CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0147-0155
DOI: 10.1055/s-0036-1590963
paper
Copyright with the author

Synthesis of N-Pyridin-2-ylmethyl and N-Quinolin-2-ylmethyl ­Substituted Ethane-1,2-diamines

Yi-Qiu Yang
a  School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, 523808, P. R. of China   Email: yshuang@gdmu.edu.cn
,
Long-Zhi Ke
b  Laboratory of Urology, Guangdong Medical University, ­Zhanjiang 524001, P. R. of China   Email: jianjunliulab@163.com
,
Gui-Fei Wang
a  School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, 523808, P. R. of China   Email: yshuang@gdmu.edu.cn
,
Shu-Yong Song
a  School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, 523808, P. R. of China   Email: yshuang@gdmu.edu.cn
,
Ming-Ning Qiu
b  Laboratory of Urology, Guangdong Medical University, ­Zhanjiang 524001, P. R. of China   Email: jianjunliulab@163.com
,
Jian-Jun Liu*
b  Laboratory of Urology, Guangdong Medical University, ­Zhanjiang 524001, P. R. of China   Email: jianjunliulab@163.com
,
Yun-Sheng Huang*
a  School of Pharmacy, Guangdong Medical University, 1 Xincheng Ave, Songshan Lake Technology Park, Dongguan, 523808, P. R. of China   Email: yshuang@gdmu.edu.cn
› Author Affiliations
This project was financially supported by the National Natural ­Science Funds of China (Grant No. 81272833) and Guangdong Science Foundation (Grant No. 2016A030313676).
Further Information

Publication History

Received: 20 September 2017

Accepted after revision: 26 October 2017

Publication Date:
23 November 2017 (online)

 

§ The authors contributed equally to this work

Abstract

Two N-(2-(bis(pyridin-2-ylmethyl)amino)ethyl)quinoline-2-carboxamides and two N-(2-(bis(quinolin-2-ylmethyl)amino)ethyl)quinoline-2-carboxamides have been synthesized. These structures contain five nitrogen atoms that can form coordinate bonds with metal ions such as Mn(II) and Fe(II). An additional coordinating bond can be formed between the metal ion and a neutral molecule of nitric oxide (NO). The resultant complexes are potentially useful agents for targeted delivery of NO to in vivo biological sites such as tumors, where the NO is released upon irradiation with long-wavelength light. Initial work involving the synthesis and characterization of these analogues is reported here.


#

Nitric oxide (NO) is an endogenously produced signaling molecule that is released into the endothelial cells by the action of nitric oxide synthases (NOSs). It plays important roles in a variety of physiological functions.[1] [2] [3] [4] [5] [6] [7] At low concentrations, NO plays its normal physiological roles as an anti-inflammatory, neurological signaling, and vasodilative agent. At high concentrations, NO is pro-inflammatory and pro-apoptotic.[8] Thus, agents that can enhance the NO concentrations at tumor sites could be used as anticancer ­therapeutics.[9] [10] [11] Recent studies have shown that NO can reverse prostate cancer resistance to chemotherapy and radiotherapy, increase tumor response to anticancer drugs, and promote cancer cell death.[12–17] NO can prohibit prostate cancer cells from entering interstitial tissue and inhibit cancer cell invasion and transmission.[18,19] Many NO delivery compounds, both organic and inorganic, have been explored as suitable NO donors.[20] [21] [22] NO has been mostly studied in the cardiovascular system and many organic nitrates, such as diazeniumdiolates, S-nitrosothiols, or hybrids of these, have been developed for application to various cardiovascular diseases.[21] These compounds are usually bio­activated in vivo by enzymes to release NO. The more recent discovery of the anticancer activities of NO has increased the interest in developing NO donors that can be delivered into the tumor tissue and release NO by light stimulus and used for photodynamic therapy (PDT) of cancer.[23] [24] Metal nitrosyls have been demonstrated to release NO effectively upon illumination with low-frequency light.[25,26] One compound with the structure of N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide (PaPy3H) has been identified as an effective complexing agent for several metal ions, such as Mn(II), Mn(III), Fe(III), and Ru(III).[27] [28] [29] On replacing the pyridyl-2-carboxamide moiety in PaPy3H with a quinolyl-carboxamide structure, the resultant compound, N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-quinoline-2-carboxamide (PaPy2QH), has a significant redshift on forming the manganese nitrosyl complex due to additional conjugation (Figure [1]). This complex can readily release NO upon illumination by near-infrared (NIR) light of low intensity (<5 mW, 780 nm).[29] A similar redshift was also observed for 1,2-bis(quinaldine-2-carboxamido)-4,5-dimethylbenzene (H2Me2bqb), in which a pyridine-2-carboxylic acid moiety was replaced with a quinolyl-2-carboxic acid group.[26] [30]

