Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation

Article abstract of DOI:10.1016/j.bmc.2018.02.044

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on different cancer cell lines.

Full text of DOI:10.1016/j.bmc.2018.02.044

Accepted Manuscript
XanthoneDerivativesasPhosphoglycerateMutase1 Inhibitors: Design,
Synthesis, and Biological Evaluation
Penghui Wang, Lulu Jiang, Yang Cao, Xiaodan Zhang, Bangjing Chen, Shiyu
Zhang, Ke Huang, Deyong Ye, Lu Zhou
PII:
S0968-0896(17)32314-3
https://doi.org/10.1016/j.bmc.2018.02.044
BMC 14230
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 November 2017
17 February 2018
23 February 2018
Please cite this article as: Wang, P., Jiang, L., Cao, Y., Zhang, X., Chen, B., Zhang, S., Huang, K., Ye, D., Zhou,
L., Xanthone Derivatives as Phosphoglycerate Mutase 1 Inhibitors: Design, Synthesis, and Biological
Evaluation, Bioorganic & Medicinal Chemistry (2018), doi: https://doi.org/10.1016/j.bmc.2018.02.044
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Xanthone Derivatives as Phosphoglycerate Mutase 1 Inhibitors: Design, Synthesis, and
Biological Evaluation
Penghui Wang, Lulu Jiang, Yang Cao, Xiaodan Zhang, Bangjing Chen, Shiyu Zhang, Ke Huang,
Deyong Ye*, Lu Zhou*
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No.826, Zhangheng Rd., Shanghai, 201203, China
Abstract
Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that dynamically converts 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG), which
was upregulated to coordinate glycolysis, pentose phosphate pathway (PPP) and serine biosynthesis to promote cancer cell proliferation and tumor growth in
a variety of cancers. However, only a few inhibitors of PGAM1 have been reported with poor molecular or cellular efficacy. In this paper, a series of
xanthone derivatives were discovered as novel PGAM1 inhibitors through scaffold hopping and sulfonamide reversal strategy based on the lead compound
PGMI-004A. Most xanthone derivatives showed higher potency against PGAM1 than PGMI-004A and exhibited moderate anti-proliferation activity on
different cancer cell lines.
Keywords: Phosphoglycerate mutase 1, Inhibitors, Xanthone derivatives, Cancer cell metabolism
ABBREVIATIONS
PGAM1, Phosphoglycerate mutase 1; 3PG, 3-phosphoglycerate; 2PG, 2-phosphoglycerate; 2,3-BPG, 2,3-bisphosphoglycerate; 6PGD, 6-phosphogluconate
dehydrogenase; PPP, pentose phosphate pathway; PHGDH, 3-phosphoglycerate dehydrogenase; SSP, serine synthesis pathway; EGCG, epigallocatechin
gallate; SAR, structure activity relationship; IC50, 50% inhibiting concentration
*Corresponding author: Tel. & Fax: +86-21-51980117. E-mail address: dyye@shmu.edu.cn (D Ye).
*Corresponding author: Tel. & Fax: +86-21-51980125. E-mail address: zhoulu@shmu.edu.cn (L Zhou).
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1. Introduction:
Cancer cells tend to competently coordinate bioenergetics, anabolic biosynthesis, and balanced redox status to provide an optimum
microenvironment for cancer cell proliferation and tumor growth [1]. This phenotype known as cancer cell metabolic reprogramming has
been established as one essential hallmark of cancer cells [2, 3]. The Warburg effect describes a phenomenon that most cancer cells
predominantly rely on the high rate of aerobic glycolysis to produce energy rather than efficient mitochondrial oxidative phosphorylation as
in most normal cells. The resulting alteration serves to supply the glycolytic intermediates as building blocks for anabolic biosynthesis of
macromolecules, such as RNA/DNA, proteins, and lipids and meet the needs of the rapid proliferation of tumor cells [4]. Thus targeting key
metabolic enzymes may provide a promising therapeutic strategy for cancer treatment [5-10].
Phosphoglycerate mutase 1 (PGAM1) catalyzes the 8th step of glycolysis, reversibly isomerizing 3-phosphoglycerate (3PG) to
2-phosphoglycerate (2PG) through 2,3-bisphosphoglycerate (2,3-BPG) as a cofactor [11, 12]. In humans, PGAM1 is widely expressed in the
non-muscle tissue, such as liver and brain [13]. Meanwhile, it is found to be overexpressed in various types of human cancer, including
breast cancer [14], prostate cancer [15], lung cancer [16], oral squamous cell carcinoma [17], hepatocellular carcinoma [18], and urothelial
bladder cancer [19]. What’s more, both pharmacological inhibition [20-23] and knockdown of PGAM1 result in suppression of cancer cell
proliferation, tumor growth [18], and even cancer cell migration [24, 25]. Hitosugi et al. has demonstrated that PGAM1 promotes tumor
growth by dynamically regulating the intracellular levels of glycolytic metabolites 3-PG and 2-PG, which function as signaling molecules to
directly affect the catalytic activity of 6-phosphogluconate dehydrogenase (6PGD) in the oxidative pentose phosphate pathway (PPP) and
3-phosphoglycerate dehydrogenase (PHGDH) in serine synthesis pathway(SSP) respectively [21]. In addition to upregulated gene expression
of PGAM1, oncogenic tyrosine kinases such as FGFR1, EGFR, FLT3 and JAK2 phosphorylate Y26 of PGAM1 enhance its enzymatic
activity and promote tumor growth in diverse human cancers [26]. Accordingly, inhibition of PGAM1 can not only reduce the indispensable
energy supply for cancer cells but also prevent anabolic processes including PPP and SSP, required for cell proliferation and tumor growth
[27]. In summary, developing PGAM1 inhibitors could become a new promising therapeutic opportunity for cancer therapy.
Figure 1 The chemical structures of reported PGAM1 inhibitors.
However, only a small amount of PGAM1 inhibitors with poor cellular efficacy have been reported so far (Fig. 1) [20-22]. MJE3 was
found to covalently label PGAM1 on K100 by its unique spiroepoxide pharmacophore [28]. Epigallocatechin gallate (EGCG), the major
extract from the green tea, was identified as a PGAM1 inhibitor with higher molecular potency but very limited cellular efficacy due to its
polyphenol structure[22]. Besides, EGCG could broadly affect multiple signaling pathways [29], suggesting that EGCG had strong
off-targets effects. Alizarin Red S (ARS), obtained from high-throughput screening, possessed medium inhibitory activity against PGAM1,
while no anti-proliferation activity was shown because of its low permeability caused by the sulfonic acid group. After structure modification
of ARS, the sulfonamide PGMI-004A was obtained. PGMI-004A, although with a weak inhibitory activity against PGAM1 in vitro, could
not only reduces cell proliferation but also suppress tumor growth in xenograft nude mice in vivo [21]. Considering the anthraquinone core of
PGMI-004A belongs to structural alerts [30] in medicinal chemistry, PGMI-004A is required to be subjected to structural optimization.
Herein, we conducted the scaffold hopping to replace the anthraquinone core of PGMI-004A with xanthone core, and take the sulfonamide
reversal strategy to design and synthesize a series of xanthone derivatives, which showed stronger efficacy and better specificity than
PGMI-004A against PGAM1, as well as higher anti-cell proliferative activity against H1299 cell line. (Fig. 2).
2 / 18

