Synthesis of amino acid derivatives of 5-alkoxy-3,4-dihalo-2(5: H)-furanones and their preliminary bioactivity investigation as linkers

Article abstract of DOI:10.1039/c9ob00736a

A series of amino acid derivatives are successfully synthesized via a metal-free C-N coupling reaction of 5-alkoxy-3,4-dihalo-2(5H)-furanones and amino acids. Their structures are well characterized with ¹H NMR, ¹³C NMR, ESI-MS and elemental analysis. As potential linkers of the 2(5H)-furanone unit with other drug moieties containing a hydroxyl or amino group, the effect of amino acids is investigated by comparison with other 2(5H)-furanone compounds by constructing C-O/C-S bonds. The preliminary results of the biological activity assay by the MTT method on a series of cancer cell lines in vitro reveal that the introduction of amino acids basically has no toxic effect. This can lead to these 2(5H)-furanone derivatives being further well-linked with other bioactive moieties with amino or hydroxy groups as expected. Thus, the biological activity assay gives a direction for the design of bioactive 2(5H)-furanones based on these amino acid linkers.

Full text of DOI:10.1039/c9ob00736a

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Synthesis of amino acid derivatives of 5-alkoxy-
3,4-dihalo-2(5H)-furanones and their preliminary
bioactivity investigation as linkers†
Cite this: DOI: 10.1039/c9ob00736a
Shi-He Luo, a,b Kai Yang,*a,c Jian-Yun Lin,a Juan-Juan Gao,d Xin-Yan Wua and
a,b
Zhao-Yang Wang
*
A series of amino acid derivatives are successfully synthesized via a metal-free C–N coupling reaction of
5-alkoxy-3,4-dihalo-2(5H)-furanones and amino acids. Their structures are well characterized with
1H NMR, 13C NMR, ESI-MS and elemental analysis. As potential linkers of the 2(5H)-furanone unit with
other drug moieties containing a hydroxyl or amino group, the effect of amino acids is investigated by
comparison with other 2(5H)-furanone compounds by constructing C–O/C–S bonds. The preliminary
results of the biological activity assay by the MTT method on a series of cancer cell lines in vitro reveal
that the introduction of amino acids basically has no toxic effect. This can lead to these 2(5H)-furanone
derivatives being further well-linked with other bioactive moieties with amino or hydroxy groups as
expected. Thus, the biological activity assay gives a direction for the design of bioactive 2(5H)-furanones
based on these amino acid linkers.
Received 31st March 2019,
Accepted 2nd May 2019
DOI: 10.1039/c9ob00736a
rsc.li/obc
because of their significant biological activities,23–25 such as
antifungal,26,27 antibacterial,28 antiviral,29,30 and anticancer.31,32
Introduction
Amino acids are very important living substances in organisms Therefore, the synthesis of different 2(5H)-furanones and their
and the basic units of enzymes and proteins.1 Due to the applications have drawn much attention in recent years.33–39
presence of both amino and carboxyl groups, amino acids are Being interested in the chemistry of 2(5H)-furanones, we also
also one of the most versatile building blocks used in many reported some studies,40–47 and investigated the bioactivities of
fields, such as organic synthesis,2 drug design,3–5 molecular partial 2(5H)-furanone derivatives.48–50
recognition,6–8 supramolecular chemistry,9,10 functional
Nowadays, there are reports on the role of amino acids as
materials,11,12 and so on.13 Importantly, the fact that amino linking units.13,19,51,52 However, it is still necessary to investi-
acids are used as key linkers between the structural molecule gate whether the amino acid unit is a safe linker without any
and bioactive unit has been widely utilized.14–19
impact on the bioactivity of 2(5H)-furanones when amino
Molecules possessing a 2(5H)-furanone moiety, a kind of acids are combined with the 2(5H)-furanone moiety by C–N
α,β-unsaturated lactone substructure, are frequently found in coupling to expand the functionalization of 2(5H)-furanones.
natural products.20–22 They have received considerable interest Thus, in order to make full use of two synthons both 2(5H)-fur-
aSchool of Chemistry and Environment, South China Normal University,
Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education,
Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine,
Guangzhou 510006, P. R. China. E-mail: wangzy@scnu.edu.cn
bSchool of Chemistry and Chemical Engineering, Key Laboratory of Functional
Molecular Engineering of Guangdong Province, South China University of
Technology, Guangzhou 510641, P. R. China
cCollege of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi province,
341000, P. R. China. E-mail: kai_yangyang@126.com
dCollege of Sports and Rehabilitation, Gannan Medical University, Ganzhou,
Jiangxi province, 341000, P. R. China
†Electronic supplementary information (ESI) available: Synthesis procedures for
contrasting compounds O1–O27, S1–S16 and SO1–SO16 and 1H NMR, 13C NMR
and ESI-MS spectra of all new compounds N1–N16. See DOI: 10.1039/
c9ob00736a
Scheme 1 Synthetic route to target compounds N1–N16.
