Synthesis of Colchicine C-10-Amino-Acid Derivatives

Article abstract of DOI:10.1007/s10600-015-1510-6

Colchicine derivatives modified on C-10 by natural and synthetic amino acids were synthesized.

Full text of DOI:10.1007/s10600-015-1510-6

DOI 10.1007/s10600-015-1510-6
Chemistry of Natural Compounds, Vol. 51, No. 6, November, 2015
SYNTHESIS OF COLCHICINE C-10-AMINO-ACID DERIVATIVES
Ya. L. Garazd,1* M. M. Garazd, and V. G. Kartsev
1
2
Colchicine derivatives modified on C-10 by natural and synthetic amino acids were synthesized.
Keywords: colchicine, amino-acid derivatives, colchicine C-10-amine derivatives.
Chemical modification of naturally-occurring biologically active compounds is one of the most promising and effective
methods for discovering new drugs. Colchicine, a tropolone alkaloid and the principal representative of the colchicine family
(
homomorphinanes), is especially interesting as this type of starting material. This secondary metabolite was first isolated
from bulbs of Colchicum autumnale L. (Liliaceae) in 1811 and has attracted attention ever since [1]. Colchicine is a potent
anti-mitotic that binds to the protein tubulin, which forms microtubules and blocks cell division in the metaphase stage.
Colchicine is one of the most cytotoxic compounds. Its use in chemotherapy is limited because of its relatively high toxicity
despite that fact that it is a potent growth inhibitor for many types of malignant cells. However, it has been used recently to
treat gout, acute pericarditis, and familial Mediterranean fever [2].
One of the most common methods for modifying colchicine is regioselective replacement of the 10-methoxy on the
tropolone ring by an amine through the reaction of colchicine with the corresponding amines [3]. Biologically active colchicine
derivatives with significantly less toxicity were prepared by such transformations using several amino acids as the amines [4, 5].
Me
Me
H
Me
H
O
O
O
O
O
O
NH
H
N
0
O
NH
O
NH
H
N
8
OMe
H
6
OH
OH
1
7
5
12
OMe
OMe
OMe
OMe
OMe
OMe
MeO
Me
MeO
Me
MeO
O
1
2
1
13
Me
O
O
O
O
O
O
NH
H
N
O
NH
NH
H
N
OH
H
OH
H
H
OH
R
OMe
OMe
OMe
OMe
OMe
OMe
MeO
2 - 11
MeO
15
MeO
14
R = H (2); CH (3); CH(CH ) (4); CH CH(CH ) (5); CH(CH )CH CH (6); CH CH SCH (7)
3
3 2
2
3 3
3
2
3
2
2
3
C H (8); CH CH (9); CH CH CH (10); CH CH CH CH (11)
6
5
2
3
2
2
3
2
2
2
3
1
) Eximed, 02160, Ukraine, Kiev, Kharꢀkovskoe Shosse, 50, e-mail: gmm@i.com.ua; 2) InterBioScreen, 119019,
Russia, Moscow, P. O. Box 218. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2015,
pp. 979–981. Original article submitted April 8, 2015.
1
138
0009-3130/15/5106-1138 ©2015 Springer Science+Business Media New York

Herein, modification of colchicine by addition of natural and synthetic amino acids is reported. Condensation of
colchicine and sodium salts of amino acids in EtOH–H O mixtures with heating followed by acidolysis of the resulting salts
2
produced in 62–76% yields colchicine amino-acid derivatives 2–14 with a free carboxylic acid that contained glycine (2),
L-alanine (3), L-valine (4), L-leucine (5), L-isoleucine (6), L-methionine (7), L-phenylglycine (8), DL-norvaline (10),
DL-norleucine (11) DL-2-aminobutanoic (9), 4-aminobutanoic (12), 6-aminohexanoic (13), and
1
-(aminomethyl)cyclohexaneacetic (gabapentin, Neurontin) (14) acids. PMR spectra of 2–14 contained resonances for the
colchicine ring and amino-acid moiety and lacked the resonance of the colchicine C-10 methoxy. The amine resonance was
observed in the range 7.44–8.12 ppm as a triplet with SSCC 5.4–6.3 Hz (for 2 and 12–14) or a doublet with SSCC 7.2–8.4 Hz
(
for 3–11).
A compound that was identified as colchicein (10-O-demethylcolchicine or N-acetyltrimethylcolchincinic acid) (15)
based on PMR spectroscopy was isolated as a side product [6–8]. Obviously, 15 was formed in low yields (5–10%) via
hydrolysis of colchicine (1) under the alkaline conditions for synthesizing the amino-acid derivatives.
