7.76 (m, 2H); 9.04 (br s, 1H). Cꢀ
) δ: 43.13, 68.73, 114.14, 114.57, 114.97, 123.61, 123.66, 128.70, 130.42, 130.58,
32.22, 139.12, 139.26, 159.64, 160.90, 164.50. Elemental Analysis for C H FN O S. Calculated:
NMR (DMSOꢀd
6
1
1
5
15
2
5
%C, 50.84; %H, 4.27; %N, 7.91; Found %C, 50.93; %H, 4.34; %N, 7.57.
N-Hydroxy-2-(4-(3-(trifluoromethoxy)benzyloxy)phenylsulfonamido)acetamide (9). The title
compound was prepared from Oꢀsilylate derivative 58 following the general procedure. The crude
product was purified by flash chromatography (CHCl
3
/MeOH 36:1) using a Isolute Flash Si II
1
cartridge to give 9 as a white solid (42% yield); mp: 83ꢀ85 °C; HꢀNMR (DMSOꢀd ) δ: 3.27 (d,
6
J=5.31 Hz, 2H); 5.25 (s, 2H); 7.17ꢀ7.21 (m, 2H); 7.31ꢀ7.38 (m, 1H); 7.48ꢀ7.56 (m, 3H); 7.72ꢀ7.76
1
3
(
m, 2H); 9.04 (br s, 2H). CꢀNMR (DMSOꢀd
6
) δ: 3.65, 29.07, 75.44, 80.54, 80.96, 87.20, 89.19,
S. Calculated:
91.00, 92.77, 99.62, 108.83, 121.34, 124.67. Elemental Analysis for C16
15 3 2 6
H F N O
%C, 45.72; %H, 3.60; %N, 6.66; Found %C, 45.79; %H, 3.76; %N, 6.49.
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2-(4-(Biphenyl-3-ylmethoxy)phenylsulfonamido)-N-hydroxyacetamide (10). The title compound
was prepared from Oꢀsilylate derivative 59 following the general procedure. The crude product was
purified by flash chromatography (nꢀhexane/EtOAc 2:3) using a Isolute Flash Si II cartridge to give
1
1
0 as a foaming pink solid (50% yield); mp: 54ꢀ55 °C; HꢀNMR (DMSOꢀd
6
) δ: 3.26 (s, 2H); 5.27
) δ: 43.13,
69.58, 114.99, 126.19, 126.37, 126.68, 126.86, 127.55, 128.72, 128.92, 129.12, 132.05, 137.03,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(
s, 2H); 7.19ꢀ7.23 (m, 2H); 7.37ꢀ7.51 (m, 5H); 7.62ꢀ7.76 (m, 6H). CꢀNMR (DMSOꢀd
6
1
4
39.77, 140.34, 161.15, 164.26. Elemental Analysis for C H N O S. Calculated: %C, 61.15; %H,
21 20 2 5
.89; %N, 6.79; Found %C, 61.23; %H, 4.96; %N, 6.78.
N-Hydroxy-2-(4-(quinolin-8-ylmethoxy)phenylsulfonamido)acetamide (11). The title compound
was prepared from Oꢀsilylate derivative 60 following the general procedure. The crude product was
purified by flash chromatography (CH Cl /MeOH 18:1) using a Isolute Flash Si II cartridge to give
2
2
1
1
7
8
1 as a white solid (70% yield); mp: 165ꢀ167 °C; HꢀNMR (DMSOꢀd ) δ: 3.29 (s, 2H); 5.82 (s, 2H);
6
.22ꢀ7.26 (m, 2H); 7.59ꢀ7.68 (m, 2H); 7.73ꢀ7.77 (m, 2H); 7.88ꢀ7.92 (m, 1H); 7.99ꢀ8.02 (m, 1H);
13
6
.42ꢀ8.46 (m, 1H); 8.91 (br s, 1H); 8.96ꢀ8.98 (m, 1H); 10.56 (br s, 1H). CꢀNMR (DMSOꢀd )
δ:43.14, 66.05, 114.90, 121.73, 126.30, 128.25, 128.43, 128,80, 131.99, 133.78, 136.48, 145.18,
1
50.15, 161.41, 164.34. Elemental Analysis for C H N O S. Calculated: %C, 55.80; %H, 4.42;
18 17 3 5
%N, 10.85; Found %C, 55.63; %H, 4.69; %N, 10.68.