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anones and amino acids,53 and make clear how they work solution, which reflects the cell growth conditions, was
together especially in a small molecular system, a series of measured by using a microplate spectrophotometer at 490 nm.
amino acid derivatives were synthesized with 5-alkoxy-3,4-
Characterization data for compounds N1–N16
dihalo-2(5H)-furanones and amino acids, including non-
natural amino acids, via a metal-free C–N coupling reaction
N-(4-Bromo-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)-N-
(Scheme 1). And the effect of amino acids as linkers on bioac- methylglycine (N1). Brown sticky liquid; yield: 222 mg (79%);
tivity was investigated by comparison with other 5-substituted- 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 3.26 (s, 3H, NCH3),
3-halo-2(5H)-furanone derivatives.
3.46 (s, 3H, OCH3), 4.34 (s, 2H, CH2), 5.77 (s, 1H, CH), 6.61 (b,
1H, COOH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 40.5,
53.9, 54.5, 74.4, 98.7, 158.2, 168.9, 172.2; ESI-MS, m/z (%):
−
calcd for C8H9BrNO5 ([M − H]−): 277.97 (100.0%), 279.97
Experimental
Materials and methods
(97.3%), found: 277.79 (100.0%), 279.79 (96.1%); anal. calcd
for C8H10BrNO5: C 34.31, H 3.60, N 5.00, found: C 34.43,
H 3.52, N 5.02.
1H and 13C NMR spectra were obtained in CDCl3 or DMSO-d6
on a Varian DRX-400 MHz spectrometer and tetramethylsilane
(TMS) was used as an internal standard. Elemental analysis
was performed on a Thermo FlashEA TM 112 elemental ana-
lyzer. Mass spectra (MS) were recorded on a Thermo LCQ
DECA XP MAX mass spectrometer.
All reagents and solvents were commercially available and
used as received. Using furfural, ethanol and methanol as
starting materials, 5-substituted-3,4-dihalo-2(5H)-furanones
1a–1d were prepared according to the literature.44–50
N-(4-Bromo-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)-N-methyl-
glycine (N2). Brown sticky liquid; yield: 208 mg (71%);
1H NMR (400 MHz, DMSO-d6), δ, ppm: 1.13 (t, J = 8.0 Hz, 3H,
CH3), 3.00–3.34 (m, 4H, NCH3, COOH), 3.61–3.70 (m, 2H,
OCH2), 4.08–4.44 (m, 2H, CH2), 6.14 (s, 1H, CH), 13.02 (b, 1H);
13C NMR (100 MHz, DMSO-d6), δ, ppm: 15.1, 40.2, 53.9, 63.8,
71.9, 98.0, 159.3, 168.3, 170.4; ESI-MS, m/z (%): calcd for
C9H11BrNO5 ([M − H]−): 291.98 (100.0%), 293.98 (97.3%),
−
found: 291.74 (100.0%), 293.74 (94.7%); anal. calcd for
C9H12BrNO5: C 36.76, H 4.11, N 4.76, found: C 36.82, H 4.02,
N 4.83.
General procedure for syntheses of compounds N1–N16
Amino acid 2 (4 mmol), KOH (4.48 mmol) and C2H5OH (5 mL)
were added into a round-bottomed flask equipped with a
magnetic stirring bar. After the mixture was dissolved under
stirring, 5-substituted 3,4-dihalo-2(5H)-furanones 1 (2 mmol)
in CH2Cl2 (5 mL) were dropped into the above system. The
mixed solution was stirred at room temperature under an N2
atmosphere for 24 h.
N-(4-Chloro-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)-N-
methylglycine (N3). Brown sticky liquid; yield: 157 mg (67%);
1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 3.24 (3H, s, NCH3),
3.48 (s, 3H, OCH3), 4.31 (s, 2H, CH2), 5.74 (s, 1H, CH), 7.46 (b,
1H, COOH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 40.2,
53.4, 54.5, 88.8, 97.7, 155.3, 168.2, 172.6; ESI-MS, m/z (%):
−
calcd for C8H9ClNO5 ([M − H]−): 234.02 (100.0%), 236.01
After the solvent was removed, the residue was dissolved in
CH2Cl2, and the pH value was adjusted to 3–4 using 15% HCl.
The organic layers were washed with saturated NH4Cl solution
three times and then dried over anhydrous MgSO4. The con-
centration under vacuum gave a crude product, which was pur-
ified by column chromatography on silica gel with gradient
eluents of petroleum ether and ethyl acetate to afford pure
compounds.
(32.0%), found: 233.71 (100.0%), 235.71 (35.0%); anal. calcd
for C8H10ClNO5: C 40.78, H 4.28, N 5.94, found: C 40.63,
H 4.25, N 5.82.