The obtained colchicine C-10-amino-acid derivatives 2–14 were interesting as multi-purpose organic synthons because
they contained an active carboxylic functional group and opened new possibilities for further modification of colchicine
derivatives.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck 60 F254 plates using CHCl3–
MeOH (9:1 and 95:5). Melting points were determined on a Kofler apparatus. PMR spectra were measured vs. TMS (internal
standard) on a Varian VXR-300 spectrometer at 300 MHz. Elemental analyses of all compounds agreed with those calculated.
General Method for Synthesizing Colchicine C-10-Amino-Acid Derivatives 2–14. A solution of colchicine (1,
4
2
.00 g, 10 mmol) in EtOH (10 mL) was treated with a solution of the appropriate amino acid (20 mmol) and NaOH (0.80 g,
0 mmol) in distilled H O (10 mL), stirred vigorously, and heated (60–70°C) for 5–7 h (end of reaction determined by TLC).
2
After the reaction was finished, the EtOH was removed in vacuo in a rotary evaporator. The residue was extracted with EtOAc
3 ꢁ 10 mL). The aqueous phase was acidified to pH 5. The resulting precipitate of 2–14 was filtered off and crystallized from
aqueous EtOH. The organic phase was dried over anhydrous Na SO . The EtOAc was removed in vacuo in a rotary evaporator.
(
2
4
The residue was triturated with Et O to isolate 15.
2
1
0-Colchincidylglycine (2). Yield 2.74 g (62%), mp 186–187ꢂÑ (lit.: 226–227ꢂÑ), C H N O . PMR spectrum
23 26 2 7
(
(
300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.78–1.94 (1Í, m, H-6ꢄ), 1.86 (3Í, s, NAc), 1.96–2.22 (2Í, m, H-5ꢄ, 6ꢅ), 2.45–2.55
6
1Í, m, H-5ꢅ), 3.48 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.83 (3Í, s, OCH ), 4.16 (2Í, d, J = 6.3, H glycine), 4.33–4.42 (1Í,
3
3
3
2
m, H-7), 6.55 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.14 (1Í, s, Í-8), 7.17 (1Í, d, J = 11.1, H-11), 7.73 (1Í, t, J = 5.4,
NH-10), 8.58 (1Í, d, J = 7.5, NH-7), 13.04 (1Í, br.s, COOH).
1
0-Colchincidyl-L-alanine (3). Yield 3.10 g (68%), mp 166–167ꢂÑ, C H N O . PMR spectrum (300 MHz, DMSO-d , ꢃ,
24 28 2 7 6
ppm, J/Hz): 1.48 and 1.50 (3Í, two d, J = 7.2, ÑÍ alanine), 1.78–1.92 (1Í, m, H-6ꢄ), 1.86 (3Í, s, NAc), 1.97–2.23 (2Í, m,
3
H-5ꢄ, 6ꢅ), 2.45–2.55 (1Í, m, H-5ꢅ), 3.48 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.83 (3Í, s, OCH ), 4.30–4.51 (2Í, m, H-7, 2
3
3
3
alanine), 6.65 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.16 (1Í, s, Í-8), 7.19 (1Í, d, J = 11.1, H-11), 7.56 and 7.58 (1Í, two
d, J = 7.2, NH-10), 8.58 (1Í, d, J = 7.5, NH-7), 13.16 (1Í, br.s, COOH).
1
0-Colchicidyl-L-valine (4). Yield 3.36 g (70%), mp 161–162ꢂÑ, C H N O . PMR spectrum (300 MHz, DMSO-d ,
26 32 2 7 6
ꢃ, ppm, J/Hz): 0.96 and 1.03 (6Í, two d, J = 6.6, 2ÑÍ valine), 1.81–1.93 (1Í, m, H-6ꢄ), 1.86 (3Í, s, NAc), 1.98–2.23 (2Í,
3
m, H-5ꢄ, 6ꢅ), 2.23–2.29 (1Í, m, H-3 valine), 2.50–2.58 (1Í, m, H-5ꢅ), 3.47 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.83 (3Í,
3
3
s, OCH ), 4.26–4.42 (2Í, m, H-7, 2 valine), 6.71 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.17 (1Í, s, Í-8), 7.20 (1Í, d,
3
J = 11.1, H-11), 7.49 (1Í, d, J = 7.8, NH-10), 8.59 (1Í, d, J = 7.8, NH-7), 13.27 (1Í, br.s, COOH).