2
-(4-(3,5-Difluorobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide
(12).
The
title
compound was prepared from Oꢀsilylate derivative 61 following the general procedure. White solid
1
(
85% yield); mp: 125ꢀ127 °C; HꢀNMR (DMSOꢀd
6
) δ: 3.27 (d, J=6.04 Hz, 2H); 5.23 (s, 2H); 7.16ꢀ
13
7
.27 (m, 5H); 7.72ꢀ7.76 (m, 2H); 7.83 (t, J=6.04 Hz, 2H); 10.54 (br s, 1H). CꢀNMR (DMSOꢀd ) δ:
6
4
3.11, 68.18, 103.38, 110.33, 110.82, 114.99, 128.74, 132.42, 160.70, 164.26. Elemental Analysis
S. Calculated: %C, 48.39; %H, 3.79; % N, 7.52; Found %C, 48.66; %H, 3.91;
14 2 2 5
for C15H F N O
%N, 7.46.
General procedure for the synthesis of Benzyloxy-phenylesulfonamido N-hydroxy acetamides
6
, 7, 13. Protected Hydroxamates 62-64 (0.33 mmol) were dissolved in dioxane (0.6 mL) and a
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solution of HCl 4 N (5.94 mL) was added dropwise followed by MeOH (1.32 mL). After stirring
for 30 min, the reaction was evaporated in vacuo.
2
-(4-(Biphenyl-4-ylmethoxy)phenylsulfonamido)-N-hydroxyacetamide (6). The title compound
was prepared from the THPꢀprotected hydroxamate 62 following the general procedure. The crude
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
product was purified by flash chromatography (nꢀhexane/EtOAc 1:1) using a Isolute Flash Si II
1
cartridge to give 6 as a white solid (39% yield). Mp: 163ꢀ165 °C; HꢀNMR (DMSOꢀd ) δ: 3.25 (s,
6
1
3
2
H); 5.23 (s, 2H); 7.18ꢀ7.22 (m, 2H); 7.33ꢀ7.57 (m, 5H); 7.66ꢀ7.76 (m, 6H); 8.97 (br s, 1H). Cꢀ
NMR (DMSOꢀd ) δ: 30.70, 69.29, 114.94, 126.61, 126.76, 127.49, 128.39, 128.70, 128.89, 132.15,
35.46, 139.65, 139.85, 161.10. Elemental Analysis for C21 S. Calculated: %C, 61.15; %H,
4.89; %N, 6.79; Found %C, 61.21; %H, 4.99; %N, 6.66.
-(4-(3-Bromobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide (7). The title compound was
prepared from the THPꢀprotected hydroxamate 63 following the general procedure. Hydroxamate
6
1
20 2 5
H N O
2
7
2
a was obtained after trituration with Et O as a white crystalline solid (79% yield); mp: 124ꢀ125
1
°
C; HꢀNMR (DMSOꢀd
6
) δ: 3.28 (d, J=6.02 Hz, 2H); 5.20 (s, 2H); 7.17ꢀ7.21 (m, 2H); 7.34ꢀ7.58 (m,
3H); 7.68ꢀ7.69 (m, 1H); 7.72ꢀ7.76 (m, 2H); 7.80ꢀ7.86 (t, J=6.02 Hz, 1H); 8.88 (br s, 1H); 10.55 (br
13
s, 1H). CꢀNMR (DMSOꢀd ) δ: 43.10, 68.60, 114.96, 121.66, 126.68, 128.72, 130.32, 130.67,
6
1
4
30.83, 132.25, 139.10, 160.89, 164.28. Elemental Analysis for C H BrN O S. Calculated: %C,
15
15
2
5
3.39; %H, 3.64; %N, 6.75; Found %C, 43.41; %H, 3.75; %N, 6.49.