N-(4-Chloro-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)-N-methyl-
glycine (N4). Brown sticky liquid; yield: 139 mg (56%);
1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.27 (t, J = 8.0 Hz,
3H, CH3), 3.27 (s, 3H, NCH3), 3.69–3.91 (m, 2H, OCH2),
4.24–4.39 (m, 2H, CH2), 5.81 (s, 1H, CH), 8.74 (b, 1H, COOH);
13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 14.7, 40.2, 53.6, 64.5,
Biochemical approach
88.3, 97.4, 156.2, 169.1, 172.4; ESI-MS, m/z (%): calcd for
The cell viability of the compounds was determined by C9H11ClNO5 ([M − H]−): 248.03 (100.0%), 250.03 (32.0%),
measuring the ability of cells to transform MTT into a purple found: 248.46 (100.0%), 250.46 (27.8%); anal. calcd for
formazan dye.54,55 All compounds were dissolved in DMSO C9H12ClNO5: C 43.30, H 4.85, N, 5.61, found: C 43.36, H 4.82,
with stock solution at 10 mM. The cells were seeded in 96-well N 5.55.
−
tissue culture plates at 5 × 103 cells per well and incubated in
2-(4-Bromo-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-2-
an incubator at 37 °C and 5% CO2 for 24 h. Then, the cells phenylacetic acid (N5). Brown sticky liquid; yield: 153 mg
were incubated with the tested compounds in a concentration (45%); 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 3.41 (s, 3H,
range of 4–300 mM, ensuring an equal volume of 200 μL OCH3), 5.35–6.44 (m, 3H, NH, COOH, CH), 5.75 (s, 1H, CH),
across the wells of the plate. These plates were incubated at 7.38–7.42 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3-TMS),
37 °C in a 5% CO2 incubator for 72 h. After incubation, 20 μL δ, ppm: 58.6, 65.6, 81.5, 98.1, 127.0, 129.3, 129.4, 135.4, 153.2,
of MTT solution (5 mg mL−1) was added across the plate and 167.7, 172.1; ESI-MS, m/z (%): calcd for C13H13BrNO5
+
further incubated for 4 h. Finally, the medium was aspirated ([M + H]+): 342.00 (100.0%), 344.00 (97.3%), found: 341.64
and replaced with a 150 μL per well of DMSO to dissolve the (100%), 343.64 (93.2%); anal. calcd for C13H12BrNO5: C 45.64,
formazan salt formed. The color intensity of the formazan H 3.54, N 4.09, found: C 45.64, H 3.74, N 4.19.
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2-(4-Bromo-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-2- 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.93–1.99 (m, 2H,
phenylacetic acid (N6). Brown sticky liquid; yield: 159 mg CH2), 2.46–2.50 (m, 2H, CH2), 3.50–3.60 (m, 5H, NCH2, OCH3),
(45%); 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.27 (t, J = 5.19–5.35 (m, 2H, CH, NH), 5.67 (s, 1H, COOH); 13C NMR
8.0 Hz, 3H, CH3), 3.62–3.79 (m, 2H, OCH2), 5.20–5.80 (m, 2H, (100 MHz, CDCl3-TMS), δ, ppm: 25.3, 30.8, 43.0, 55.2, 83.0,
CH), 6.29 (b, 1H, N–H), 6.37 (b, 1H, COOH), 7.35–7.41 (m, 5H, 97.5, 155.5, 166.3, 177.9; ESI-MS, m/z (%): calcd for
+
ArH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 15.0, 58.7, C9H13ClNO5 ([M + H]+): 250.05 (100.0%), 252.04 (32.0%),
65.3, 83.3, 97.5, 127.0, 129.3, 129.5, 135.0, 152.4, 167.4, 172.9; found: 249.80 (100.0%), 251.80 (30.4%); anal. calcd for
+
ESI-MS, m/z (%): calcd for C14H15BrNO5 ([M + H]+): 356.01 C9H12ClNO5: C 43.30, H 4.85, N 5.61, found: C 43.45, H 5.06,
(100.0%), 358.01 (97.3%), found: 355.74 (97.3%), 357.74 N 5.51.
(100%); anal. calcd for C14H14BrNO5: C 47.21, H 3.96, N 3.92,
found: C 46.91, H 4.06, N 3.93.
4-(4-Chloro-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-buta-
noic acid (N12). Brown liquid; yield: 183 mg (70%); 1H NMR
2-(4-Chloro-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-2- (400 MHz, CDCl3-TMS), δ, ppm: 1.29 (3H, t, J = 8.0 Hz, CH3),
phenylacetic acid (N7). Brown sticky liquid; yield: 112 mg 1.95–2.25 (m, 2H, CH2), 2.50 (t, J = 8.0 Hz, 2H, CH2), 3.51–3.61
(38%); 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 3.43 (s, 3H, (m, 2H, NCH2), 3.70–3.91 (m, 2H, OCH2), 4.63 (b, 1H, COOH),
OCH3), 5.27–5.74 (m, 4H, NH, COOH, 2CH), 7.32–7.46 (m, 5H, 5.31 (s, 1H, NH), 5.74 (s, 1H, CH); 13C NMR (100 MHz, CDCl3-
ArH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 58.6, 64.0, TMS), δ, ppm: 14.9, 25.3, 30.9, 43.0, 64.9, 82.5, 96.8, 156.5,
−
85.1, 96.4, 127.0, 129.3, 129.4, 132.2, 149.0, 163.5, 172.7; 163.1, 178.3; ESI-MS, m/z (%): calcd for C10H13ClNO5
ESI-MS, m/z (%): calcd for C13H13ClNO5 ([M + H]+): 298.05 ([M − H]−): 262.05 (100.0%), 264.05 (32.0%), found: 261.80
+
(100.0%), 300.04 (32.0%), found: 297.76 (100.0%), 300.05 (100.0%), 263.75 (42.1%); anal. calcd for C10H14ClNO5:
(43.0%); anal. calcd for C13H12ClNO5: C 52.45, H 4.06, N 4.71, C 45.55, H 5.35, N 5.31, found: C 45.45, H 5.36, N 5.30.
found: C 52.35, H 4.10, N 4.82.