Figure 2 Designing of xanthones by scaffold hopping and sulfonamide reversal strategy.
2. Results and discussion
2.1 Chemistry
Scheme 1 General synthetic route of xanthone derivatives. Reagents and conditions: a. BnBr, K2CO3, acetone, r.t, 85%; b. 2,6-dimethoxybenzoic acid, TFAA, DCM,
0℃, 66%; c. H2, Pd/C, THF, r.t, 98%; d. Me4NOH, pyridine, H2O, reflux, 92%; e. BCl3, DCM, 0℃, 92%; f. piperidine, H2O, mw, 120℃, 50%; g. Tf2O, pyridine, DCM,
0℃, 73%; h. Pd(OAc)2, BINAP, diphenylmethanimine, Cs2CO3, dioxane, reflux, 78%; i. HCl, THF, H2O, r.t, 80%; j. substituted benzenesulfonyl chloride, pyridine, r.t,
40~70%; k. BBr3, DCM, 0℃, 30~50%.
The xanthone derivatives were synthesized as shown in Scheme 1. 3,4,5-trimethoxy phenol was protected with benzyl to afford the benzyl
ether 2, which was reacted with dimethoxy benzoic acid via Friedel–Crafts reaction to give benzophenone 3. After debenzylation of 3 and
cyclization of 4, the xanthan 5 was obtained and demethylated with 1 eq. boron trichloride to afford the demethylation product 6. Continued
demethylation of compound 6 was achieved via a microwave-assisted modified condition of Gil’s work[31] to lead the trihydroxy xanthone
7a and the dihydroxy xanthone 7b. 7b was converted to the triflate 8 by treating with Tf2O. The key intermediate amino xanthone 10 was
obtained via Buchwald–Hartwig amination/hydrolysis protocol [32] from triflate 8. From the amine 10, a series of sulfonamides 11 were
synthesized and then demethylated the protecting groups with BBr3 to afford the desired compounds 12a~12p.
Since the para-N-substituted benzenesulfonyl chloride could hardly be separated from its meta isomer during the preparation of
4-(pyrrolidin-1-yl)benzenesulfonyl chloride and 4-(piperidin-1-yl)benzenesulfonyl chloride, as well as the sulfonamide products, 12r and 12s
were synthesized with an alternative route. The intermediates 11r and 11s were synthesized from 11j with pyrrolidine and piperidine via
conventional Buchwald–Hartwig coupling according to Scheme 2 respectively.
3 / 18

Scheme 2 Synthetic route of 12r and 12s. Reagents and conditions: a. Pd2(dba)3, BINAP, t-BuONa, pyrrolidine or piperidine, NMP, 100℃; b. BBr3, DCM, 0℃,
30~50%.
2.2 Biological evaluation and molecular docking
2.2.1 In vitro PGAM1 enzyme inhibitory activity
Table 1. PGAM1 inhibition activity and counter-screen assay of xanthones derivatives
Counter-screen assay c
PGAM 1 inhibition IC50
Entry
Compounds
R
(μM)a
(inhibition ratio@ 5 μM)
1
2
>> 20 μM b
11a-11s
12a
ND
phenyl
2.8 ± 1.1
6%
3
4-methyl phenyl
benzyl
7.2 ± 1.8
1.9 ± 0.4
3.5 ± 0.8
6.3 ± 1.8
5.8 ± 0.4
5.5 ± 2.3
3.6 ± 0.5
2.9 ± 0.1
1.9 ± 0.2
4.2 ± 0.3
2.1 ± 0.5
1.7 ± 0.5
1.6 ± 0.0
1.2 ± 0.2
2.6 ± 0.4
0.5 ± 0.1
2.7 ± 0.1
2%
12b
12c
12d
12e
12f
4
12%
-1%
2%
5
4-(trifluoromethyl)phenyl
2,5-bis(trifluoromethyl)phenyl
3-(trifluoromethoxy)phenyl
4-fluorophenyl
6
7
12%
1%
8
12g
12h
12i
9
4-chlorophenyl
15%
6%
10
11
12
13
14
15
16
17
18
19
4-bromophenyl
4-iodophenyl
11%
10%
13%
7%
12j
4-cyanophenyl
12k
12l
3-cyanophenyl
naphthalen-1-yl
12m
12n
12o
12p
12q
12r
naphthalen-2-yl
9%
[1,1'-biphenyl]-4-yl
4-(tert-butyl)phenyl
4-cyclohexylphenyl
4-(pyrrolidin-1-yl)phenyl
8%
1%
9%
4%
4 / 18

20
21
21
4-(piperidin-1-yl)phenyl
1.0 ± 0.3
0.49
5%
12s
63% (@0.625 μM)
EGCG
PGMI-004A
13.0 ± 0.1
38%
a The IC50 data were presented as mean ± sd. Each experiment was run in triplicate.
b The inhibition ratios of 11a-11s against PGAM1 were less than 10% at 20 μM
c The counter-screen assay was conducted to exclude the false-positive results
The enzyme inhibitory activities of the xanthone derivatives were determined by multiple enzymes coupled assay [21]. The results shown in
Table 1 exhibited that all final xanthone products (12a-12s) displayed much more potency than PGMI-004A against PGAM1. Especially,
12q with IC50 of 0.5 μM, compared to PGMI-004A, the PGAM1 inhibitory activity increased by 26 times. Furthermore, the counter-screen
assay data were measured to exclude the non-specific inhibitory activity against to PGAM1. EGCG with IC50 of 0.49 μM, showed an
inhibition ratio of 63% at a concentration of 0.625 μM in the counter-screen assay system. However, all xanthone derivatives almost showed
no inhibitory activities against the latter three downstream enzymes including enolase, pyruvate kinase and lactate dehydrogenase in the
multiple enzymes coupled assay system at a concentration up to 5 μM.
In order to explore the interesting enzymatic profiles, a preliminary structure-activity relationship (SAR) was discussed as follow. All
final xanthone products (12a-12s) showed significant inhibitory activities against PGAM1 as compared to their methylation precursors
(11a-11s), suggesting that exposed hydroxyl groups in these positions were essential for activities. While for different substituents on the
sulfonamide benzene ring, the IC50 values were approximately in the same order of magnitude. This might indicate that the benzene ring
binds to a large cave of PGAM1.For the derivatives with mono-substituted on the C4 of the benzene ring, their inhibitory activities were
significantly enhanced with the increase of the substituents’ volume, such as from 12g to 12j, the IC50 values increased from 5.5 μM to 1.9
μM. In addition, the derivatives with a larger ring system (including phenyl, cyclohexyl, heterocycle) substituted on the C4 of benzene ring
showed much more potency than those small function group substitutions.
2.2.2 Thermal shift assay
To examine whether 12q binds to PGAM1, the thermal shift assay was performed to validate the interaction of protein and small molecule
(Fig 3.). Incubation of increasing concentrations from 12.5 μM to 50 μM of 12q raised PGAM1’s melting temperature (Tm) in a
dose-dependent manner, suggesting that 12q directly binds to PGAM1.
1
0
8
6
4
2
0
0
0
0
0
0
C
1
2
5
o
n
. 5
u
t r o
l
2
u
M
5
0
M
u
M
5
0 . 5 ° C
4
8 . 5 ° C
4
0
4
5
5
0
5
5
6 0
T
m
° C
Figure 3 Thermal shift melting curves of PGAM1 and 12q.
2.2.3 Molecular docking
We selected the representative compounds 12b, 12q and 12s to reveal the structure-activity relationships by using molecular docking. The
PGAM1-ARS complex structure model, our unpublished result, showed the ARS bind to the allosteric site next to the substrate-binding
5 / 18