2-(4-(3,5-Dibromobenzyloxy)phenylsulfonamido)-N-hydroxyacetamide
(13).
The
title
compound was prepared from the THPꢀprotected hydroxamate 64 following the general procedure.
Hydroxamate 13 was obtained after trituration with Et O as a white solid (77% yield). Mp: 94ꢀ96
2
1
°
C; HꢀNMR (DMSOꢀd ) δ: 3.28 (d, J=6.02 Hz, 2H); 5.20 (s, 2H); 7.17ꢀ7.21 (m, 2H); 7.70ꢀ7.72 (m,
6
13
3
6
H); 7.76ꢀ7.77 (m, 1H); 7.80ꢀ7.86 (m, 2H); 10.55 (br s, 1H). CꢀNMR (DMSOꢀd ) δ: 43.11, 67.80,
114.96, 122.50, 128.72, 129.47, 132.42, 132.87, 141.10, 160.68, 164.25. Elemental Analysis for
C
15
H14Br
2
N
2
O
5
S. Calculated: %C, 36.46; %H, 2.86; %N, 5.67; Found %C, 36.51; %H, 2.93; %N,
5
.43.
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tert-Butyl 2-(4-(3,5-dibromobenzyloxy)phenylsulfonamido)acetate (65). To a solution of glycine
tertꢀbutyl ester hydrochloride (176 mg, 1.05 mmol), in H O (1.0 mL) and dioxane (5.0 mL)
2
containing TEA (0.44 mL, 3.15 mmol), sulfonyl chloride 43 (500 mg, 1.05 mmol) was added. The
mixture was stirred at RT overnight, dioxane was evaporated and the residue was diluited with
10
11
12
13
14
15
16
17
18
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58
59
60
EtOAc and washed with H
2
2 4
O and brine. The organic phase was dried over Na SO , filtered and
1
concentrated in vacuo to give a white solid (512 mg, 90% yield). HꢀNMR (CDCl ) δ: 1.34 (s, 9H);
3
3
.65 (d, J=5.3 Hz, 2H); 4.99 (t, J=5.4 Hz, 1H); 5.04 (s, 2H); 6.99ꢀ7.04 (m, 2H); 7.50 (m, 2H); 7.65
s, 1H); 7.79ꢀ7.83 (m, 2H).
General procedure for the synthesis of tert-butyl esters 66 and 67. A solution of aryl bromide 65
(250 mg, 0.48 mmol) in dioxane (4.8 mL)/H O (1.0 mL) was sequentially treated under nitrogen
with K PO (306 mg, 1.4 mmol), the appropriate arylboronic acid (0.52 mmol), and Pd(PPh ) (22
(
2
3
4
3 4
mg, 0.02 mmol). The resulting mixture was stirred for 1 h at 85 °C. After being cooled to RT, the
mixture was treated with NaHCO and extracted with CHCl . The combined organic extracts were
dried over anhydrous Na SO , filtered, and evaporated under reduced pressure. The crude was
3
3
2
4
purified by flash chromatography on silica gel column.
tert-Butyl 2-(4-((5-bromo-4'-methoxybiphenyl-3-yl)methoxy)phenylsulfonamido)acetate (66).
The title compound was prepared from 4ꢀmethoxyphenylboronic acid following the general
1
procedure. Purified with nꢀhexane/EtOAc 7:2 (40% yield) as colorless oil. HꢀNMR (CDCl
3
) δ: 1.33
(s, 9H); 3.65 (d, J=5.5 Hz, 2H); 3.85 (s, 3H); 4.96 (t, J=5.5 Hz, 1H); 5.12 (s, 2H); 6.94ꢀ7.00 (m,
H); 7.02ꢀ7.07 (m, 2H); 7.47ꢀ7.51 (m, 4H); 7.66 (s, 1H); 7.77ꢀ7.83 (m, 2H).