6-(4-Bromo-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-
2-(4-Chloro-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-2- hexanoic acid (N13). Yellow sticky liquid; yield: 244 mg (76%);
phenylacetic acid (N8). Brown sticky liquid; yield: 127 mg 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.43–1.48 (m, 2H,
1
(41%); H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.26 (t, J = 8.0 CH2), 1.63–1.71 (m, 4H, 2CH2), 2.40 (t, J = 8.0 Hz, 2H, CH2),
Hz, 3H, CH3), 3.57–3.82 (m, 2H, CH2), 5.13–5.79 (m, 3H, NH, 3.32–3.47 (m, 2H, NCH2), 3.50 (s, 3H, OCH3), 4.94 (s, 1H,
2CH), 6.96 (b, 1H, COOH), 7.31–7.41 (m, 5H, ArH); 13C NMR COOH), 5.35 (b, 1H, NH), 5.72 (s, 1H, CH); 13C NMR
(100 MHz, CDCl3-TMS), δ, ppm: 15.0, 58.9, 65.3, 83.8, 97.2, (100 MHz, CDCl3-TMS), δ, ppm: 24.0, 25.7, 30.1, 33.6, 43.5,
127.0, 129.2, 129.4, 135.5, 150.1, 167.5, 172.9; ESI-MS, m/z (%): 54.8, 84.6, 98.4, 157.1, 163.4, 178.9; ESI-MS, m/z (%): calcd for
+
+
calcd for C14H15ClNO5 ([M + H]+): 312.06 (100.0%), 314.06 C11H17BrNO5 ([M + H]+): 322.03 (100.0%), 324.03 (97.3%),
(32.0%), found: 311.68 (100.0%), 313.68 (48.6%); anal. calcd found: 321.65 (100%), 323.65 (88.7%); anal. calcd for
for C14H14ClNO5: C 53.94, H 4.53, N 4.49, found: C 54.05, C11H16BrNO5: C 41.01, H 5.01, N 4.35, found: C 40.92, H 5.16,
H 4.46, N 4.51.
N 4.45.
6-(4-Bromo-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-hexa-
4-(4-Bromo-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-
butanoic acid (N9). Yellow sticky liquid; yield: 157 mg (54%); noic acid (N14). Yellow sticky liquid; yield: 267 mg (80%);
1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.63–1.70 (m, 2H, 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.28 (t, J = 8.0 Hz,
CH2), 1.96–2.01 (m, 2H, CH2), 3.51 (s, 3H, OCH3), 3.55 (b, 1H, 3H, CH3), 1.34–1.47 (m, 2H, CH2), 1.61–1.70 (m, 4H, 2CH2),
COOH), 3.62–3.90 (m, 2H, NCH2), 5.33 (s, 1H, NH), 5.73 (s, 1H, 2.33–2.41 (m, 2H, CH2), 3.36–3.60 (m, 2H, NCH2), 3.70–3.89
CH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 25.2, 30.5, 43.2, (m, 2H, OCH2), 5.36 (s, 1H, CH), 5.78 (b, 1H, NH), 6.88 (b, 1H,
65.6, 85.0, 98.3, 149.5, 167.8, 178.0; ESI-MS, m/z (%): calcd for COOH); 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 15.0, 24.0,
C9H13BrNO5 ([M + H]+): 294.00 (100.0%), 296.00 (97.3%), 25.7, 30.2, 33.6, 40.7, 64.5, 84.7, 97.6, 138.8, 163.5, 178.8;
+
found: 293.71 (100%), 295.72 (94.8%); anal. calcd for ESI-MS, m/z (%): calcd for C12H19BrNO5 ([M + H]+): 336.04
+
C9H12BrNO5: C 36.76, H 4.11, N 4.76, found: C 36.75, H 4.38, (100.0%), 338.04 (97.3%), found: 335.73 (100%), 337.75
N 4.84.
