Synthesis of chiral macrocycles: I. Synthesis and study of cyclo (N α-dinicotinoyl)pentapeptide candidates

Article abstract of DOI:10.1134/S1070363215050278

A series of linear tetrapeptides and macrocyclic pentapeptides has been synthesized starting with N,N-bis(1-carboxy-2-substituted)-3,5-diaminocarbonyl)pyridine and N,N-bis(1-hydrazonyl-2-substituted)-3,5-diaminocarbonyl)pyridine. Structures of newly synth

Full text of DOI:10.1134/S1070363215050278

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 5, pp. 1161–1166. © Pleiades Publishing, Ltd., 2015.
Synthesis of Chiral Macrocycles: I. Synthesis and Study
of Cyclo (Nα-Dinicotinoyl)pentapeptide Candidates1
Abd El-Galil E. Amra,b, Osama I. Abd El-Salamb, and Mohamed A. Al-Omara
a Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy,
King Saud University, Riyadh, 11451 Saudi Arabia
b Applied Organic Chemistry Department, National Research Center, Cairo, Dokki, 1262, Egypt
e-mail: aeamr1963@yahoo.com
Received February 20, 2015
Abstract—A series of linear tetrapeptides and macrocyclic pentapeptides has been synthesized starting with
N,N-bis(1-carboxy-2-substituted)-3,5-diaminocarbonyl)pyridine and N,N-bis(1-hydrazonyl-2-substituted)-3,5-
1
diaminocarbonyl)pyridine. Structures of newly synthesized compounds were elucidated by IR, H and 13C
NMR, and MS spectral data and elemental analysis.
Keywords: synthesis, amino acids, 3,5-bis(tetrapeptide)pyridine, macrocyclic pentapeptide
DOI: 10.1134/S1070363215050278
In the earlier publications [1–6] we presented
synthesis of new macrocyclic peptide derivatives based
on pyridinedicarboxylic acids and their biological
activity. Synthesis and complexing ability of azacrown
compounds have been the subject of intensive study
[7–13]. Synthesis and chemical modification of existing
antibacterial agents is important because of the
emergence of multidrug-resistant bacteria [14]. Peptides
rarely function well as drugs because of their low
bioavailability and rapid degradation within cells [15].
in methanol gave the corresponding acid hydrazide
derivative VII (Scheme 2). H NMR spectrum of the
1
product V contained the singlet (6H) at δ = 3.64 ppm
(ester-CH3). IR spectra of the compound VI demon-
strated absence of ν(C=O, ester) and presence of the
1
band at 1726 cm–1 (C=O, acid). H NMR spectrum of
VI demonstrated no singlet δ = 3.64 ppm (6H) (ester-
CH3), and appearance of the singlet δ = 11.74 ppm
(2H) for carboxylic OH exchangeable with D2O.
Cyclization of tetrapeptide acid VI or tetrapeptide
bis-hydrazide VII with L-ornithine methyl ester or L-
lysine methyl ester by different methods afforded the
corresponding cyclic pentapeptide esters VIII and IX
respectively. Tetrapeptides VI and VII were cyclized
with aliphatic diamines by different methods to afford
the corresponding cyclo-(Nα-dinicotinoyl)-bis[L-leu-L-
phenylanyl]aliphatic diamines (Xa, Xb) respectively
In the current study we report synthetic approach to
several linear tetrapeptide and macrocyclic penta-
peptide derivatives based on N,N-bis[1-carboxy-2-(p-
hydroxybenzyl)]-3,5-(diamino-carbonyl)pyridine (III)
and hydrazide IV synthesized from the corresponding
ester II [16] (Scheme 1).
Synthesis of Nα-dipicolinoyl-bis[dipeptide methyl
ester] derivative (V) was based on the dipeptide acid
III and dipeptide hydrazide IV. Treatment of L-
phenylalanine methyl ester hydrochloride with di-
peptide acid III (Mixed anhydride method) or
dipeptide acid hydrazide (III) (Azide method) afforded
the corresponding Nα-dinicotinoyl-bis[dipeptide methyl
ester] derivative (V). The latter was hydrolyzed with
NaOH in methanol to afford the corresponding Nα-
dinicotinoyl-bis[dipeptide acid] derivative (VI).
