Synthesis of chloramphenicol conjugate with fullerene C60

Full text of DOI:10.1134/S1070428016040217

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 4, pp. 587–589. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © S.A. Torosyan, V.V. Mikheev, Yu.N. Biglova, M.S. Miftakhov, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 4, pp. 600–602.
SHORT
COMMUNICATIONS
Synthesis of Chloramphenicol Conjugate with Fullerene C60
a
b
b
a
S. A. Torosyan , V. V. Mikheev , Yu. N. Biglova , and M. S. Miftakhov
a
Institute of Chemistry, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
b
Bashkir State University, ul. Zaki Validi 32, Ufa, 450074 Bashkortostan, Russia
Received January 11, 2016
DOI: 10.1134/S1070428016040217
Main efforts in the design and synthesis of organo-
functionalized derivatives of fullerene C for medical
activity profile was retained; however, it may change
since a radically new molecular architecture is
concerned.
6
0
purposes are addressed to create water-soluble com-
pounds [1–3]. Among them, antiviral [4], anticarcino-
genic [5], and antibacterial agents [6], radical scaven-
gers [7], etc. [8], have been found. An important
research line in this field is the synthesis of coordina-
tion and covalently bound C60 compounds with bio-
logically active molecules used in medical practice.
For example, the anticancer activity of the C ‒doxo-
In the antibiotics series, an exceptionally important
problem is pathogen resistance to drugs [16]; therefore,
either modification of known antibiotics or design of
compounds with novel mechanisms of action is neces-
sary. In this work we made an attempt to synthesize
C conjugate with a broad-spectrum antibiotic, chlor-
6
0
6
0
amphenicol (1). Molecule 1 contains a dichloromethyl
group which should be active in the Bingel cyclo-
propanation of C60 [17, 18]. In fact, compound 1
smoothly reacted with C in o-dichlorobenzene in the
rubicin complex is higher by a factor of 1.5‒2 than the
activity of doxorubicin taken alone [9]; analogous
effect is observed for the complex C ‒dexamethasone
6
0
6
0
[
10]. As a rule, the complexation improves transport
presence of 2‒3 equiv of DBU to give 20% of adduct
. Compound 2 is soluble in technological solvents,
including DMSO.
and prolongs action of drugs, and in some cases
synergistic effect is achieved.
2
A different situation is observed with covalent
bonding of C60 with drugs. Zakharian et al. [11] pro-
posed to use C conjugate with paclitaxel (Taxol) for
The cyclopropanation of C with diacetate 3 was
60
carried out under analogous conditions. The product,
methanofullerene 4, was soluble in chloroform and
toluene, but its solubility in DMSO was lower than
that of adduct 2. Diacetate 4 and diol 2 may be regard-
ed as new potential biologically active compounds and
prodrugs since acetates and amides are known to
readily undergo in vivo hydrolysis to alcohols and
amines, respectively.
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lipophilic chemotherapy of lung cancer. It was noted
that C60 is an ideal partner for the lipophilization of
drugs via conjugation. Conjugates of C60 with anti-
biotics [12] have been patented, and C60 conjugates
with isoniazid [13], dehydroabietylamine [14], amino
acids [15], and other biologically active molecules
have been synthesized. In most cases, the biological
OR
OR
OR
OR
Cl
DBU, toluene
or o-Cl C H
HN
Cl
2 6 4
O N
2
+
HN
O
O N
Cl
2
O
1
, 3
2, 4
1
, 2, R = H; 3, 4, R = Ac.
5
87