(94.5%); anal. calcd for C12H18BrNO5: C 42.87, H 5.40, N 4.17,
4-(4-Bromo-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino- found: C 43.02, H 5.45, N 4.20.
butanoic acid (N10). Yellow sticky liquid; yield: 187 mg
6-(4-Chloro-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-
(61%); 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.28 (t, J = hexanoic acid (N15). Brown liquid; yield: 214 mg (78%);
8.0 Hz, 3H, CH3), 1.90–2.56 (m, 5H, COOH, 2CH2), 3.70–3.90 1H NMR (400 MHz, CDCl3-TMS), δ, ppm: 1.26–1.36 (m, 2H,
(m, 4H, OCH2, NCH2), 5.36 (s, 1H, CH), 5.77 (s, 1H, NH); CH2), 1.40–1.55 (m, 2H, CH2), 1.62–1.70 (m, 2H, CH2),
13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 15.0, 25.2, 30.5, 43.2, 2.34–2.41 (m, 2H, CH2), 3.37–3.47 (m, 2H, NCH2), 3.50 (s, 3H,
65.6, 85.0, 98.3, 149.5, 167.8, 178.0; ESI-MS, m/z (%): calcd for OCH3), 5.26 (b, 1H, NH), 5.32 (s, 1H, CH), 5.69 (b, 1H, COOH);
+
C10H15BrNO5 ([M + H]+): 308.01 (100.0%), 310.01 (97.3%), 13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 24.0, 25.7, 30.2, 33.7,
found: 307.74 (100.0%), 309.74 (94.8%); anal. calcd for 43.4, 55.0, 84.3, 97.6, 156.0, 167.8, 179.2; ESI-MS, m/z (%):
C10H14BrNO5: C 38.98, H 4.58, N 4.55, found: C 39.00, H 4.48, calcd for C11H17ClNO5 ([M + H]+): 278.08 (100.0%), 280.08
+
N 4.62.
(32.0%), found: 277.78 (100%), 279.78 (30.2%); anal. calcd for
4-(4-Chloro-2-methoxy-5-oxo-2,5-dihydrofuran-3-yl)amino- C11H16ClNO5: C 47.58, H 5.81, N 5.04, found: C 47.62, H 5.86,
butanoic acid (N11). Brown liquid; yield: 136 mg (55%); N 5.05.
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6-(4-Chloro-2-ethoxy-5-oxo-2,5-dihydrofuran-3-yl)amino-hexa- used in (entries 7–9). In addition, we did not notice any signifi-
noic acid (N16). Brown liquid; yield: 228 mg (79%); 1H NMR cant advantages when altering the reaction temperature
(400 MHz, CDCl3-TMS), δ, ppm: 1.25 (t, J = 8.0 MHz, 3H, CH3), (entries 10 and 11 vs. entry 6). Fortunately, when the dosage
1.31–1.44 (m, 2H, CH2), 1.58–1.65 (m, 4H, 2CH2), 2.31–2.37 ratio of 2d with 1b is increased to 2 equiv., the desired product
(m, 2H, CH2), 3.31–3.55 (m, 2H, NCH2), 3.67–3.86 (m, 2H, N14 can be obtained in 80% yield (Table 1, entry 12). Thus,
OCH2), 5.31 (s, 1H, CH), 5.39 (b, 1H, NH), 5.72 (b, 1H, COOH); using C2H5OH/CH2Cl2 as a solvent and KOH (4.48 mmol) as a
13C NMR (100 MHz, CDCl3-TMS), δ, ppm: 14.9, 24.0, 25.7, 30.2, base, we successfully achieved the reaction of 1b (2 mmol) and
33.7, 43.4, 64.6, 85.5, 96.9, 156.0, 167.8, 179.2; ESI-MS, m/z 2d (4 mmol) at room temperature for 24 h to obtain a satisfac-
(%): calcd for C12H19ClNO5 ([M + H]+): 292.09 (100.0%), tory yield.
+
294.09 (32.0%), found: 291.84 (100%); 293.84 (25.8%); anal.
Under the optimized reaction conditions, four typical
calcd for C12H18ClNO5: C 49.41, H 6.22, N 4.80, found: amino acids were used in the transformation to establish the
C 49.42, H 6.42, N 4.75.
scope and generality of this protocol (Table 2). Generally, irre-
spective of whether bromine or chlorine is used in 5-alkoxyl-
3,4-dihalo-2(5H)-furanones 1, the reaction can work well.
What’s more, the type of amino acid also has some effects on
the yield. In most cases, on using secondary amine sarcosine
as the substrate, the yield of products is higher than that when
using primary amines (e.g. phenylglycine and 4-aminobutyric
acid, N1–N4 vs. N5–N11). This means that the secondary
amine is beneficial for this reaction. Furthermore, the yield of
products is increased with the increase in the alkyl chain
length of primary amines, especially for 6-aminohexanoic acid
(N13–N16). This is because, the longer the chain, the greater
the flexibility and the smaller the steric resistance. In addition,
due to the large steric hindrance of the benzene ring, though
the yield of products obtained by phenylglycine can be over
38% (N5–N8), it is obviously lower than that of others.
Results and discussion
Chemical synthesis by metal-free C–N coupling reaction
Based on our previous work,40–47 the reaction conditions were
optimized firstly. Using 2 mmol 3,4-dibromo-5-ethoxy-2(5H)-
furanone (1b) and 6-aminohexanoic acid (2d)56 as repre-
sentative reactants, the reaction parameters, such as catalysts,
bases, additives and temperature, were examined. The obtained
results are listed in Table 1.