Hydrazinolysis of compound V with hydrazine hydrate
1
(Scheme 3). IR and H NMR spectra of VIII and IX
demonstrated the presence of the ester group registered
at 1744 and 1748 cm–1 ν(C=O) and signals at δ = 3.58
and 3.62 ppm (ester-CH3). IR spectra of
X
demonstrated absence of ν(C=O, acid) in VI and
absence of ν(NH2, hydrazide) in VII. 1H NMR
spectrum revealed disappearance of the singlet at δ =
11.74 ppm (2H) for the carboxylic protons in VI.
EXPERIMENTAL
Melting points were determined in open glass
capillary tubes with an Electro Thermal Digital
1 The text was submitted by the authors in English.
1161

1162
ABD EL-GALIL E. AMR et al.
Scheme 1. Synthetic approach to starting compounds III and IV [16].
N
R1
.
O
O
Cl H2N
*
N
R1
O
NH
HN
O
R1
O
COOMe
*
*
TEA
O
O
O
Cl
Cl
CH3
CH3
I
II
.
EtOH
NH2NH2 H2O
1 N NaOH
N
N
O
O
O
O
R1
NH
HN
R1
O
R1
NH
HN
R1
O
*
*
*
*
O
O
H
O
H
O
O
O
NH2
NH2
IV
III
R1 = CH2CH(CH3)2.
melting point apparatus (IA9100). HCN microanalysis
was carried out with Microanalytical Unit, NRC. IR
spectra (KBr) were recorded on a Nexus 670 FTIR
from ethanol/ether to give the corresponding title
compound ester derivatives V.
Method B (azide method). The cold mixture (–5°C)
of dihydrazide IV (1 mmol), 5 N hydrochloric acid
(1.2 mL), glacial acetic acid (2.4 mL) and water
(10 mL) was stirred for 10 min followed by addition of
aqueous sodium nitrite (0.138 g, 2 mmol in 6 mL of
water) in one portion and the mixture stirred for
30 min. The synthesized azide was extracted with
dichloromethane (120 mL), washed with cold water,
3% aqueous sodium bicarbonate followed by cold
water, and dried over anhydrous sodium sulphate. The
azide solution was added in one portion to cold
solution (−5°C) of L-phenyl alanine methyl ester
(2 mmol) in dry dichloromethane (25 mL). The
reaction mixture was stirred at the same temperature
for 3 h, then overnight at room temperature, washed
with 1 N hydrochloric acid, 1 N aqueous sodium
bicarbonate, water and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced
pressure to give the corresponding dimethyl ester V
(mp, TLC). Yield 92% [A], 62% [B], mp 186–188°C.
IR spectrum, ν, cm–1: 3370 (NH), 3087 (CH-Ar), 2968
(CH-aliph.), 1755 (C=O, ester), 1656, 1538, 1255
1
Nicolet, Fourier Transform spectrometer. H and 13C
NMR spectra were recorded in DMSO-d6 by a Jeol
500 MHz spectrometer. Mass spectra were recorded on
a MAT Finnigan SSQ 7000 spectrometer using the
electron impact technique (EI). Analytical TLC was
performed on silica gel aluminum sheets, 60 F254
(E. Merck).
Nα-Dinicotinoyl-bis[L-leucyl-L-phenylalanine
methyl ester] (V). Method A (mixed anhydride). To a
suspension of diacid III (1 mmol) in dichloromethane
(25 mL, –20°C) containing triethylamine (0.2 g,
2 mmol), ethyl chloroformate (22 g, 2 mmol) was
added upon stirring. The reaction mixture was stirred
for 20 min and then L-phenylalanine methyl ester
(2 mmol) was added. The reaction mixture was stirred
at (–20°C) for 6 hrs and then overnight at room
temperature. The resulting mixture was washed with
water, 1N hydrochloric acid, 1 N sodium bicarbonate
and water then dried over anhydrous calcium chloride.
The solvent was evaporated under reduced pressure
and the crude product was purified by recrystallization
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SYNTHESIS OF CHIRAL MACROCYCLES: I.
1163
Scheme 2. Synthetic approach to compounds V, VI, and VII.
R2
COOMe
*
N
.