pocket by hydrogen bonds and hydrophobic interaction (Fig 4A.). Besides, the 1-OH group of ARS was linked with R191 and N209 through
a water bridge.
Figure 4 The model of PGAM1- inhibitor interaction (A: the crystal structure of the PGAM1-ARS complex; B: the docking model of 12b bind to PGAM1; C:
the docking model of 12q bind to PGAM1; D: the docking model of 12s bind to PGAM1)
We retained this water bridge during docking study of compound 12b. As a result, compound 12b showed a similar mode of action
compare to ARS (Fig 4B.). The sulfonamide benzene ring formed a weak hydrophobic interaction with F22 in PGAM1. Then the compound
12q was docked to this model, but no reasonable results generated. We conjectured that the cyclohexyl of 12q and the piperidin-1-yl of 12s
would result in a spatial collision with F22 in PGAM1 if we take the same docking method with 12b. Therefore, we abandoned the water
bridge during the docking study of compound 12q and 12s. The results showed the binding modes of compound 12q and 12s with PGAM1
were immensely different with 12b (Fig 4C & 4D). The hydroxyl groups and sulfonamide group contacted with polar residues (including
Q89, R191, and N209) through hydrogen bonds directly. Moreover, the cyclohexyl of 12q and the piperidin-1-yl of 12s occupied the
hydrophobic pocket consisting of P123, W115, and L95, which was held by the xanthone ring in ARS and compound 12b’s model.
2.2.4 In vitro cell proliferation inhibitory activity
6 / 18

Table 2 Anti-proliferation activitives of xanthone derivatives
H1299
MCF-7
PANC-1
IC50 (μM)
＞200 b
Entry Compounds
R
IC50 (μM)a
59.0 ± 20.6
IC50 (μM)
112.6 ± 38
1
phenyl
12a
2
4-methyl phenyl
13.2 ± 2.0
62.9 ± 12.8
10.3 ± 1.8
16.8 ± 0.8
13.9 ± 0.9
21.9 ± 2.3
10.2 ± 1.1
＞ 40 c
44.9 ± 1.8
＞200
20.7 ± 2.8
＞200
12b
12c
3
benzyl
4
4-(trifluoromethyl)phenyl
2,5-bis(trifluoromethyl)phenyl
3-(trifluoromethoxy)phenyl
4-fluorophenyl
30.2 ± 21.4
15.8 ± 3.4
20.5 ± 1.3
20.8 ± 2.6
15.5 ± 5
58.5 ± 17.4
10.5 ± 1.6
116.0 ± 9.8
＞200
12d
12e
5
6
12f
7
12g
8
4-chlorophenyl
91.4 ± 5.3
＞200
12h
12i
9
4-bromophenyl
6.8 ± 3.5
10
11
12
13
14
15
16
17
18
19
20
4-iodophenyl
24.3 ± 1.9
＞ 40
13.5 ± 2.9
40.1 ± 7.9
18.4 ± 4.7
27.3 ± 2.5
43.3 ± 12.8
44.9 ± 1.8
13.4 ± 3.4
26.6 ± 4.0
＞200
34.5 ± 9.7
＞200
12j
4-cyanophenyl
12k
12l
3-cyanophenyl
53.0 ± 7.8
23.2 ± 0.3
22.6 ± 1.2
12.9 ± 1.2
10.7 ± 2.5
10.7 ± 1.0
5.0 ± 0.9
8.1 ± 1.5
＞200
naphthalen-1-yl
100.8 ± 33.7
＞200
12m
12n
12o
naphthalen-2-yl
[1,1'-biphenyl]-4-yl
4-(tert-butyl)phenyl
4-cyclohexylphenyl
4-(pyrrolidin-1-yl)phenyl
4-(piperidin-1-yl)phenyl
＞200
12p
12q
12r
＞200
35.3 ± 4.9
137.0 ± 11.0
＞200
47.6 ± 16.8
12s
26.0 ± 2.1
32.0 ± 3.7
PGMI-004A
＞ 40
a The IC50 data were presented as mean ± sd. Each experiment was run in triplicate.
b The inhibition ratios were less than 50% at 200 μM
c The inhibition ratios were less than 50% at 40 μM
The MTT cell proliferation assay was employed to evaluate the cell proliferation inhibitory activity of those xanthone derivatives. As
mentioned above, PGAM1 was overexpressed in a variety of cancers, such as lung cancer, breast cancer, and pancreatic cancer, so we
performed the anti-proliferation assay on the representative cell lines including H1299, MCF-7 and PANC-1 (Table 2). For H1299 cells,
most of the xanthone derivatives exhibited comparable anti-cell proliferative activity to that of PGMI-004A although the PGAM1 enzymatic
inhibitory activities of those xanthone derivatives were significantly stronger than that of PGMI-004A. This might be due to the poor
7 / 18

permeability of the xanthone derivatives. It is worth mentioning that when nitrogen atom was introduced into the saturated ring (12r and 12s)
which would increase the solubility, the antiproliferation activities were slightly increased. The most potent compound 12r’s cellular
inhibitory activity (IC50= 5.0 μM) was increased by 5 times compared to PGMI-004A on H1299 cells. As for MCF-7 and PANC-1 cells, these
xanthone derivatives showed weaker inhibition activity. We conjectured the different sensitivity of the above three cell lines to those
xanthone derivatives might be caused by the different expression levels of PGAM1.
To validate these xanthone compounds exert anti-proliferative effect through PGAM1, we next measured the anti-proliferation activities
of 12e on PGAM knockdown and overexpressed PANC-1 cells respectively (Table 3). The IC50 values shifted from 5.1 μM to 42.8 μM and
13.8 μM to 25.0 μM respectively in PGAM1 knockdown and overexpressed PANC1 cells, suggesting that 12e exerts anti-proliferative
activity by inhibiting PGAM1 at cellular level.
Table 3 Anti-proliferation activitives of 12e on PGAM1 knockdown and overexpressed PANC1 cells
Blank
IC50 (μM)
IC50 (μM) a
PGAM1 KD PANC1 cells
5.1 ± 2.4
42.8 ± 13.6
25.0 ± 5.1
PGAM1 overexpressed PANC1 cells
13.8 ± 4.0
a The IC50 data were presented as mean ± sd. Each experiment was run in triplicate
3. Conclusion
In summary, starting from the lead compound PGMI-004A, we discovered a new series of xanthone derivatives as novel PGAM1 inhibitors
through scaffold hopping and sulfonamide reversal strategy. Nineteen xanthone sulfonamides were synthesized and biologically evaluated.
PGAM1 enzymatic inhibitory activity assays showed that all designed xanthone derivatives exhibited more potency against PGAM1 than
PGMI-004A. Especially 12q with IC50 of 0.5 μM was the most effective PGAM1 specific inhibitor so far which was supported by
counter-screen assay and thermal shift assay. Besides, a preliminary SAR of those xanthone derivatives was obtained, and molecular docking
revealed the rational binding models of those xanthone derivatives. The anti-proliferation activities of our designed compounds was evaluated on the
representative cancer cell lines. What’s more, 12e’s IC50 shifts on PGAM1 knockdown and overexpressed PANC-1 cells revealed that 12e was an
effective PGAM1 inhibitor on cellular level.
4. Experimental protocols
Reagents were purchased from commercial suppliers and used without further purification unless specifically noted. Flash column
chromatography was carried on CombiFlash® Rf 150 from Teledyne Isco with the standard silica gel column. Mass spectra were given with
electrospray ionization (ESI) produced by a Finnigan MAT-95, LCQ-DECA spectrometer and IonSpec 4.7 T. MS. NMR spectra were
recorded on a Varian Mercury 400 or 600 spectrometer with tetramethylsilane as an internal reference. OD (Optical density) was measured
with a microplate reader (SpectraMax M5, Molecular Devices).
4.1 General procedures for preparation of key intermediate 10.
4.1.1 5-(benzyloxy)-1,2,3-trimethoxybenzene (2).
3,4,5-Trimethoxy phenol (5.0 g, 27.2 mmol) was dissolved in acetone(100 mL), and then K2CO3 (5.63 g, 40.7 mmol) was added. After
vigorously stirring for 5 min, benzyl bromide (3.4 mL, 28.5 mmol) was added dropwise. The reaction mixture was maintained at room
temperature overnight, the solid was filtered out and the reaction solution was concentrated to remove the solvent. The residue was dissolved
in ethyl acetate (100 mL) and then washed with 1 mol/L NaOH aqueous solution twice. The organic phase was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure to afford compound 2 as a white solid (6.36 g, yield: 85%).
8 / 18