In an effort to develop effective NO donors for the treatment of prostate cancer, we selected (PaPy2QH) as the base structure and added moieties that can enable incorporation onto carboxylic group-containing gold-nanoparticles whose surfaces would be further modified with prostate-specific membrane antigens (PSMA-a10) for targeted delivery. Additionally, more conjugational moieties could be added to increase the redshift of the manganese nitrosyl complexes. These NO-Mn(II)-ligand-Au-PSMA nanoparticles could be delivered to the prostate tumor sites with high specificity and thus minimize toxicity in other tissues. Herein, we report the synthesis and characterization of these compounds; their biological evaluation is ongoing and results will be reported elsewhere.

Zoom Image
Figure 1 Representative structures of some metal ion nitrosyl ligands

PaPy2QH has been reported to be an effective manganese nitrosyl chelator and was used as the lead structure for our design studies. In order for the ligand to be attached to carboxyl groups on the surface of nanoparticles, an amino­ethoxy group was selected, attached to the quinoline ring at either the 4- or 6-position due to the availability of the corresponding starting materials. In addition, a N,N-bis(2-quinolyl­methyl)amino moiety was used to replace the N,N-bis(2-pyridylmethyl)amino group with the goal of inducing a redshift in the resultant compound UV absorption. We designed four PaPy3H derivatives (Figure [2]). These analogues can form amide bonds with carboxyl groups and therefore can be incorporated onto gold-nanoparticles whose ­surfaces will be further modified with prostate-specific membrane antigens (PSMA-a10) after forming complexes with manganese(II) and NO (Scheme [1]). According to the published results for PaPy2QH, compounds 11, 18, 12, and 19 formed complexes with Mn(II)-NO likely release NO by NIR light at or above 780 nm wavelength illumination.[29]

Zoom Image
Figure 2 Structures of the newly designed manganese nitrosyl ligands with an aminoethoxy link that is to attach to a carboxylic group on the gold nanoparticles

The chemistry used for the preparation of the 6-amino­ethoxy substituted quinoline-2-carboximide analogues is shown in Scheme [1]. Both 11 and 12 were synthesized in 10 steps from the starting material 6-methoxyquinoline. N-Oxidation of the 6-methoxyquinoline with m-chloroperbenzoic acid (mCPBA) gave 2, which was treated with trimethylsilyl cyanide to afford 3, followed with hydrolysis with concentrated hydrochloride to give 4 in excellent yield, according to reported procedures.[31] [32] Demethylation of 4 with boron tribromide resulted in a low yield and impurities. Treatment of 4 with either aluminum trichloride (refluxing in 1,2-dichloroethane) or sodium dodecane-1-thiolate (up to 140 °C) did not give any desired product.[33] Finally, HBr (48%) was used for this reaction and the demethylated product 5 was successfully obtained in good yield.[34] Analogue 5 was esterified in methanol to give methyl ester 6 and subsequently reacted with BOC-aminoethylbromide to afford intermediate 7, which was then treated with excess ethylenediamine to form 8. It should be noted that 20 mole equivalents of ethylene­diamine are required for the conversion of 7 into 8 in order to avoid the formation of the double amidation product. It is also interesting to note that when N-(2-bromoethyl)phthalimide, instead of BOC-aminoethylbromide, was used to react with 6, methyl 6-(phthalimidoethoxy)quinoline-2-carboxylate was obtained in excellent yield. However, when the 6-phthalimidoethoxy intermediate was used to react with ethylenediamine, a significant amount of impurity (more polar then the expected product) was formed. This is likely due to the cleavage of the phthalimido moiety by ethylenediamine. Reaction of 8 with 2-chloromethylpyridine or 2-chloromethylquinoline gave intermediates 9 and 10, respectively. A 10% excess of 2-chloromethylpyridine or 2-chloromethylquinoline for this reaction was desirable to get the best yields and to avoid the formation of quaternary ammonium by-product. Treatment of 9 and 10 with trifluoro­acetic acid afforded the desired products 11 and 12, respectively, in high yields.