It is well known that the formation of a Csp2–N bond
between a Csp2–X bond and N–H is usually catalyzed by tran-
sition metal catalysts,57–60 especially the inexpensive Cu(I)
salts.61–64 Thus, under the same conditions, we initially inves-
tigated the effect of the available Cu(I) salt. Using three sets of
test comparisons, it can be found that CuI (0.015 mmol) does
not work well as a catalyst in this reaction system irrespective
of the base (Table 1, entries 1–6). And obviously, among the
selected bases, KOH (1.12 equiv. of amino acid 2d) is the best
and the isolated yield of the target compound, 6-(4-bromo-2-
ethoxy-5-oxo-2,5-dihydrofuran-3-yl)aminohexanoic acid (N14),
is 71% (entry 6). However, mixing the additive of KI into the
base system is not effective irrespective of the proportion it is
The structures of all amino acid derivatives have been sys-
tematically characterized by 1H NMR, 13C NMR, ESI-MS and
elemental analysis. In the 1H NMR spectra, there is a single
peak between 5.27–6.14 ppm, and the chemical shift belongs
to the C–H of the furanone ring. The significant chemical shift
of NH and COOH in the amino acid unit usually appears near
Table 2 Substrate scope of various 5-substituted 3,4-dihalo-2(5H)-
furanones 1 and amino acids 2a,b
Table 1 Optimization of the reaction conditionsa
Entry 2d : 1b Base (equiv.)
Cat. Temp. (°C) Yieldb (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
K3PO4 (1.12)
CuI r.t.
r.t.
CuI r.t.
r.t.
CuI r.t.
45
57
47
39
66
71
58
30
49
45
45
80
K3PO4 (1.12)
—
tBuOK (1.12)
tBuOK (1.12)
—
KOH (1.12)
KOH (1.12)
KOH + KI (1.12, 1 : 1)
KOH + KI (1.12, 1 : 2)
KOH + KI (1.12, 2 : 1)
KOH (1.12)
—
—
—
—
—
—
—
r.t.
r.t.
r.t.
r.t.
40
60
r.t.
9
10
11
12
KOH (1.12)
KOH (1.12)
a Using C2H5OH/CH2Cl2 as a solvent, the reaction was carried out for a Using KOH as a base and C2H5OH/CH2Cl2 as a solvent at room tem-
24 h. b Isolated yield.
perature. b Isolated yield.
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5.35 ppm and 6.88 ppm, respectively. The characteristic chemi- EC-1 (human esophageal carcinoma cells), MDA-MB-231
cal shift of the furanone ring and amino acid moiety also can (estrogen receptor-negative human breast cells), MCF-7
be found in 13C NMR spectra. Furthermore, the ESI-MS results (estrogen receptor-positive human breast cells), HepG2
are consistent with the data of their corresponding theoretical (human hepatoma cells), CNE-1 (nasopharyngeal carcinoma
value. Thus, all structural testing results confirm that the cells) and A549 (human lung adenocarcinoma cells).54,55 Using
metal-free C–N coupling reaction between 5-substituted 3,4- cisplatin as the positive control, the antitumor activities of the
dihalo-2(5H)-furanones and amino acids is carried out indeed. above-mentioned 2(5H)-furanone derivatives are summarized
There have been many research studies to make the C–N in Table 3.
bond construction reaction more eco-friendly.64–66 Particularly,
It can be seen that, N1–N16, the serial amino acid deriva-
due to high cost and environmental pollution in transition tives of 5-alkoxy-3,4-dihalo-2(5H)-furanones basically have no
metal catalysis, the development of metal-free methodologies obvious antiproliferative activity, so the tumor cells can grow
in the C–N coupling reaction is becoming popular.67–69 without exerting cytotoxicity from the target compounds.
Therefore, our design for the formation of the Csp2–N bond is However, most of the O1–O27 furanone derivatives have
practical and allows for the successful combination of amino certain cytotoxic activity on HepG2 hepatocellular carcinoma
acids with the 2(5H)-furanone unit.
cells, especially for O5 and O10 both containing a trifluo-
roethyl group. For S1–S16 and SO1–SO16 series, most deriva-
tives of furanones have certain antiproliferative activity on
MDA-MB-231 breast cancer cells, C6 brain glioma cells and
MCF-7 breast cancer cells. Therefore, the preliminary results
reveal that the introduction of amino acids as safe linkers basi-
cally has no toxic effect as anticipated.
At the same time, due to the presence of an amino acid
structural unit in N1–N16 series, they can be expected to be
further studied in the field of cell compatibility. And in combi-
nation with other bioactive results, it is possible to introduce a
fluorine-containing group into N1–N16 series via esterification
with trifluoroethanol to develop the potential 2(5H)-furanone
drugs. Studies on these aspects are in progress.