NH2 HCl
O
O
III
Mixed anhydride method
R1
NH
NH
HN
HN
O
R1
R2
COOMe
*
O
R2
O
O
*
*
.
R2
O
NH2 HCl
IV
O
Azide method
CH3
CH3
V
.
MeOH
NH2NH2 H2O
1 N NaOH
MeOH
N
N
O
O
O
O
R1
NH
NH
HN
HN
R1
R1
NH
NH
HN
R1
O
R2
O
O
O
R2
O
HN
*
O
*
*
*
R2
O
R2
O
O
H
O
H
O
O
NH2
NH2
VI
VII
R1 = CH2CH(CH3)2; R2 = CH2Ph.
(C=O, amide I, II and III). 1H NMR spectrum (DMSO-
d6), δH, ppm:1.02–0.92 m (12H, 4CH3), 1.68–1.72 m
(4H, 2CH2), 2.30–2.35 m (2H, 2CH), 3.36 d (4H,
2CH2), 3.64 s (6H, 2OCH3), 4.18–4.25 m (2H, 2CH),
4.56–4.65 m (2H, 2CH), 6.98–7.45 m (10H, 2Ph-H),
8.40 s, 9.01 s (3H, pyr-H) and 8.65 s, 8.85 s (4H, 4NH,
exchangeable with D2O). 13C NMR spectrum (DMSO-
d6), δC, ppm: 17.54, 18.65 (4C, 4CH3), 23.75 (2C,
2CH), 40.93 (2C, 2CH2), 42.14 (2C, 2CH2), 52.56,
52.82 (4C, 4CH), 55.65 (2C, 2OCH3), 124.15, 128.35,
129.45, 138.62 (12C, 2Ph), 131.64, 140.08, 152.16
(5C, pyr-C), 163.74, 168.95 (4C, 4CO-amide), 172.45
(2C, 2CO-ester). Mass spectrum: m/z 716 [M]+. Found,
%: C 65.32; H 6.80; N 9.70. C39H49N5O8. Calculated,
%: C 65.44; H 6.90; N 9.78.
same temperature then for 3 h at room temperature.
The solvent was distilled off under reduced pressure
and the remaining aqueous solution was cooled and
acidified with 1 N hydrochloric acid to pH ca 3. The
obtained solid was filtered off, washed with water,
dried and recrystallized from ethanol/water to give the
corresponding tetrapeptide diacid (VI). Yield 90%, mp
232–234°C. IR spectrum, ν, cm–1: 4560–3378 (OH,
NH), 3085 (CH-Ar), 2972 (CH-aliph.), 1726 (C=O,
1
acid), 1655, 1534, 1256 (C=O, amide I, II and III). H
NMR spectrum (DMSO-d6), δH, ppm: 0.96-0.82 m
(12H, 4CH3), 1.69-1.70 m (4H, 2CH2), 2.14–2.32 m
(2H, 2CH), 3.40 d (4H, 2CH2), 4.24–4.28 m (2H,
2CH), 4.36–4.52 m (2H, 2CH), 7.00–7.42 m (10H,
2Ph-H), 8.45, 9.06 m (3H, pyr-H), 8.65 s, 8.82 s (4H,
4NH, exchangeable with D2O), 11.74 s (2H, 2OH,
exchangeable with D2O). 13C NMR spectrum (DMSO-
d6), δC, ppm: 17.95, 18.62 (4C, 4CH3), 33.70 (2C,
2CH), 39.85 (2C, 2CH2), 41.96 (2C, 2CH2), 52.55,
53.10 (4C, 4CH), 124.22, 128.25, 129.42, 138.65
(12C, 2Ph-C), 131.55, 140.12, 152.15 (5C, pyr-C),
Nα-Dinicotinoyl-bis[L-leucyl-L-phenylalanine]
derivative (VI). To a stirred cold methanol solution
(–5°C, 20 mL) of the corresponding tetrapeptide ester
(V) (1 mmol), NaOH (1 N, 25 mL) was gradually
added. The reaction mixture was stirred for 2 h at the
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

1164
ABD EL-GALIL E. AMR et al.
Scheme 3. Synthetic approach to compounds VIII, IX, Xa, and Xb.