4.1.2 (6-(benzyloxy)-2,3,4-trimethoxyphenyl)(2,6-dimethoxyphenyl)methanone (3).
The benzyl ether 2 (3.7 g, 13.4 mmol) and 2,6-dimethoxybenzoic acid (2.6 g, 14. 1 mmol) were dissolved in dry DCM (140 mL) under an
ice-water bath and then 14 mL trifluoroacetic anhydride (TFAA) was added dropwise. After the substrate 2 was disappeared monitoring by
TLC, the reaction solution was poured into 150 mL ice-water mixture with vigorously stirring. The organic phase was washed with 1 mol/L
NaOH aqueous solution (twice) and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford
compound 3 as a white solid (3.93 g, yield: 66%) without purification. 1H NMR (400 MHz, Chloroform-d) δ 7.29 – 7.25 (m, 3H), 7.22 (t, J =
8.4 Hz, 1H), 7.16 – 7.12 (m, 2H), 6.48 (s, 1H), 6.46 (s, 1H), 6.26 (s, 1H), 4.89 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H), 3.57 (s, 6H).
4.1.3 (2,6-dimethoxyphenyl)(6-hydroxy-2,3,4-trimethoxyphenyl)methanone (4).
To a solution of ketone 3 (3.93 g, 8.96 mmol) in THF (50 mL) was added 10% Pd/C (100 mg). The reaction mixture was hydrogenated under
a hydrogen balloon overnight and then the mixture was filtered through a celite bed, washed with ethyl acetate, and concentrated in vacuo to
afford the debenzylation product 4 (3.06 g, 98%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.32 (t, J = 8.3 Hz, 1H),
6.72 (d, J = 8.3 Hz, 2H), 6.40 (s, 1H), 3.87 (s, 3H), 3.69 (s, 6H), 3.58 (s, 3H), 3.23 (s, 3H).
4.1.4 1,2,3,8-tetramethoxy-9H-xanthen-9-one (5).
To a solution of compound 4 (3.06 g) in a mixture of pyridine (38 mL) and water (38 mL) was added Me4NOH (6.25 mL) at room
temperature. The resulting solution was heated to reflux for 8 h and poured into a mixture of hydrochloric acid (1 mol/L, 200 mL) and ethyl
acetate (200 mL) with vigorous stirring. The resulting mixture was separated into two phases. The organic phase was separated, washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure successively. The residue was purified by flash column
chromatography to afford tetra-methoxy xanthone 5 as a yellow solid (2.55 g, yield: 92%).
4.1.5 1-hydroxy-2,3,8-trimethoxy-9H-xanthen-9-one (6).
To a solution of xanthone 5 (1.05 g, 3.32 mmol) in dry DCM (80 mL) was added a solution of BCl3 (1 mol/L, 3.5 mL) in DCM dropwise at
-80 ℃under argon. After 30 min, the reaction was quenched with dry methanol (100 mL) and concentrated in vacuo. The residue was washed
with ether (10 mL) to afford the desire product 6 (920 mg, yield: 92%). 1H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 7.75 (t, J = 8.4 Hz,
1H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 3.92 (s, 6H), 3.72 (s, 3H).
4.1.6 1,3-dihydroxy-2,8-dimethoxy-9H-xanthen-9-one (7).
Compound 6 (1.97 g, 6.52 mmol), piperidine (12 mL) and H2O (3 mL) was added to a microwave vial (20 mL) and heated with microwave
reactor (Biotage) with a programmed procedure of 120 °C for 24 h. After cooling to r.t, the clear red-brown solution was added to
hydrochloric acid (1 mol/L, 100 mL) with vigorously stirring and yellow solids were precipitated. The mixture was filtered and the filter cake
was washed with water, dried and purified by flash column chromatography to afford 7a (850 mg, yield: 48%) and 7b (930 mg, yield: 50%)
as yellow solids respectively. 7a: 1H NMR (400 MHz, Chloroform-d) δ 12.20 (s, 1H), 11.87 (s, 1H), 7.57 (t, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.4,
0.9 Hz, 1H), 6.78 (dd, J = 8.3, 0.9 Hz, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 4.04 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 185.11, 161.16, 157.02,
156.17, 153.37, 152.79, 136.86, 129.76, 110.75, 107.26, 107.04, 102.79, 93.77, 61.04. 7b: 1H NMR (400 MHz, Chloroform-d) δ 13.49 (s,
1H), 7.59 (t, J = 8.4 Hz, 1H), 7.00 (dd, J = 8.5, 1.0 Hz, 1H), 6.79 (dd, J = 8.3, 1.0 Hz, 1H), 6.66 (s, 1H), 6.45 (s, 1H), 4.03 (s, 3H), 4.01 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 181.88, 160.53, 157.95, 155.89, 153.92, 152.37, 135.29, 129.62, 110.53, 109.84, 105.50, 104.38, 92.62,
60.92, 56.51.
4.2.7 1-hydroxy-2,8-dimethoxy-3-trifluoromethanesulfonyloxy-9H-xanthen-9-one (8).
To a solution of xanthone 7b (0.900 g, 3.12 mmol) and pyridine (0.503 mL, 6.24 mmol) in dry DCM (30 mL) was added Tf2O (0.630 mL,
3.75 mmol) dropwise at 0 ℃. The reaction was completed after 1 h monitored by TLC. Then the mixture was quenched with hydrochloric
acid (1 mol/L, 20 mL) and the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine successively. After
dried over with sodium sulfate, the solution was filtered and concentrated in vacuo. The residue was purified by flash column
chromatography to afford the desired triflate 8 as a yellow solid (963 mg, yield: 73%). 1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 7.82
9 / 18