Inhibition activities on various anticancer cells in vitro
In order to investigate the potential bioactive compounds with
no/less cytotoxicity, other 2(5H)-furanone compounds O1–O27,70
S1–S16,46 and SO1–SO1647 were selected as contrasting
substances (their structures can be seen in Scheme 2) by con-
structing C–O/C–S bonds at the same site of 5-substituted 3,4-
dihalo-2(5H)-furanones (their corresponding synthesis pro-
cedures are described in the ESI†); the effect of amino acids as
potential linkers in the 2(5H)-furanone unit with other drug
moieties containing amino or hydroxy groups was investigated
through the biological activity assay by the MTT method on a
series of cancer cell lines in vitro, such as C6 (rat glioma cells),
Conclusions and outlook
A series of amino acid derivatives are synthesized with
5-alkoxy-3,4-dihalo-2(5H)-furanones and amino acids via a
metal-free C–N coupling reaction as expected after the optimal
reaction conditions are established. As linkers, the effect of
amino acids has been investigated by comparison with other
2(5H)-furanone compounds by constructing C–O/C–S bonds.
The results of the biological activity assay reveal that the
amino acids in these 2(5H)-furanone derivatives exhibiting
good biocompatibility can be good linkers as expected. What’s
more, a fluorine-containing group is beneficial for improving
the bioactivity of 2(5H)-furanone drugs. The introduction of
fluorine-containing groups into 2(5H)-furanones will be our
future work.
Importantly, as linkers of potential 2(5H)-furanone drugs,
amino acids can provide a well-reactive site into 2(5H)-
furanone derivatives by reacting with the carboxyl group in our
amino acid linking unit under mild conditions. Particularly,
some amino acids with long chains may improve the tolerance
of 2(5H)-furanone substrates for the introduction of some
complex, sensitive and sterically hindered bioactive moieties
with amino or hydroxy groups.71–73 Thus, the introduction of
amino acids as linkers will provide a new effective approach
for the development of 2(5H)-furanone derivative drugs with
good biocompatibility.
Scheme 2 2(5H)-Furanone derivatives synthesized previously.
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Table 3 Inhibitory effects of target molecules N1–N16, contrasting substances and cisplatin against the growth of the selected cell lines
IC50/μM (Max concentration: 300 μM)
No.
HepG2
MDA-MB-231
C6
MCF-7
A549
EC-1
CNE-1
N1
N2
N3
N4
N5
N6
N7
N8
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
104.67 8.50
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
284.98 20.15
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
66.69 2.25
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
N9
N10
N11
N12
N13
N14
N15
N16
O1
O2
O3
O4
O5
O6
O7
O8
O9
196.08 8.46
190.05 3.85
152.40 2.28
151.04 3.26
40.22 0.57
>300
127.48 2.55
268.65 4.28
149.64 6.47
>300
>300
161.59 33.99
>300
127.06 1.25
>300
>300
>300
>300
>300
>300
>300
>300
73.11 0.61
266.23 6.85
>300
>300
>300
239.43 12.43
>300
>300
>300
73.53 1.57
>300
>300
>300
>300
299.79 8.33
>300
>300
223.73 12.06
>300
>300
>300
286.20 12.94
>300
>300
229.70 7.49
>300
>300
299.13 3.03
230.58 3.54
>300
>300
220.98 12.11
>300
>300
127.38 0.76
271.60 7.83
>300
>300
>300
274.53 2.00
>300
O10
O11
O12
O13
O14
O15
O16
O17
O18
O19
O20
O21
O22
O23
O24
O25
O26
O27
41.12 0.94
120.68 4.39
107.51 2.41
195.15 7.25
292.53 3.82
110.13 2.91
>300
>300
>300
186.63 3.68
>300
>300
>300
>300
>300
>300
416.03 4.1
85.79 3.04
123.49 1.96
>300
>300
>300
257.21 9.05
>300
>300
>300
>300
288.69 3.81
>300
181.45 1.93
>300
>300
297.26 7.76
233.76 10.25
221.64 2.6
215.44 6.57
58.47 0.52
279.32 6.40
>300
>300
>300
>300
>300
>300
>300
>300
>300
109.13 2.39
>300
269.43 5.91
>300
>300
231.35 2.24
158.83 1.21
19.67 0.37
>300
>300
223.30 10.27
>300
>300
>300
>300
>300
193.52 3.58
>300
145.12 1.23
>300
>300
299.34 9.65
>300
192.44 3.80
130.73 2.20
108.36 1.09
>300
>300
150.25 8.62
>300
>300
>300
>300
>300
186.87 3.96
>300
182.53 3.50
>300
>300
>300
>300
212.16 4.57
152.05 1.23
44.68 0.68
>300
284.35 10.33
281.50 16.25
>300
>300
>300
>300
>300
246.71 5.86
159.90 3.95
>300
>300