N
O
O
NH2
*
NH2
NH2
NH2
R1
NH
NH
NH
HN
HN
R1
MeOOC
*
n
(
)
n
(
)
COOMe
*
*
O
R2
O
O
Mixed anhydride method
[A]
*
*
Azide method
[B]
R2
O
HN
*
( )n
COOMe
VIII, n = 1
IX, n = 2
N
N
O
O
O
O
R1
NH
NH
HN
HN
R1
R1
NH
HN
R1
*
*
*
*
*
*
O
R2
O
O
O
R2
O
NH
HN
O
O
*
*
R2
O
R2
O
O
H
O
H
O
N
NH2
NH2
O
O
VI
VII
R1
NH
HN
R1
*
*
*
Azide method
[B]
Mixed anhydride method
[A]
O
R2
O
NH
NH
HN
HN
O
*
R2
O
NH2
NH2
( )n
Xa, Xb
NH2
NH2
(
)
n
(
)
n
R1 = CH2CH(CH3)2, R2 = CH2Ph.
164.08, 169.12 (4C, 4CO-amide), 171.45 (2C, 2CO-
acid). Mass spectrum: m/z 688 [M]+. Found, %: C
64.50; H 6.50; N 10.10. C37H45N5O8. Calculated, %: C
64.61; H 6.59; N 10.18.
with ether, filtered off and recrystallized from ethanol/
ether to give the corresponding title compound VII.
Yield 90%, mp 250–252°C. IR spectrum, ν, cm–1:
3460–3350 br (NH2, NH), 3076 (CH-Ar), 2985 (CH-
aliph.), 1654, 1532, 1255 (C=O, amide I, II and III). 1H
NMR spectrum (DMSO-d6), δH, ppm: 0.98–0.86 m
(12H, 4CH3), 1.67–1.74 m (4H, 2CH2), 2.17-2.26 m
(2H, 2CH), 3.40 d (4H, 2CH2), 4.05 br.s (4H, 2NH2,
exchangeable with D2O), 4.24–4.32 m (2H, 2CH),
4.54–4.68 m (2H, 2CH), 6.99–7.45 m (10H, 2Ph-H),
8.36, 9.00 m (3H, pyr-H), 8.65 s, 8.78 s, 9.16 s (6H,
6NH, exchangeable with D2O). 13C NMR spectrum
Nα-Dinicotinoyl-bis[L-leucyl-L-phenylalanine]
hydrazide (VII). To a solution of Nα-dinicotinoyl-bis-
[L-leucyl-L-phenylalaninyl]methyl ester (V) (1 mmol)
in methanol (20 mL), anhydrous hydrazine hydrate
(0.35 mL, 10 mmol) was added. The reaction mixture
was refluxed for 3 h, the solvent was evaporated under
reduced pressure, thus obtained residue was triturated
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SYNTHESIS OF CHIRAL MACROCYCLES: I.
1165
(DMSO-d6), δC, ppm: 17.35, 18.56 (4C, 4CH3), 33.74
(2C, 2CH), 40.05 (2C, 2CH2), 42.25 (2C, CH2), 52.43,
53.03 (4C, 4CH), 124.13, 128.21, 129.37, 138.67
(12C, 2Ph-C), 131.58, 140.10, 152.10 (5C, pyr-C),
163.73, 169.02 (4C, 4CO-amide), 170.43 (2C, 2CO-
hydrazide). Mass spectrum: m/z 716 [M]+. Found, %:
C 62.00; H 6.78; N 17.53. C37H49N9O6. Calculated, %:
C 62.08; H 6.90; N 17.61.
[B], mp 192–194°C. IR spectrum, ν, cm–1: 3375 (NH),
3072 (CH-Ar), 2968 (CH-aliph.), 1744 (C=O, ester),
1
1654, 1537, 1256 (C=O, amide I, II and III). H NMR
spectrum (DMSO-d6), δH, ppm: 0.80–1.90 m (12H,
4CH3), 1.24–1.46 m (4H, 2CH2), 1.60–1.75 m (4H,
2CH2), 2.30–2.35 m (2H, 2CH), 3.00–3.20 m (2H,
CH2), 3.36 d (4H, 2CH2), 3.58 s (3H, OCH3), 3.90–
4.05 m (4H, 4CH), 4.38–4.44 m (1H, CH), 7.12–7.30
m (10H, 2Ph-H), 8.42 s, 9.05 s (3H, pyr-H), 8.88 s,
Cyclic pentapeptide methyl esters VIII and IX.