1
0-Colchicidyl-L-leucine (5). Yield 3.64 g (74%), mp 155–156ꢂÑ, C H N O . PMR spectrum (300 MHz, DMSO-d ,
27 34 2 7 6
ꢃ, ppm, J/Hz): 0.87 and 0.95 (6Í, two d, J = 5.4, 2ÑÍ leucine), 1.81–1.93 (4Í, m, H-6ꢄ, 4, H -3 leucine), 1.86 (3Í, s, NAc),
3
2
1
4
.96–2.23 (2Í, m, H-5ꢄ, 6ꢅ), 2.45–2.55 (1Í, m, H-5ꢅ), 3.48 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.83 (3Í, s, OCH ),
.26–4.44 (2Í, m, H-7, 2 leucine), 6.63 (1Í, d, J = 11.1, H-11), 6.77 (1Í, s, Í-4), 7.15 (1Í, s, Í-8), 7.18 (1Í, d, J = 11.1,
3 3 3
H-11), 7.44 (1Í, d, J = 7.8, NH-10), 8.54 (1Í, d, J = 7.8, NH-7), 13.17 (1Í, br.s, COOH).
1
139

1
0-Colchicidyl-L-isoleucine (6). Yield 3.49 g (71%), mp 158–159ꢂÑ, C H N O . PMR spectrum (300 MHz,
27 34 2 7
DMSO-d , ꢃ, ppm, J/Hz): 0.93 (3Í, t, J = 7.2, ÑÍ -5 isoleucine), 0.95 (3Í, d, J = 6.8, ÑÍ -3 isoleucine), 1.22–1.37 (1Í, m,
6
3
3
Í-4ꢄ isoleucine), 1.53–1.67 (1Í, m, Í-4ꢅ isoleucine), 1.80–1.91 (1Í, m, H-6ꢄ), 1.86 (3Í, s, NAc), 1.96–2.23 (3Í, H-5ꢄ, 6ꢅ,
isoleucine), 2.52–2.62 (1Í, m, H-5ꢅ), 3.47 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.83 (3Í, s, OCH ), 4.30–4.42 (2Í, m,
3
3
3
3
H-7, 2 isoleucine), 6.68 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.18 (1Í, s, Í-8), 7.21 (1Í, d, J = 11.1, H-11), 7.54 (1Í, t,
J = 8.1, NH-10), 8.60 (1Í, d, J = 7.5, NH-7), 13.19 (1Í, br.s, COOH).
1
0-Colchicidyl-L-methionine (7). Yield 3.56 g (69%), mp 153–152ꢂÑ (lit. ꢆ5ꢇ: 147ꢂÑ, dec.), C H N O S.
26 32 2 7
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.81–1.92 (1Í, m, H-6ꢄ), 1.87 (3Í, s, NAc), 2.05 (3Í, s, CH S methionine),
6
3
1
.98–2.25 (4Í, H-5ꢄ, 6ꢅ, CH S methionine), 2.55–2.62 (1Í, m, H-5ꢅ), 3.48 (3Í, s, OCH ), 3.79 (3Í, s, OCH ), 3.83 (3Í, s,
2
3
3
OCH ), 4.33–4.43 (1Í, m, H-7), 4.50–4.56 (1Í, m, H-2 methionine), 6.69 (1Í, d, J = 11.1, H-11), 6.76 (1Í, s, Í-4), 7.17 (1Í,
3
s, Í-8), 7.19 (1Í, d, J = 11.1, H-11), 7.60 (1Í, t, J = 8.1, NH-10), 8.60 (1Í, d, J = 7.5, NH-7), 13.29 (1Í, br.s, COOH).
1
0-Colchicidyl-L-phenylglycine (8). Yield 3.94 g (76%), mp 203–204ꢂÑ, C H N O . PMR spectrum (300 MHz,
29 30 2 7
DMSO-d , ꢃ, ppm, J/Hz): 1.79–1.93 (1Í, m, H-6ꢄ), 1.85 (3Í, s, NAc), 1.96–2.20 (2Í, m, H-5ꢄ, 6ꢅ), 2.45–2.55 (1Í, m,
6
H-5ꢅ), 3.348 (3Í, s, OCH ), 3.74 (3Í, s, OCH ), 3.81 (3Í, s, OCH ), 4.33–4.38 (1Í, m, H-7), 5.50 (1Í, d, J = 6.6, H-2
3
3
3
phenylglycine), 6.45 (1Í, d, J = 11.1, H-11), 6.73 (1Í, s, Í-4), 7.04 (1Í, d, J = 11.1, H-11), 7.19 (1Í, s, Í-8), 7.33–7.49 (5Í,
m, Ph), 8.12 (1Í, t, J = 6.6, NH-10), 8.58 (1Í, d, J = 7.5, NH-7), 13.35 (1Í, br.s, COOH).