>300
293.68 7.9
>300
197.19 7.37
>300
>300
>300
256.45 6.08
295.63 7.74
>300
>300
>300
>300
203.88 3.24
>300
>300
185.65 2.58
>300
>300
154.90 2.82
>300
108.72 1.57
>300
S1
S2
S3
S4
>300
>300
184.70 1.27
>300
>300
>300
>300
180.77 2.77
116.69 2.38
>300
175.32 1.41
176.68 4.81
138.88 2.18
84.52 1.44
>300
252.41 8.31
165.10 4.34
181.02 3.18
86.19 2.84
>300
>300
224.25 8.04
185.17 10.56
229.75 9.35
248.79 3.73
>300
>300
>300
>300
>300
218.16 5.70
296.80 2.70
143.73 5.42
>300
S5
>300
S6
S7
S8
S9
S10
S11
S12
S13
S14
S15
S16
259.97 4.51
155.90 1.65
>300
>300
231.03 1.44
>300
224.00 3.05
>300
>300
>300
251.28 2.72
249.08 5.48
218.76 2.17
176.29 3.62
167.66 1.48
214.58 3.42
197.28 4.77
215.34 3.43
168.41 4.70
>300
147.08 3.32
207.33 3.58
178.15 1.58
165.51 2.64
166.01 2.14
162.49 3.17
157.99 2.07
152.69 2.97
158.05 2.64
146.55 1.72
167.40 3.88
196.05 9.83
175.37 5.75
212.89 4.82
187.98 4.19
184.67 3.13
211.02 7.35
130.12 5.53
178.06 6.30
>300
262.89 7.59
262.98 3.59
>300
230.93 3.95
239.34 1.98
>300
>300
268.61 7.82
>300
160.80 9.25
112.53 3.56
250.79 8.83
169.95 3.08
>300
224.22 12.31
144.78 11.34
205.52 4.64
>300
>300
>300
>300
190.79 3.73
>300
>300
>300
>300
>300
185.54 6.72
295.29 8.66
191.93 11.57
175.21 5.34
256.50 8.67
258.95 2.16
207.351 10.57
187.75 11.82
>300
>300
SO1
SO2
SO3
SO4
SO5
>300
>300
246.52 3.72
>300
>300
184.71 4.58
>300
142.23 1.94
175.28 3.36
216.38 3.32
198.43 4.76
128.90 3.52
115.98 2.15
129.44 6.93
101.25 3.43
181.12 7.73
168.99 2.74
119.12 1.69
134.66 5.44
216.78 7.16
>300
>300
173.78 2.67
282.91 9.71
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
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Table 3 (Contd.)
IC50/μM (Max concentration: 300 μM)
No.
HepG2
MDA-MB-231
C6
MCF-7
A549
EC-1
CNE-1
SO6
SO7
SO8
SO9
SO10
SO11
SO12
SO13
SO14
SO15
SO16
Cisplatin
295.97 4.38
>300
>300
266.74 2.41
>300
>300
>300
>300
>300
>300
86.19 1.95
174.93 3.96
183.81 6.59
145.58 2.23
216.27 3.60
283.00 5.54
198.36 5.51
159.93 2.74
131.58 4.22
161.48 1.97
147.13 4.65
17.8 0.9
67.87 1.32
96.39 1.21
106.69 2.66
49.80 0.97
117.68 3.70
>300
105.17 2.12
153.07 3.29
92.70 3.62
108.28 2.73
65.93 2.73
18.7 0.5
>300
>300
>300
>300
253.47 3.74
>300
199.58 10.07
>300
>300
>300
>300
>300
>300
>300
293.03 11.18
>300
154.22 6.66
>300
>300
>300
>300
>300
>300
>300
186.76 7.86
>300
122.02 4.57
112.87 3.65
83.24 2.68
150.63 6.98
262.22 10.25
124.86 1.81
123.13 3.62
>300
>300
255.38 1.52
240.55 4.87
>300
235.38 7.38
216.27 8.55
ND
117.14 4.25
86.30 2.18
76.9 0.9
>300
93.1 0.9
170.43 2.80
ND
123.23 2.67
19.1 0.5
T. Steinmetzer and M. Guetschow, A fluorescent-labeled
phosphono bisbenzguanidine as an activity-based probe
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Conflicts of interest
There are no conflicts to declare.
7 G. F. Li, W. L. Feng, N. Corrigan, C. Boyer, X. Wang and
J. T. Xu, Precise synthesis of poly(N-acryloyl amino acid)
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8 T. Smidlehner, A. Kurutos, J. Slade, R. Belužić, D. L. Ang,
A. Rodger and I. Piantanida, Versatile click cyanine amino
acid conjugates showing one-atom-influenced recognition
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9 Y. M. Liu, L. Y. Zhao, R. R. Xing, T. F. Jiao, W. X. Song and
X. H. Yan, Covalent assembly of amphiphilic bola-amino
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H.-C. Lin, The role of amino acids on supramolecular coas-
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11 K. S. Yu, M. M. Lin, H. J. Lee, K.-S. Tae, B.-S. Kang,
J. H. Lee, N. S. Lee, Y. G. Jeong, S.-Y. Han and
D. K. Kim, Receptor-meditated endocytosis by hyaluronic
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Acknowledgements
We gratefully acknowledge financial support from the
Guangdong Natural Science Foundation (No. 2014A030313429),
the Guangzhou Science and Technology Project Scientific Special
(General Items, No. 201607010251), the Open Fund of the Key
Laboratory of Functional Molecular Engineering of Guangdong
Province in SCUT (No. 2017kf01), and the Guangdong Provincial
Science and Technology Project (No. 2017A010103016).
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