Method A (mixed anhydride method). Ethyl chloro-
formate (0.2 mL, 2 mmol) was added to a stirred cold
(–15°C) dichloromethane solution (20 mL) of the cor-
responding Nα-dinicotinoyl-bis[dipeptide] VI (1 mmol),
containing triethylamine (2 mmol). The reaction
mixture was stirred for additional 20 min then free L-
ornithine or L-lysine methyl ester (1 mmol) in di-
chloromethane solution (20 mL, –15°C) was added.
Stirring was maintained for 3 h at –15°C then for 12 h
at room temperature. The reaction mixture was washed
with water, 1 N sodium bicarbonate, 1 N potassium
hydrogen sulfate and water then dried over anhydrous
calcium chloride. The solvent was evaporated under
reduced pressure to dryness and the obtained oily
residue was solidified by trituration with dry ether–
n-hexane mixture. The crude product was purified by
preparative TLC using methanol–benzene eluent (1 : 9
by volume) to give the corresponding cyclic penta-
peptide methyl esters VIII and IX respectively.
13
8.96 s, 9.22 s (6H, 6NH, exchangeable with D2O). C
NMR spectrum (DMSO-d6), δC, ppm: 17.65, 18.97
(4C, 4CH3), 28.30, 30.35, 38.00 (3C, 4CH2), 23.85
(2C, 2CH), 41.99, 42.05 (4C, 4CH2), 52.36, 52.80 (4C,
4CH), 54.48 (1C, CH3-ester), 60.50 (1C, CH-ester),
124.32, 128.30, 129.42, 138.74 (12C, 2Ph-C), 131.48,
140.10, 152.15 (5C, pyr-C), 163.81, 169.15, 170.64
(6C, 6CO, amide), 173.89 (1C, CO-ester). Mass
spectrum: m/z 798 [M]+. Found, %: C 64.62; H 6.84; N
12.20. C43H55N7O8. Calculated, %: C 64.72; H 6.95; N
12.29.
Cyclo-(Nα-dinicotinoyl)bis[L-leucyl-L-phenyl-
alaninyl]-L-lysine (IX). Yield 78% [A], 58% [B], mp
186–188°C. IR spectrum, ν, cm–1: 3365 (NH), 3082
(CH-Ar), 2977 (CH-aliph.), 1748 (C=O, ester), 1656,
1
1533, 1253 (C=O, amide I, II and III). H NMR
spectrum (DMSO-d6), δH, ppm:0.95–0.88 m (12H,
4CH3), 1.23–1.45 m (4H, 2CH2), 1.61–1.76 m (4H,
2CH2), 2.28–2.36 m (2H, 2CH), 3.02–3.22 m (4H,
2CH2), 3.35 d (4H, 2CH2), 3.62 s (3H, OCH3), 3.91–
4.04 m (4H, 4CH), 4.38–4.46 m (1H, CH), 7.08–7.45
m (10H, 2Ph-H), 8.32 s, 9.01 s (3H, pyr-H), 8.85 s,
Method B (azide method). The cold mixture (–15°C)
of dihydrazide derivative (VII) (1 mmol) in
hydrochloric acid (6 N, 2 mL) and glacial acetic acid
(1 mL) was stirred for 10 min followed by addition of
aqueous solution of sodium nitrite (5 M, 2 mL).
Stirring was maintained for 30 min. at the same
temperature, after which the reaction mixture was
extracted with ether (60 mL), washed with cold water,
5% sodium bicarbonate and then dried over anhydrous
sodium sulfate. Cold ethereal azide solution (–15°C)
was added to free L-ornithine or L-lysine methyl ester
(1 mmol). Stirring was maintained for 5 h at the same
temperature then for 20 h at room temperature. The
reaction mixture was washed with water, 5% potas-
sium hydrogen sulfate and water then dried over
anhydrous sodium sulfate. Ether was evaporated to
dryness and thus obtained oily residue was solidified
by trituration with dry ether–n-hexane mixture to give
the corresponding cyclic pentapeptide methyl esters
VIII and IX, respectively (mp, TLC).