(t, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H). 13C NMR (151 MHz, DMSO) δ
181.35, 160.26, 157.20, 154.88, 149.92, 145.90, 137.24, 134.21, 118.03 (q, J = 320.3 Hz), 109.63, 109.24, 109.15, 106.87, 99.85.
4.1.8 3-((diphenylmethylene)amino)-1-hydroxy-2,8-dimethoxy-9H-xanthen-9-one (9).
The triflate 8 (200 mg, 0.476 mmol), benzophenone imine (0.16 mL, 0.952 mmol), BINAP (44 mg, 0.071 mmol), Pd(OAc)2 (11 mg, 0.048
mmol) and Cs2CO3 (217 mg, 0.666 mmol) were suspended in dioxane (5 mL) under argon and the resulting mixture was heated to reflux for
12 h. After cooling to r.t, the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a celite bed and concentrated in vacuo
successively. The residue was purified by flash column chromatography to afford the desired product 9 as a yellow solid (168 mg, yield:
78%).
4.1.9 3-amino-1-hydroxy-2,8-dimethoxy-9H-xanthen-9-one (10).
To a solution of compound 9 (168 mg, 0.372 mmol) in THF (10 mL) was added hydrochloric acid (4 mol/L, 4 mL). After 30 min, the
reaction mixture was diluted with ethyl acetate (10 mL) and quenched with saturated aqueous sodium bicarbonate solution. The organic
phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo successively. The residue was crystallized in
hexane/ethyl acetate to afford the desired amine 10 as a yellow solid (85 mg, yield: 80%). 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H),
7.66 (t, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.43 (s, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.72 (s, 3H). 13C NMR
(151 MHz, DMSO) δ 179.29, 159.81, 156.90, 153.27, 152.10, 149.89, 135.04, 127.73, 109.61, 109.11, 106.16, 100.09, 89.36, 59.10, 56.09.
+
MS (ESI+) m/z 288.1 (M + H)+. HRMS (ESI+) m/z: 288.0858 (M + H)+ (calcd for C15H14NO5 : 288.0866).
4.2 General synthetic procedure of compound 11a-11q
To a solution of amine 10 (30 mg, 0.1 mmol) in dry pyridine (2 mL) was added substituted benzenesulfonyl chloride (1.5 - 2 eq.). The
reaction mixture was kept at r.t overnight and poured into a mixture of hydrochloric acid (1 mol/L, 10 mL) and ethyl acetate (10 mL) with
vigorous stirring. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo successively.
The residue was purified by flash column chromatography to afford the desired sulfonamides 11 as yellow solids (yield: 40% - 70%).
4.2.1 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11a).
Yield: 50%. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.57 (s, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.76 (t, J = 8.3 Hz, 1H), 7.63 (q, J = 7.6
Hz, 3H), 7.13 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.94 (s, 1H), 3.90 (s, 3H), 3.62 (d, J = 1.8 Hz, 3H). MS (ESI-) m/z 426.1 (M - H)-
4.2.2 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-4-methylbenzenesulfonamide (11b).
Yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 10.46 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.75 (t, J = 8.5 Hz, 1H), 7.41 (d, J = 8.0
Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 3.90 (s, 3H), 3.64 (s, 3H), 2.34 (s, 3H). 13C NMR (151 MHz, DMSO)
δ 180.84, 160.03, 157.18, 153.36, 150.42, 143.81, 138.02, 136.66, 136.37, 131.64, 129.83, 126.60, 109.61, 109.27, 106.48, 105.20, 94.94,
60.14, 56.22, 20.89.
4.2.3 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-4-(trifluoromethyl)benzenesulfonamide (11d).
Yield: 67%. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.79 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.76 (t, J = 8.4
Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.96 (s, 1H), 3.91 (s, 3H), 3.62 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.95,
160.08, 157.22, 153.53, 150.41, 143.51, 137.26, 136.51, 132.85 (q, J = 32.4 Hz), 132.19, 127.57, 126.73, 125.93, 123.22 (q, J = 273.1 Hz),
109.63, 109.28, 106.53, 105.73, 95.79, 60.14, 56.25.
4.2.4 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-2,5-bis(trifluoromethyl)benzenesulfonamide (11e).
Yield: 64%. 1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 11.10 (brs, 1H), 8.51 (s, 1H), 8.29 (s, 2H), 7.76 (t, J = 8.4 Hz, 1H), 7.11 (d, J =
8.5 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 3.91 (s, 3H), 3.62 (s, 3H). 13C NMR (151 MHz, DMSO) δ 181.07, 160.11, 157.23, 153.64,
150.13, 140.31, 136.62, 133.14, 133.02 (q, J = 37.6 Hz), 130.56, 130.23, 129.70 (q, J = 33.5, 31.7 Hz), 127.01, 122.47 (q, J = 273.5 Hz),
121.95 (q, J = 274.0, 273.4 Hz), 109.61, 109.27, 106.55, 106.30, 97.85, 59.97, 56.26.
10 / 18

4.2.5 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-3-(trifluoromethoxy)benzenesulfonamide (11f).
Yield: 52%. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.70 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.84 – 7.67 (m, 3H), 7.12
(d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.95 (s, 1H), 3.91 (s, 3H), 3.60 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.95, 160.09, 157.23,
153.52, 150.38, 148.22, 141.57, 137.23, 136.51, 132.31, 131.97, 126.08, 125.67, 119.78 (q, J = 257.4 Hz), 118.98, 109.62, 109.25, 106.52,
105.76, 96.06, 60.07, 56.25.
4.2.6 4-fluoro-N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11g).
Yield: 56%. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.57 (s, 1H), 8.03 (dd, J = 8.7, 5.1 Hz, 2H), 7.75 (t, J = 8.4 Hz, 1H), 7.47 (t, J
= 8.8 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 3.91 (s, 3H), 3.64 (s, 3H). 13C NMR (151 MHz, DMSO) δ
180.91, 164.49 (d, J = 252.3 Hz), 160.05, 157.21, 153.44, 150.44, 137.66, 136.45, 135.94, 131.90, 129.72 (d, J = 9.3 Hz), 116.68 (d, J = 22.9
Hz). 109.61, 109.27, 106.49, 105.45, 95.37, 60.17, 56.23.
4.2.7 4-chloro-N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11h).
Yield: 65%. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.63 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.77 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.5
Hz, 2H), 7.13 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 3.91 (s, 3H), 3.64 (s, 3H).
4.2.8 4-bromo-N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11i).
Yield: 68%. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.65 (s, 1H), 7.87 (dd, J = 3.7, 1.8 Hz, 4H), 7.76 (t, J = 8.2 Hz, 1H), 7.12 (d, J
= 8.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 3.90 (s, 3H), 3.64 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.89, 160.03, 157.18,
153.46, 150.41, 138.80, 137.51, 136.44, 132.54, 131.93, 128.55, 127.27, 109.60, 109.26, 106.47, 105.51, 95.39, 60.17, 56.23.
4.2.9 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-4-iodobenzenesulfonamide (11j).
Yield: 65%. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.61 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.75 (t, J = 8.1 Hz, 1H), 7.70 (d, J = 8.6
Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 3.90 (s, 3H), 3.65 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.90,
160.06, 157.21, 153.46, 150.43, 139.17, 138.34, 137.58, 136.43, 131.91, 128.18, 109.63, 109.28, 106.50, 105.49, 101.78, 95.32, 60.18,
56.24.
4.2.10 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)naphthalene-1-sulfonamide (11m).
Yield: 61%. 1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H), 10.92 (s, 1H), 8.87 (d, J = 9.4 Hz, 1H), 8.34 (d, J = 7.5 Hz, 1H), 8.28 (d, J = 8.5
Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.83 – 7.61 (m, 4H), 7.08 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.86 (s, 1H), 3.87 (s, 3H), 3.50 (s,
3H). 13C NMR (151 MHz, DMSO) δ 180.80, 160.02, 157.15, 153.35, 150.37, 137.66, 136.36, 134.87, 134.02, 133.75, 131.56, 129.73,
129.05, 128.33, 127.19, 127.12, 124.45, 124.28, 109.58, 109.24, 106.47, 105.16, 94.91, 60.01, 56.20.
4.2.11 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)naphthalene-2-sulfonamide (11n).
Yield: 55%. 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 10.65 (s, 1H), 8.65 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H),
8.02 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.79 – 7.62 (m, 3H), 7.10 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.88 (s,
3H), 3.64 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.87, 160.03, 157.19, 153.39, 150.43, 137.84, 136.57, 136.37, 134.34, 131.80, 131.42,
129.69, 129.29, 129.16, 127.86, 127.78, 121.80, 109.61, 109.26, 106.46, 105.34, 95.19, 60.17, 56.21.
4.2.12 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-[1,1'-biphenyl]-4-sulfonamide (11o).
Yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.61 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.79 – 7.65 (m,
3H), 7.55 – 7.37 (m, 3H), 7.12 (d, J = 9.1 Hz, 1H), 7.02 – 6.94 (m, 2H), 3.89 (s, 3H), 3.68 (s, 3H). 13C NMR (151 MHz, DMSO) δ 180.80,
159.98, 157.13, 153.37, 150.40, 144.64, 138.21, 137.99, 137.82, 136.33, 131.68, 128.94, 128.50, 127.50, 127.19, 126.93, 109.55, 109.21,
106.42, 105.27, 94.99, 60.12, 56.16.
4.2.13 4-(tert-butyl)-N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11p).
Yield: 59%. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.51 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.74 (t, J = 8.4 Hz, 1H), 7.64 (d, J = 8.2
11 / 18

Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H), 6.97 (t, J = 4.5 Hz, 2H), 3.89 (s, 3H), 3.64 (s, 3H), 1.26 (s, 9H).
4.2.14 4-cyclohexyl-N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (11q).
Yield: 60%. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.48 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.73 (td, J = 8.4, 2.3 Hz, 1H), 7.46 (d, J
= 8.1 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.01 – 6.94 (m, 2H), 3.89 (s, 3H), 3.63 (s, 3H), 2.60 – 2.53 (m, 1H), 1.86 – 1.61 (m, 5H), 1.34 (h, J =
12.4 Hz, 4H), 1.24 – 1.11 (m, 1H). 13C NMR (151 MHz, DMSO) δ 180.86, 160.04, 157.19, 153.39, 153.27, 150.45, 138.01, 137.10, 136.37,
131.65, 127.69, 126.70, 109.62, 109.27, 106.47, 105.24, 95.00, 60.09, 56.22, 43.45, 33.28, 26.00, 25.29.
4.2.15 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-4-(pyrrolidin-1-yl)benzenesulfonamide (11r).
11j (50 mg, 0.09 mmol), Pd2dba3 (8.3 mg, 0.009 mmol), BINAP (16.9 mg, 0.027 mmol), pyrrolidine (0.022 mL, 0.271 mmol), and t-BuONa
(43 mg, 0.452 mmol) were suspended in NMP (2 mL) under argon and the resulting mixture was heated to 80℃for 8 h. After cooling to r.t,
the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a celite bed and concentrated in vacuo successively. The residue
was purified by flash column chromatography to afford the desired product 11r as a yellow solid (25 mg, yield: 54%).
4.2.16 N-(1-hydroxy-2,8-dimethoxy-9-oxo-9H-xanthen-3-yl)-4-(piperidin-1-yl)benzenesulfonamide (11s).
11j (50 mg, 0.09 mmol), Pd2dba3 (8.3 mg, 0.009 mmol), BINAP (16.9 mg, 0.027 mmol), piperidine (0.025 mL, 0.271 mmol), and t-BuONa
(43 mg, 0.452 mmol) were suspended in NMP (2 mL) under argon and the resulting mixture was heated to 80℃for 8 h. After cooling to r.t,
the reaction mixture was diluted with ethyl acetate (10 mL), filtered through a celite bed and concentrated in vacuo successively. The residue
was purified by flash column chromatography to afford the desired product 11s as a yellow solid (30 mg, yield: 65%).
4.3 General synthetic procedure of compound 12a-12s
To a solution of compound 11 in dry DCM (c = 0.1 mol/L) was added a solution of BBr3(1 mol/L, 5 eq.) in DCM at 0 ℃. The reaction
solution was quenched with dry methanol after 2 h and concentrated in vacuo. The residue was recrystallized from methanol/ethyl acetate to
afford the desired sulfonamides 12 as yellow solids (yield: 30% - 50%).
4.3.1 N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12a).
Yield: 48%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.60 (s, 1H), 10.39 (s, 1H), 9.68 (s, 1H), 7.98 (d, J = 7.7 Hz, 2H), 7.73 – 7.55
(m, 4H), 7.03 (d, J = 8.5 Hz, 1H), 6.98 (s, 1H), 6.78 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.24, 160.05, 155.74, 148.58,
146.89, 139.73, 137.41, 135.07, 133.28, 130.13, 129.37, 126.61, 110.12, 107.18, 106.89, 103.66, 96.00. MS (ESI-) m/z 398.0 (M - H)-.
HRMS (ESI-) m/z: 398.035 (M - H)- (calcd for C19H13NO7S-: 398.0340).
4.3.2 4-methyl-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12b).
Yield: 50%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.58 (s, 1H), 10.25 (s, 1H), 9.64 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.69 (t, J =
8.3 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.78 (d, J = 8.3 Hz, 1H), 2.35 (s, 3H). 13C NMR (151 MHz,
DMSO) δ 184.20, 160.05, 155.72, 148.62, 146.86, 143.76, 137.36, 136.83, 135.22, 129.97, 129.78, 126.69, 110.11, 107.15, 106.87, 103.56,
95.81, 20.90. MS (ESI-) m/z 411.7 (M - H)-. HRMS (ESI-) m/z: 412.0492 (M - H)- (calcd for C20H15NO7S-: 412.0496).
4.3.3 1-phenyl-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)methanesulfonamide (12c).
Yield: 30%. 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.62 (s, 1H), 9.74 (s, 1H), 9.45 (s, 1H), 7.71 (t, J = 8.5 Hz, 1H), 7.41 – 7.24 (m,
5H), 7.03 (d, J = 8.5 Hz, 1H), 6.89 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.71 (s, 2H). 13C NMR (151 MHz, DMSO) δ 184.15, 160.09, 155.75,
148.76, 146.74, 137.40, 136.26, 130.96, 129.50, 128.83, 128.27, 128.27, 110.10, 107.14, 106.82, 103.32, 95.98, 58.30. MS (ESI-) m/z 411.8
(M - H)-. HRMS (ESI-) m/z: 412.0487 (M - H)- (calcd for C20H15NO7S-: 412.0496).
4.3.4 4-(trifluoromethyl)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12d)
Yield: 45%. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 11.62 (s, 1H), 10.64 (s, 1H), 9.67 (s, 1H), 8.17 (d, J = 8.2 Hz, 2H), 8.01 (d, J =
8.2 Hz, 2H), 7.71 (t, J = 8.3 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.28,
160.02, 155.72, 148.43, 146.97, 143.73, 134.35, 137.43, 132.67 (q, J = 32.4 Hz), 130.74, 127.56, 126.54, 126.52, 123.20 (q, J = 272.9 Hz),
12 / 18