2
tert-Butyl 2-(4-(3-bromo-5-(pyridin-3-yl)benzyloxy)phenylsulfonamido)acetate (67). The title
compound was prepared from 3ꢀpyridinylboronic acid following the general procedure. Purified
1
with nꢀhexane/EtOAc 2:1 (36% yield) as white solid. HꢀNMR (CDCl
3
) δ: 1.32 (s, 9H); 3.63 (d, J=
5.6 Hz, 2H); 5.14 (s, 2H); 5.29 (t, J=5.4 Hz, 1H); 7.02ꢀ7.06 (m, 2H); 7.39ꢀ7.71 (m, 4H); 7.78ꢀ7.83
(
m, 2H); 7.91 (dt, J
1
= 8 Hz, J
2
= 2 Hz, 1H); 8.64 (d, J=3.6 Hz, 1H); 8.84 (s, 1H).
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General Procedure for the Preparation of Carboxylic Acids 68 and 69. TFA (10.44 mmol, 0.8
mL) was added dropwise to a stirred, iceꢀchilled solution of tertꢀbutyl esters 66 and 67 (0.18 mmol)
in freshly distilled dichloromethane (2.0 mL). The mixture was stirred under these reaction
conditions for 5 h, and the solvent was removed in vacuo to give the corresponding carboxylic acids
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5
6
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9
0
6
2
8 and 69. The crude products were purified by trituration with Et O.
2-(4-((5-Bromo-4'-methoxybiphenyl-3-yl)methoxy)phenylsulfonamido)acetic acid (68). The
title compound was prepared from tertꢀbutyl ester 66 following the general procedure. White solid
1
(
87% yield). HꢀNMR (CD
3
OD) δ: 3.65 (s, 2H); 3.82 (s, 3H); 5.12 (s, 2H); 6.93ꢀ6.97 (m, 2H); 7.03ꢀ
7
.08 (m, 2H); 7.45ꢀ7.50 (m, 4H); 7.63 (s, 1H); 7.76ꢀ7.80 (m, 2H).
3-(3-Bromo-5-((4-(N-(carboxymethyl)sulfamoyl)phenoxy)methyl)phenyl)pyridinium
2,2,2-
trifluoroacetate (69). The title compound was prepared from tertꢀbutyl ester 67 following the
1
general procedure. White solid (58% yield). HꢀNMR (DMSOꢀd ) δ: 3.53 (d, J=6.0 Hz, 2H); 5.26
6
(s, 2H); 7.19ꢀ7.23 (m, 2H); 7.57ꢀ7.63 (m, 2H); 7.72ꢀ7.76 (m, 3H); 7.88ꢀ7.97 (m, 3H); 8.24 (d, J=7.8
Hz, 1H); 8.67 (s, 1H); 8.98 (s, 1H).
General Procedure for the Synthesis of Hydroxamates 17 and 18. EDC was added portionwise
(
92 mg, 0.48 mmol) to a stirred and cooled solution (0 °C) of the appropriate carboxylic acid 68, 69
0.19 mmol) and Oꢀ(tertꢀbutyldimethylsilyl)hydroxylamine (113 mg, 0.77 mmol) in dry CH Cl (10
(
2
2
mL). After stirring at RT overnight, the mixture was washed with water and the organic phase was
dried and evaporated in vacuo. Silyl precursors (0.12 mmol) were then dissolved in dry CH Cl (2
2
2
mL) and TFA (0.5 mL, 6.56 mmol) was added dropwise at 0 °C. After 5 h of stirring, TFA was
evaporated. The crude products were purified by trituration with nꢀhexane/Et O to give the desired
2
hydroxamates 17 and 18.
2-(4-((5-Bromo-4'-methoxybiphenyl-3-yl)methoxy)phenylsulfonamido)-N-hydroxyacetamide
(17). The title compound was prepared from carboxylic acid 68 following the general procedure. Oꢀ
Silylate derivative was purified by flash chromatography on silica gel (nꢀhexane/EtOAc 1:1) to give
1
a white solid (60% yield). HꢀNMR (CDCl ) δ: 0.02 (s, 6H); 0.85 (s, 9H); 3.65 (s, 2H); 3.82 (s, 3H);
3
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5.16 (s, 2H); 6.93ꢀ6.97 (m, 2H); 7.03ꢀ7.08 (m, 2H); 7.45ꢀ7.50 (m, 4H); 7.63 (s, 1H); 7.76ꢀ7.80 (m,
2
H); 10.39 (s, 1H).