1
0-Colchicidyl-DL-2-aminobutanoic Acid (9). Yield 3.06 g (65%), mp 184–185ꢂÑ, C H N O . PMR spectrum
25 30 2 7
(
300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 0.89 and 0.91 (3Í, two t, J = 7.5, ÑÍ amino-acid), 1.86 (3Í, s, NAc), 1.81–2.33 (5Í,
6
3
m, H-5ꢄ, 6ꢄ, 6ꢅ, ÑÍ amino-acid), 2.50–2.60 (1Í, m, H-5ꢅ), 3.48 and 3.50 (3Í, two s, OCH ), 3.79 (3Í, s, OCH ), 3.83 (3Í,
2
3
3
s, OCH ), 4.31–4.46 (2Í, m, H-7, 2 amino-acid), 6.68 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.17 (1Í, s, Í-8), 7.20 (1Í,
3
d, J = 11.1, H-11), 7.53 and 7.56 (1Í, two d, J = 8.4, NH-10), 8.58 (1Í, d, J = 7.5, NH-7), 13.10 (1Í, br.s, COOH).
1
0-Colchicidyl-DL-norvaline (10). Yield 3.48 g (72%), mp 167–168ꢂÑ, C H N O . PMR spectrum (300 MHz,
26 32 2 7
DMSO-d , ꢃ, ppm, J/Hz): 0.89 and 0.92 (3Í, two t, J = 7.5, ÑÍ norvaline), 1.34 (2Í, q, J = 7.5, ÑÍ -4 norvaline), 1.86 (3Í,
6
3
2
s, NAc), 1.80–2.23 (5Í, m, H-5ꢄ, 6ꢄ, 6ꢅ, ÑÍ -3 norvaline), 2.50–2.60 (1Í, m, H-5ꢅ), 3.48 and 3.50 (3Í, two s, OCH ), 3.78
2
3
(
(
3Í, s, OCH ), 3.83 (3Í, s, OCH ), 4.31–4.46 (2Í, m, H-7, 2 norvaline), 6.66 (1Í, d, J = 11.1, H-11), 6.74 (1Í, s, Í-4), 7.16
1Í, s, Í-8), 7.18 (1Í, d, J = 11.1, H-11), 7.49 and 7.53 (1Í, two d, J = 8.4, NH-10), 8.55 (1Í, d, J = 7.5, NH-7), 13.01 (1Í,
3 3
br.s, COOH).
1
0-Colchicidyl-DL-norleucine (11). Yield 3.24 g (65%), mp 145–146ꢂÑ, C H N O . PMR spectrum (300 MHz,
2
7 34 2 7
DMSO-d , ꢃ, ppm, J/Hz): 0.86 (3Í, t, J = 7.5, ÑÍ norleucine), 1.22–1.40 (4Í, m, ÑÍ -4, 5 norleucine), 1.86 (3Í, s, NAc),
6
3
2
1
.78–2.22 (5Í, m, H-5ꢄ, 6ꢄ, 6ꢅ, ÑÍ -3 norleucine), 2.50–2.60 (1Í, m, H-5ꢅ), 3.47 and 3.48 (3Í, two s, OCH ), 3.78 (3Í, s,
2
3
OCH ), 3.83 (3Í, s, OCH ), 4.32–4.47 (2Í, m, H-7, 2 norleucine), 6.66 (1Í, d, J = 11.1, H-11), 6.75 (1Í, s, Í-4), 7.15 (1Í,
3
3
s, Í-8), 7.18 (1Í, d, J = 11.1, H-11), 7.52 and 7.55 (1Í, two d, J = 8.1, NH-10), 8.59 (1Í, d, J = 7.5, NH-7), 13.20 (1Í, br.s,
COOH).