110.10, 107.12, 106.86, 104.03, 96.91. MS (ESI-) m/z 466.0 (M - H)-. HRMS (ESI-) m/z: 466.0207 (M - H)- (calcd for C20H12F3NO7S-:
466.0214).
4.3.5 2,5-bis(trifluoromethyl)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12e).
Yield: 46%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.62 (s, 1H), 10.93 (s, 1H), 9.81 (s, 1H), 8.49 (s, 1H), 8.23 (s, 2H), 7.65 (t, J =
8.3 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.40, 160.03, 155.73, 148.09,
147.10, 140.42, 137.51, 132.9 (q, J = 33.4 Hz), 131.80, 130.35, 130.11, 130.06, 129.67 (q, J = 35.0 Hz), 126.87, 122.43 (q, J = 273.8 Hz),
121.93 (q, J = 274.9 Hz), 110.10, 107.11, 106.88, 104.55, 98.8. MS (ESI-) m/z 534.0 (M - H)-. HRMS (ESI-) m/z: 534.0084 (M - H)- (calcd
for C21H11F6NO7S-: 534.0088).
4.3.6 3-(trifluoromethoxy)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12f).
Yield: 48%. 1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 11.61 (s, 1H), 10.57 (s, 1H), 9.71 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H),
7.81 – 7.65 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.35, 160.09, 155.79,
148.47, 148.16, 147.03, 141.85, 137.51, 131.84, 130.80, 125.93, 125.72, 122.35, 119.79 (q, J = 258.0 Hz), 119.13, 110.16, 107.16, 106.91,
104.08, 96.93. MS (ESI-) m/z 482.0 (M - H)-. HRMS (ESI-) m/z: 482.0152 (M - H)- (calcd for C20H12F3NO8S-: 482.0163).
4.3.7 4-fluoro-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12g)
Yield: 45%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.60 (s, 1H), 10.38 (s, 1H), 9.66 (s, 1H), 8.05 (dd, J = 8.7, 5.3 Hz, 2H), 7.70 (t,
J = 8.4 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H). 13C NMR (151 MHz, DMSO) δ
184.22, 164.42 (d, J = 252.2 Hz), 160.02, 155.69, 148.52, 146.89, 137.38, 136.09, 134.79, 130.32, 129.74 (d, J = 10.0 Hz), 116.50 (d, J =
22.7 Hz), 110.08, 107.10, 106.84, 103.76, 96.33. MS (ESI-) m/z 416.0 (M - H)-. HRMS (ESI-) m/z: 416.0237 (M - H)- (calcd for
C19H12FNO7S-: 416.0246).
4.3.8 4-chloro-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12h)
Yield: 43%. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.61 (s, 1H), 10.46 (s, 1H), 9.68 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.75 – 7.65
(m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.25, 160.02, 155.71, 148.47,
146.94, 138.57, 138.10, 137.40, 134.57, 130.47, 129.44, 128.54, 110.09, 107.11, 106.85, 103.88, 96.54. MS (ESI-) m/z 432.0 (M - H)-.
HRMS (ESI-) m/z: 431.9941 (M - H)- (calcd for C19H12ClNO7S-: 431.9950).
4.3.9 4-bromo-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12i)
Yield: 43%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.61 (s, 1H), 10.49 (s, 1H), 9.68 (s, 1H), 7.93 – 7.80 (m, 4H), 7.70 (t, J = 8.3
Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.28, 160.05, 155.74, 148.51,
146.94, 139.04, 137.44, 134.64, 132.42, 130.49, 128.63, 127.18, 110.13, 107.17, 106.90, 103.90, 96.53. MS (ESI-) m/z 476.0 (M - H)-.
HRMS (ESI-) m/z: 475.9426 (M - H)- (calcd for C19H12BrNO7S-: 475.9445).
4.3.10 4-iodo-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12j)
Yield: 41%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.61 (s, 1H), 9.66 (s, 1H), 8.66 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.75 – 7.65
(m, 3H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.24, 160.01, 155.71, 148.50,
146.91, 139.34, 138.17, 137.39, 134.68, 130.38, 128.22, 110.08, 107.12, 106.85, 103.82, 101.64, 96.39. MS (ESI-) m/z 523.8 (M - H)-.
HRMS (ESI-) m/z: 523.9287 (M - H)- (calcd for Chemical Formula: C19H12INO7S-: 523.9306).
4.3.11 4-cyano-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12k)
Yield: 34%. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.62 (s, 1H), 10.65 (s, 1H), 9.68 (s, 1H), 8.16 – 8.06 (m, 4H), 7.70 (t, J = 8.3
Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.37, 160.09, 155.78, 148.44,
147.10, 143.85, 137.53, 134.16, 133.49, 130.96, 127.37, 117.46, 115.60, 110.16, 107.17, 106.92, 104.21, 97.26. MS (ESI-) m/z 422.9 (M - H)-.
HRMS (ESI-) m/z: 423.0285 (M - H)- (calcd for Chemical Formula: C20H12N2O7S-: 423.0292).
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4.3.12 3-cyano-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12l)
Yield: 33%. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 11.62 (s, 1H), 10.56 (s, 1H), 9.69 (s, 1H), 8.44 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H),
8.15 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H). 13C
NMR (151 MHz, DMSO) δ 184.37, 160.09, 155.80, 148.50, 147.04, 141.21, 137.51, 136.72, 131.01, 130.90, 130.76, 130.30, 117.33, 112.51,
110.15, 107.18, 106.94, 104.19, 97.29. MS (ESI-) m/z 422.8 (M - H)-. HRMS (ESI-) m/z: 423.0278 (M - H)- (calcd for Chemical Formula:
C20H12N2O7S-: 423.0292).
4.3.13 N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)naphthalene-1-sulfonamide (12m)
Yield: 42%. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.54 (s, 1H), 10.73 (s, 1H), 9.62 (s, 1H), 8.84 (d, J = 8.6 Hz, 1H), 8.33 (d, J =
7.5 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.79 – 7.59 (m, 4H), 6.99 (d, J = 8.5 Hz, 1H), 6.92 (s, 1H), 6.76 (d, J = 8.1 Hz,
1H). 13C NMR (151 MHz, DMSO) δ 184.11, 159.98, 155.64, 148.47, 146.72, 137.29, 135.00, 134.69, 134.36, 133.69, 129.92, 129.35, 128.91,
128.20, 127.19, 127.01, 124.37, 124.32, 110.04, 107.08, 106.79, 103.44, 95.77. MS (ESI-) m/z 447.8 (M - H)-. HRMS (ESI-) m/z: 448.0478
(M - H)- (calcd for Chemical Formula: C23H15NO7S-: 448.0496).
4.3.14 N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)naphthalene-2-sulfonamide (12n)
Yield: 41%. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.57 (s, 1H), 10.44 (s, 1H), 9.66 (s, 1H), 8.66 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H),
8.13 (d, J = 8.8 Hz, 1H), 8.06 – 7.94 (m, 2H), 7.76 – 7.61 (m, 3H), 7.05 (s, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H). 13C NMR
(151 MHz, DMSO) δ 184.18, 159.98, 155.67, 148.52, 146.84, 137.32, 136.73, 134.97, 134.29, 131.37, 130.20, 129.50, 129.22, 129.04,
127.78, 127.71, 127.64, 121.89, 110.04, 107.09, 106.82, 103.67, 96.20. MS (ESI-) m/z 447.9 (M - H)-. HRMS (ESI-) m/z: 448.0478 (M - H)-
(calcd for Chemical Formula: C23H15NO7S-: 448.0496).