2
Hydroxamic acid 17 was obtained as white solid (87% yield) after trituration with Et O. Mp: 175ꢀ
1
1
77 °C; HꢀNMR (CDCl
3
) δ: 3.52 (s, 2H); 3.85 (s, 3H); 5.31 (s, 2H); 7.02ꢀ7.08 (m, 2H); 7.20ꢀ7.25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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35
36
37
38
39
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
(
m, 2H); 7.62ꢀ7.68 (m, 4H); 7.75 (s, 1H); 7.81ꢀ7.86 (m, 2H); 10.20 (br s, 1H). CꢀNMR (DMSOꢀ
d6) δ: 42.10; 57.90; 69.30; 114.95; 122.49; 127.90; 128.72; 129.47; 130.10; 132.42; 132.87; 138.70;
1
42.20; 159.15; 161.67; 165.21. Elemental Analysis for C H BrN O S. Calculated: %C, 50.68;
22 21 2 6
%
H, 4.06; %N, 5.37; Found %C, 50.75; %H, 4.19; %N, 5.29.
3
-(3-Bromo-5-((4-(N-(2-(hydroxyamino)-2-
oxoethyl)sulfamoyl)phenoxy)methyl)phenyl)pyridinium 2,2,2-trifluoroacetate (18). The title
compound was prepared from carboxylic acid 69 following the general procedure. OꢀSilylate
derivative was purified by flash chromatography on silica gel (nꢀhexane/EtOAc 1:1) to give a white
1
solid (67% yield). HꢀNMR (DMSOꢀd
6
) δ: 0,03 (s, 6H); 0,86 (s, 9H); 5,27 (s, 2H); 7.20ꢀ7.24 (m,
=8 Hz, J =1.6 Hz, 1H);
2
H); 7.48ꢀ7.63 (m, 3H); 7.72ꢀ7.76 (m, 3H); 7.86ꢀ7.94 (m, 2H); 8.13 (dt, J
8.61 (dd, J =4.7 Hz, J =1.4 Hz, 1H); 8.92 (d, J=1.6 Hz, 1H); 10.75 (s, 1H).
1
2
1
2
Hydroxamic acid 18 was obtained as pale yellow solid (37% yield) after a flash chromatography
1
(
CHCl /MeOH 25:1) using a Isolute Flash Si II cartridge. Mp: 135 °C (dec.); HꢀNMR (DMSOꢀd )
3
6
δ: 3.28 (d, 2H); 5.27 (s, 2H); 7.20ꢀ7.24 (m, 2H); 7.47ꢀ7.54 (m, 1H); 7.72ꢀ7.94 (m, 6H); 8.13 (dt,
=8 Hz, J =1.6 Hz, 1H); 8.61 (dd, J =4.8 Hz, J =1.4 Hz, 1H); 8.88 (s, 1H); 8.92 (d, J=1.6 Hz, 1H).
CꢀNMR (CD OD) δ: 44.57; 70.30; 116.37; 124.27; 125.42; 125.98; 130.33; 130.64; 131.13;
36.54; 136.83; 141.33; 148.39; 149.49; 163.23; 167.64. Elemental Analysis for C H BrF N O S.
J
1
2
1
2
1
3
3
1
22
19
3
3
7
Calculated: %C, 43.58; %H, 3.16; %N, 6.93; Found %C, 43.75; %H, 3.29; %N, 6.69.
General procedure for the synthesis of sulfonamides 70, 72 and 73. To a solution of sarcosine
tertꢀbutyl ester hydrochloride or HꢀDꢀOrn(Z)ꢀOH or HꢀDꢀOrn(carbamoyl)ꢀOH (0.59 mmol) in H
mL) and dioxane (1 mL) containing TEA (1.76 mmol, 0.25 mL) 4ꢀ(3,5ꢀ
2
O
(1
dibromobenzyloxy)benzeneꢀ1ꢀsulfonyl chloride 43 (0.59 mmol, 280mg) was added, and the
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