13
8.97 s, 9.18 s (6H, 6NH, exchangeable with D2O). C
NMR spectrum (DMSO-d6), δC, ppm: 17.64, 18.96
(4C, CH3), 22.57, 28.32, 30.31, 38.02 (4C, 4CH2),
23.82 (2C, 2CH), 41.96 (2C, 2CH2), 42.15 (2C, 2CH2),
52.40, 52.85 (4C, 4CH), 54.43 (1C, OCH3), 60.52 (1C,
CH-ester), 124.35, 128.32, 129.41, 138.77 (12C, 2Ph-C),
131.74, 140.12, 151.98 (5C, pyr-C), 163.75, 169.32
170.68 (6C, 6CO, amide), 173.85 (1C, CO, ester).
Mass spectrum: m/z 812 [M]+. Found, %: C 65.00; H
7.00; N 12.00. C44H57N7O8. Calculated, %: C 65.09; H
7.08; N 12.08.
Synthesis of cyclo-(Nα-dinicotinoyl)bis[L-Leucyl-
L-phenylalaninyl]aliphatic diamines (Xa, Xb).
Method A (mixed anhydride method). To a suspension
of diacid VI (1 mmol) in cold and stirred dichloro-
methane (25 mL, –20°C) containing triethylamine
(0.2 g, 2 mmol), ethyl chloroformate (22 g, 2 mmol)
was added. Stirring was continued for 20 min, then
either 1,4-butane diamine or 1,6-hexane diamine
Cyclo-(Nα-dinicotinoyl)bis[L-Leucyl-L-phenyl-
alaninyl]-L-ornithine (VIII). Yield 72% [A], 55%
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ABD EL-GALIL E. AMR et al.
(1 mmol) was added. The reaction mixture was stirred
at (–20°C) for 6 hrs and then overnight at room
temperature. The resulting mixture was washed with
water, 1 N hydrochloric acid, 1 N sodium bicarbonate
and water then dried over anhydrous calcium chloride.
The solvent was evaporated under reduced pressure,
and the crude product was purified by crystallization
from ethanol to give the corresponding cyclic peptides
Xa, Xb, respectively.
2CH2), 2.28–2.36 m (2H, 2CH), 3.42 d (4H, 2CH2),
4.10–4.22 m (4H, 4CH), 6.98–7.46 m (10H, 2Ph-H),
8.40 and 9.02 (2s, 3H, pyridyl-H), 8.74 s, 8.95 s, 9.18 s
(6H, 6NH, exchangeable with D2O). Mass spectrum:
m/z 768 [M]+. Found, %: C 67.16; H 7.40; N 12.70.
C43H57N7O6. Calculated, %: C 67.25; H 7.48; N 12.77.
ACKNOWLEDGMENTS
The authors extend their sincere appreciation to the
Deanship of Scientific Research at King Saud
University for its funding this research through the
Research Group project no. RGP-172.
Method B (azide method). An aqueous solution of
sodium nitrite (10%, 0.13 g, 2 mmol) was added to cold
(–5°C) stirred solution of dihydrazide (VII) (1 mmol)
in 5 N HCl (3 mL) and acetic acid (3 mL). Stirring of
the mixture was continued for 30 min followed by
extraction with ether and washing with water, NaHCO3,
and water, then dried over anhydrous sodium sulfate.
Cold ether solution (–5°C) was added to cold (–5°C)
dichloromethane solution of either 1,4-butanediamine
or 1,6-hexanediamine (1 mmol, 10 mL dichloro-
methane). Stirring of cold mixture was lasted for 5 h
and at room temperature for 2 hrs. The reaction
mixture was washed with 1 N hydrochloric acid, water
and dried over anhydrous sodium sulfate. Evaporation
of the solvent afforded crude products Xa, Xb, that
upon preparative TLC were determined to be identical
with those obtained via the mixed anhydride method.