4.3.15 N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)-[1,1'-biphenyl]-4-sulfonamide (12o).
Yield: 48%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.60 (s, 1H), 10.41 (s, 1H), 9.68 (s, 1H), 8.06 (d, J = 8.2 Hz, 2H), 7.91 (d, J =
8.1 Hz, 2H), 7.74 – 7.66 (m, 3H), 7.53 – 7.38 (m, 3H), 7.06 – 7.00 (m, 2H), 6.78 (d, J = 8.3 Hz, 1H). 13C NMR (151 MHz, DMSO) δ 184.2,
160.0, 155.7, 148.6, 146.9, 144.6, 138.5, 138.1, 137.4, 135.1, 130.1, 129.0, 128.5, 127.5, 127.3, 127.0, 110.1, 107.2, 106.9, 103.7, 95.9. MS
(ESI-) m/z 473.9 (M - H)-. HRMS (ESI-) m/z: 474.0631 (M - H)- (calcd for Chemical Formula: C23H14NO7S-: 474.0653).
4.3.16 4-(tert-butyl)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12p)
Yield: 45%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.59 (s, 1H), 10.30 (s, 1H), 9.67 (brs, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.73 –
7.56 (m, 3H), 7.06 – 6.99 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 1.27 (s, 9H). 13C NMR (151 MHz, DMSO) δ 184.19, 160.05, 156.33, 155.72,
148.70, 146.86, 137.36, 136.96, 135.34, 129.77, 126.54, 126.25, 110.12, 107.17, 106.87, 103.49, 95.45, 34.84, 30.59. MS (ESI-) m/z 454.1
(M - H)-. HRMS (ESI-) m/z: 454.0953 (M - H)- (calcd for Chemical Formula: C23H21NO7S-: 454.0966).
4.3.17 4-cyclohexyl-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12q)
Yield: 41%. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.59 (s, 1H), 10.28 (s, 1H), 9.66 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.68 (t, J =
8.4 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.06 – 6.98 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 2.62 – 2.53 (m, 1H), 1.82 – 1.61 (m, 5H), 1.47 – 1.12 (m,
5H). 13C NMR (151 MHz, DMSO) δ 184.20, 160.06, 155.73, 153.21, 148.70, 146.88, 137.36, 137.24, 135.35, 129.81, 127.64, 126.79, 110.12,
107.17, 106.88, 103.51, 95.55, 43.45, 33.28, 26.01, 25.30. MS (ESI-) m/z 480.1 (M - H)-. HRMS (ESI\-) m/z: 480.1103 (M - H)- (calcd for
Chemical Formula: C25H23NO7S-: 480.1122).
4.3.18 4-(pyrrolidin-1-yl)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12r)
Yield: 33%. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 11.56 (s, 1H), 9.77 (s, 1H), 7.76 – 7.60 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 6.98
(s, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.8 Hz, 2H), 3.25 (t, J = 6.6 Hz, 4H), 1.92 (d, J = 6.6 Hz, 4H). 13C NMR (151 MHz, DMSO) δ
184.09, 160.06, 155.70, 150.22, 148.85, 146.65, 137.29, 136.04, 129.26, 128.62, 123.31, 110.86, 110.11, 107.16, 106.85, 103.09, 94.92,
47.15, 24.80. MS (ESI-) m/z 466.8 (M - H)-. HRMS (ESI-) m/z: 467.0899 (M - H)- (calcd for Chemical Formula: C23H20N2O7S-: 467.0918).
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4.3.19 4-(piperidin-1-yl)-N-(1,2,8-trihydroxy-9-oxo-9H-xanthen-3-yl)benzenesulfonamide (12s)
Yield: 35%. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 11.57 (s, 1H), 9.92 (s, 1H), 9.63 (s, 1H), 7.76 – 7.66 (m, 3H), 7.07 – 6.94 (m,
4H), 6.78 (d, J = 8.2 Hz, 1H), 3.32 (s, 4H), 1.54 (s, 6H). 13C NMR (151 MHz, DMSO) δ 184.10, 160.05, 155.70, 153.39, 148.81, 146.68,
137.30, 135.89, 129.35, 128.55, 125.46, 113.10, 110.10, 107.17, 106.85, 103.16, 94.98, 47.44, 24.69, 23.70. MS (ESI-) m/z 480.9 (M - H)-.
HRMS (ESI-) m/z: 481.1070 (M - H)- (calcd for Chemical Formula: C24H22N2O7S-: 481.1075).
4.4 General biological evalution procedures
4.4.1 In vitro PGAM1 enzyme inhibitory activity assay
1 µL of test compound (dissolved in DMSO) with specific concentration, 1 µL of recombinant PGAM1 and 48 µL of Tris buffer solution (50
mM, pH 8.0) were added into a 96-well plate followed by preincubated for 2 min at room temperature. Then 49 µL of enzymes buffer
(containing 0.5 U/mL enolase, 0.5 U/mL PK, 0.1 U/mL LDH, 5 mM MgCl2, 1 mM ADP, 100 mM KCl, 0.2 mM NADH, 100 mM Tris pH8.0)
was added to the mixture. At last, 1 µL of 3PG solution (200 mM) was added to initiate the reaction. The decrease in OD (λ=340 nm) from
the oxidation of NADH was measured by a microplate reader as PGAM1 activity.
Counterscreen assay: 1 µL of test compound (0.5 mM) and 49 µL of Tris buffer solution (50 mM, pH 8.0) were added into a 96-well plate
followed by preincubated for 2 min at room temperature. Then 49 µL of enzymes buffer (containing 0.5 U/mL enolase, 0.5 U/mL PK, 0.1
U/mL LDH, 5 mM MgCl2, 1 mM ADP, 100 mM KCl, 0.2 mM NADH, 100 mM Tris pH8.0) was added to the mixture. At last, 1 µL of 2PG
solution (200 mM) was added to initiate the reaction. The decrease in OD (λ=340 nm) from the oxidation of NADH was measured as
counter-screen assay activity.
4.4.2 Thermal shift assay of 12q
In brief, thermal shift assay of 12q with PGAM1 was performed in 384-well PCR plates with different concentrations of 12q (from 12.5 μM
to 50 μM) and 200 μg/ml protein in a buffer solution (20 mM Tris-HCl, 100 mM NaCl, pH 7.4). SYPRO orange was used as a dye to monitor
the fluorescence change at 610 nm.
4.4.3 In vitro cell proliferation inhibitory activity assay
Cell viability was measured using MTT colorimetric assay. 2×103 cells were seeded in 96-well plate before the assay starts and were cultured
at 37 °C. After seeding for 24 h, cells were treated with inhibitors with specific concentration and incubated at 37 °C for 72 h followed by
incubation with 0.5 mg mL−1 MTT for 4 h at 37 °C. 200 µL of DMSO was added and absorbance was measured at 570 nm.
Acknowledgements:
This work was supported by the National Natural Science Foundation of China (No 21472026 to Lu Zhou), the Shanghai Municipal
Committee of Science and Technology (No 14XD1400300) and the program for Shanghai Rising Star (No 15QA1400300).
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Highlights



A series of xanthone derivatives were discovered as novel phosphoglycerate mutase 1 inhibitors.
12q with IC50 of 0.5 μM, was the most effective PGAM1 specific inhibitor so far
12r could effectively inhibit H1299 cell proliferation at micromolar level
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Graphical abstract
Discovery of xanthone derivatives as novel phosphoglycerate mutase 1 inhibitors.
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