1
0-Colchicidyl-4-aminobutanoic Acid (12). Yield 3.58 g (76%), mp 182–183ꢂÑ, C H N O . PMR spectrum
25 30 2 7
(
300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.80–1.98 (3Í, m, H-6ꢄ, CH -3 amino-acid), 1.86 (3Í, s, NAc), 1.97–2.24 (2Í, m, H-5ꢄ,
6
2
6
ꢅ), 2.33 (2Í, t, J = 7.5, CH -2 amino-acid), 2.45–2.55 (1Í, m, H-5ꢅ), 3.38 (2Í, q, J = 6.6, CH -4 amino-acid), 3.49 (3Í, s,
2 2
OCH ), 3.79 (3Í, s, OCH ), 3.83 (3Í, s, OCH ), 4.34–4.42 (1Í, m, H-7), 6.69 (1Í, d, J = 11.1, H-11), 6.74 (1Í, s, Í-4), 7.10
3
3
3
(
1Í, s, Í-8), 7.19 (1Í, d, J = 11.1, H-11), 7.69 (1Í, t, J = 6.0, NH-10), 8.52 (1Í, d, J = 7.5, NH-7), 12.08 (1Í, br.s, COOH).
0-Colchicidyl-6-aminohexanoic Acid (13). Yield 3.56 g (72%), mp 155–156ꢂÑ, C H N O . PMR spectrum
1
2
7 34 2 7
(
300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.35–1.40 (2Í, m, CH -4 amino-acid), 1.52–1.66 (4Í, m, CH -3, 5 amino-acid),
6 2 2
1
.80–1.92 (1Í, m, H-6ꢄ), 1.85 (3Í, s, NAc), 1.97–2.22 (2Í, m, H-5ꢄ, 6ꢅ), 2.22 (2Í, t, J = 7.5, CH -2 amino-acid), 2.45–2.55
2
(
1Í, m, H-5ꢅ), 3.35 (2Í, q, J = 6.6, CH -6 amino-acid), 3.47 (3Í, s, OCH ), 3.77 (3Í, s, OCH ), 3.82 (3Í, s, OCH ),
2 3 3 3
4
.30–4.44 (1Í, m, H-7), 6.67 (1Í, d, J = 11.1, H-11), 6.74 (1Í, s, Í-4), 7.08 (1Í, s, Í-8), 7.19 (1Í, d, J = 11.1, H-11), 7.61
(
1Í, t, J = 6.0, NH-10), 8.54 (1Í, d, J = 7.5, NH-7), 11.98 (1Í, br.s, COOH).
0-Colchicidyl-1-(aminomethyl)cyclohexaneacetic Acid (14). Yield 4.03 ã (75%), mp 161–162ꢂÑ, C H N O .
1
3
0 38 2 7
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.26–1.58 (10Í, m, cyclohexane amino-acid protons), 1.80–1.91 (1Í,
6
m, H-6ꢄ), 1.85 (3Í, s, NAc), 1.97–2.23 (2Í, m, H-5ꢄ, 6ꢅ), 2.32 (2Í, s, CH -2 amino-acid), 2.45–2.55 (1Í, m, H-5ꢅ), 3.44
2
(
(
2Í, t, J = 6.6, CH -4 amino-acid), 3.48 (3Í, s, OCH ), 3.78 (3Í, s, OCH ), 3.82 (3Í, s, OCH ), 4.29–4.44 (1Í, m, H-7), 6.74
2 3 3 3
1Í, s, Í-4), 6.83 (1Í, d, J = 11.1, H-11), 7.12 (1Í, s, Í-8), 7.19 (1Í, d, J = 11.1, H-11), 7.61 (1Í, t, J = 6.3, NH-10), 8.54 (1Í,
d, J = 7.5, NH-7), 12.06 (1Í, br.s, COOH).
1
140

Colchicein (15). Mp 174–175ꢂÑ (lit. 150ꢂÑ [8], 169–172ꢂÑ [10], 177–178ꢂÑ [11], 178–180ꢂÑ [12]), C H NO .
2
1
32
6
PMR spectrum (300 MHz, DMSO-d , ꢃ, ppm, J/Hz): 1.84–1.99 (1Í, m, H-6ꢄ), 1.87 (3Í, s, NAc), 2.04–2.22 (2Í, m, H-5ꢄ,
6
6
ꢅ), 2.54–2.62 (1Í, m, H-5ꢅ), 3.52 (3Í, s, OCH ), 3.79 (3Í, s, OCH ), 3.84 (3Í, s, OCH ), 4.30–4.40 (1Í, m, H-7), 6.80
3 3 3
(
1Í, s, Í-4), 7.16 (1Í, d, J = 12.0, H-11), 7.32 (1Í, s, Í-8), 7.34 (1Í, d, J = 12.0, H-11), 8.63 (1Í, d, J = 6.9, NH-7).
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