REFERENCES
1. Amr, A.E., Mohamed, A.M., and Ibrahim, A.A.,
Z. Naturforsch. B, 2003, vol. 58, p. 861.
2. Amr, A.E., Z. Naturforsch. B, 2005, vol. 60, p. 990.
3. Abou-Ghalia, M.H., Amr, A.E., and Abdalah, M.M.,
Z. Naturforsch. B, 2003, vol. 58, p. 903.
4. Abu-Ghalia, M.H., Abd El-Hamid, M., Zweel, M.A.,
Amr, A.E., and Moafi, S.A., Z. Naturforsch. B, 2012,
vol. 67, p. 806.
5. Amr, A.E., Abo-Ghalia, M.H., and Abdalah, M.M.,
Z. Naturforsch. B, 2006, vol. 61, p. 1335.
6. Amr, A.E., Abo-Ghalia, M.H., and Abdalah, M.M.,
Arch. Pharm., 2007, vol. 340, p. 304.
Cyclo-(Nα-dinicotinoyl)bis[L-Leucyl-L-phenyl-
alaninyl]-1,4-butanediamine (Xa). Yield 82% [A],
54% [B], mp 188–190°C. IR spectrum, ν, cm–1: 3365
(NH), 3058 (CH-Ar), 2975 (CH-aliph.), 1660, 1530,
7. Krakowiak, K.E., Bradshaw, J.S., and Zamecka-
Krakowiak, D.J., Chem. Rev., 1989, vol. 89, p. 929.
8. Bradshaw, J.S., Krakowiak, K.E., and Izatt, R.M.,
Tetrahedron, 1992, vol. 48, p. 4475.
1
9. Bradshaw, J.S., Krakowiak, K.E., and Izatt, R.M., The
Chemistry of Heterocyclic Compounds, Taylor, E.C.,
Ed., New York: John Wiley & Sons, 1993, vol. 51,
pp. 1–885.
10. Izatt, R.M., Pawlak, K., Bradshaw, J.S., and Bruening, R.L.,
Chem. Rev., 1991, vol. 91, p. 1721.
11. Izatt, R.M., Pawlak, K., Bradshaw, J.S., and Bruening, R.L.,
Chem. Rev., 1995, vol. 95, p. 2529.
12. Izatt, R.M., Pawlak, K., Bradshaw, J.S., Bruening, R.L.,
and Tarbet, B.J., Chem. Rev., 1992, vol. 92, p. 1261.
13. Elwahy, A.H.M., J. Heterocycl. Chem., 2003, vol. 40,
1246 (C=O, amide I, II and III). H NMR spectrum
(DMSO-d6), δH, ppm: 1.05–0.85 m (12H, 4CH3), 1.22–
1.35 m (4H, 2CH2), 1.38–1.42 m (4H, 2CH2), 1.62–
1.74 m (4H, 2CH2), 2.28–2.36 m (2H, 2CH), 3.35 d
(4H, 2CH2Ph), 4.10–4.00 m (4H, 4CH), 6.95–7.42 m
(10H, 2Ph-H), 8.42 s, 9.10 s (3H, pyr-H), 8.78 s, 8.95
s, 9.18 s (6H, 6NH, exchangeable with D2O). Mass
spectrum: m/z 740 [M]+. Found, %: C 66.44; H 7.15; N
13.20. C41H53N7O6. Calculated, %: C 66.55; H 7.22; N
13.25.
Cyclo-(Nα-dinicotinoyl)bis[L-Leucyl-L-phenyl-
alaninyl]-1,6-hexanediamine (Xb). Yield 86% [A],
55% [B], mp 204–206°C. IR spectrum, ν, cm–1: 3358
(NH, str.), 3085 (CH-Ar), 2966 (CH-aliph.), 1662,
p. 1.
14. Chu, T.D.W., Plattner, J.J., and Kotz, L., J. Med. Chem.,
1996, vol. 39, p. 3853.
15. Hirschmann, R., Smith, A.B., and Sprengeler, P.A., New
Perspectives in Drug Design, New York: Academic,
1995.
1
1532, 1247 (C=O, amide I, II and III). H NMR
spectrum (DMSO-d6), δH, ppm: 1.00–0.80 m (12H,
4CH3), 1.20–1.28 m (4H, 2CH2), 1.30–1.36 m (4H,
2CH2), 1.40–1.48 m (4H, 2CH2), 1.70–1.60 m (4H,
16. Khayyat, S. and Amr, A.E., Molecules, 2014, vol. 19,
p. 10698.
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