5
88
TOROSYAN et al.
(
1R,2R)-2-{[3′-Chloro-3′H-cyclopropa[1,9]-
nitrophenyl)propyl acetate (4). Fullerene C , 0.1 g
60
(
C -I )[5,6]fulleren-3′-yl]carbonylamino}-3-hy-
(0.138 mmol), was dissolved in 30 mL of toluene,
0.065 g (0.166 mmol) of compound 3 and 0.062 g
(0.414 mmol) of DBU were added, and the mixture
was stirred for 24 h at room temperature (TLC). The
mixture was evaporated, and the product was isolated
by silica gel column chromatography (toluene, methy-
lene chloride). Yield 0.06 g (40%), dark brown
6
0
h
droxy-1-(4-nitrophenyl)propan-1-ol (2). Fullerene
C , 0.1 g (0.138 mmol), was dissolved in 20 mL of
o-dichlorobenzene, 0.053 g (0.166 mmol) of chloram-
phenicol (1) and 0.053 g (0.414 mmol) of 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) were added, and the
mixture was stirred for 24 h at room temperature
6
0
–
1
(
TLC). The solvent was distilled off under reduced
powder. IR spectrum, ν, cm : 3318, 1745, 1681, 1522,
1
pressure, and the product was isolated by silica gel
column chromatography (methylene chloride–metha-
nol, 100:1). Yield 0.04 g (30%), dark brown powder.
IR spectrum, ν, cm : 3323, 2360, 1688, 1517, 1348,
1
ppm: 3.80 br.s (2H, CH O), 4.20 br.s (1H, CHO),
5
J = 8.6 Hz), 8.20 d (2H, Harom, J = 8.6 Hz). C NMR
spectrum (CDCl ), δ , ppm: 55.65 (CHNH), 60.01
(
(
1349, 1224, 1051, 811, 530. H NMR spectrum, δ,
ppm: 2.15 s (3H, CH ), 2.30 s (3H, CH ), 4.23 d.d (1H,
3
3
CH O, J = 6.5, 11.8 Hz), 4.40 d.d (1H, CH O, J = 6.4,
2
2
–
1
11.6 Hz), 4.97 sext (1H, CHNH, J = 5.6 Hz), 6.25 d
1
224, 1048, 749, 530. H NMR spectrum (CDCl ), δ,
3
(1H, CHO, J = 4.7 Hz), 7.18 d (1H, NH, J = 9.0 Hz),
7.63 d (2H, Harom, J = 8.6 Hz), 8.25 d (1H, Harom, J =
2
13
.25 s (1H, CHN), 5.80 s (1H, NH), 7.50 d (2H, Harom,
8.6 Hz).
C NMR spectrum, δ , ppm: 20.80 (CH ),
C 3
1
3
21.00 (CH ), 62.58 (CH O), 67.09 (CHN), 72.90
3
2
3
C
(CHO); 124.18, 127.37, 143.88, 148.00 (Carom);
139.00, 139.20, 141.13 (2C), 142.19, 143.03, 143.10,
143.15, 143.47, 143.69, 144.07, 144.19, 144.51,
Csp
60 2
3 in C ), 63.10 (CH OH), 68.0 (CCl), 72.39
CHOH); 122.75, 127.43 (Carom); 133.00, 133.45,
35.20, 142.40, 144.76, 150.34, 170.21 (C=O). Mass
1
1
44.80 (2C), 144.86, 145.22, 145.31, 145.37 (C ),
60
+
spectrum: m/z 1006.068 [M] . C H ClN O . Calcu-
lated: M 1006.035.
7
1
11
2
5
163.08 (CONH), 169.67 (C=O), 170.07 (C=O). Mass
+
spectrum: m/z 1090.076 [M] . C H ClN O . Calculat-
7
5
15
2
7
In addition, 0.04 g of unreacted C60 (mp >350°C)
was isolated.
ed: M 1090.056.
In addition, 0.03 g of unreacted C60 (mp >350°C)
was isolated.
(
1R,2R)-3-Acetoxy-2-[(dichloroacetyl)amino]-1-
4-nitrophenyl)propyl acetate (3). A solution of
.2 g (0.62 mmol) of compound 1 in 0.5 mL
(
0
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer from films. The H NMR
spectra were measured on a Bruker AM-300 spec-
trometer at 300.13 MHz using CDCl as solvent and
1
(
(
6.2 mmol) of pyridine was cooled to 0°C, 0.31 mL
3.1 mmol) of acetic anhydride was added dropwise,
3
and the mixture was stirred for 6 h at room temperature
TLC). The mixture was washed with brine and
13
tetramethylsilane as internal standard. The C NMR
(
spectra were recorded on a Bruker Avance-500 instru-
ment at 125.77 MHz. The mass spectra (MALDI) were
obtained on a Voyager-DE STR MALDI TOF mass
spectrometer. The progress of reactions was monitored
by TLC on Sorbfil plates (Russia); spots were detected
by calcination or treatment with an alkaline solution of
potassium permanganate. Column chromatography
was performed using 30–60 g of silica gel per gram of
substrate; freshly distilled solvents were used for
elution.
extracted with chloroform. The organic phase was
separated, dried over MgSO , and evaporated, and the
4
residue was purified by silica gel column chromatog-
raphy (petroleum ether–ethyl acetate, 1:1). Yield
0
.22 g (91%), amorphous solid, mp 140°C. IR spec-
–
1
trum, ν, cm : 3318, 1745, 1686, 1520, 1350, 1064,
8
1
44, 656. H NMR spectrum, δ, ppm: 2.10 s (3H,
CH ), 2.20 s (3H, CH ), 4.08 d.d (1H, J = 6.1, 11.7 Hz)
3
3
and 4.18 d.d (1H, J = 5.2, 11.7 Hz) (CH O), 4.60 sext
2
(
(
1H, CHNH, J = 5.6 Hz), 5.85 s (1H, CHCl ), 6.08 d
1H, CHO, J = 5.7 Hz), 6.75 d (1H, NH, J = 9.4 Hz),
2
This study was performed using the equipment of
the Khimiya Joint Center, Ufa Institute of Chemistry,
Russian Academy of Sciences.
7
.52 d.d (2H, Harom, J = 1.8, 6.8 Hz), 8.22 d.d (2H,
1
3
Harom, J = 1.9, 6.8 Hz). C NMR spectrum, δ , ppm:
C
2
0.63 (CH ), 20.81 (CH ), 60.38 (CHN), 62.18
3 3
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