Zoom Image
Scheme 1 Synthesis of 6-aminoethoxy substituted analogues

The 4-aminoethoxy substituted analogues 18 and 19 were synthesized by using very similar chemistry, as shown in Scheme [2]. Both were synthesized in five steps from the starting material 4-hydroxyquinaldic acid, by sequential esterification to give 13, etherification with BOC-aminoethylbromide to give 14, amidation with ethylenediamine to give 15, and reaction either with 2-chloromethylpyridine to give 16 or with 2-chloromethylquinoline to give 17. Finally, treatment of 16 and 17 with trifluoroacetic acid afforded the desired products 18 and 19, respectively, in good overall yields.

Zoom Image
Scheme 2 Synthesis of 4-aminoethoxy substituted analogues

The UV absorbance and fluorescence excitation and emission intensities of these analogues were measured. The spectroscopic wavelengths corresponding to the maximum intensities were recorded and the corresponding absorbance and fluorescence intensity measurements are shown in the Supporting Information (Table S1, Figures S1–6). Analogues 10, 12, 17, and 19 showed the highest intensities in UV absorbance (Figures S1 and S2), likely due to the presence of two additional quinolinyl moieties compared to analogues 9, 11, 16, and 18 that have two pyridinyl substituents. When the analogues were illuminated at their corresponding UV maximum absorbance wavelengths, most of them displayed high fluorescence intensities, with the exception of 16 and 17 (Figure S3 and S4). It is surprising that 18 and 19 displayed extremely high fluorescence intensities and had well over 1000 a.u. (arbitrary units) at both 0.1 μM (Figure S4) and 0.01 μM (data not shown) and still showed close to 200 a.u. even at 0.001 μM (data not shown). The analogues were further illuminated at the corresponding excitation wavelengths as shown in Table S1. Most compounds displayed high fluorescence emission intensities, with the exception of 16 and 17 (Figures S5 and S6). The same phenomenon was observed for 18 and 19, which displayed extremely high fluorescence intensities (Figure S6). The exact reasons for both the low and high fluorescence intensities for these analogues are not clear. Compounds 18 and 19 might be useful as fluorescent ligands for various imaging purposes and thus are worthy of further investigations.

The final products and the novel intermediates were characterized by both 1H NMR and 13C NMR spectroscopy. The assignments of resonances in the 1H NMR spectra in the low-frequency region were relatively straightforward, but became difficult in the aromatic proton region with multiple aromatic moieties within the same molecule, such as in analogues 912 and 1619. On the other hand, their 13C NMR spectra displayed well-defined patterns. Based on distortionless enhancement by polarization transfer (DEPT) spectroscopy, many of the C-13 resonance peaks could be assigned to their corresponding carbon atoms (Table [1]). According to the DEPT 13C NMR spectra, we could readily assign resonances at ~67–71 ppm to the 4- or 6-substituted (C4-2′ or C6-2′) -OCH2- carbon atoms, ~53 ppm to the OCH3 methyl ester carbon atom (analogues 7 and 14), ~37–40 ppm to the -CH2-NHBOC carbon atoms (C4-3′ or C6-3′), ~27.7–28.7 ppm to the three CH3 (C4-8′ or C6-8′) of the BOC group, and ~60–61 ppm to the methylene carbon atom (C2-6′) of N(CH2-pyr or -qui)2, the latter due to its apparently high intensity. Resonances at ~53.1–53.6 ppm could be assigned to the -CH2-N(heteroarylmethyl)2 carbon atom (C2-4′), with the exception of 8 and 15, which do not have bisheteroarylmethyl substituents, and ~40–41 ppm to the methylene carbon atom (C2-3′) of CO-NH-CH2- structure, with the exception of analogue 18 (45.66 ppm due to deshielding effect of the two pyridine moieties). The exact assignments between C2-3′ and C4-3′ or between C2-3′ and C6-3′ were not obvious. Based on the significant downfield shifts of C2-4′ (as well as C2-6′), it is logical to assign the lower field signals to the C2-3′ due to the deshielding effect of three nearby aromatic substituents.

By comparing the 13C spectrum of 11 to that of 9 and the spectrum of 12 to that of 10, we can conveniently assign the resonances at ~164.3 ppm to the carbonyl carbon atom (C2-1′), ~158.3 ppm to C-2, ~148.2 ppm to C-6, ~142.4 ppm to C-9, and ~130.7 ppm to C-10 based on the presence (regular 13C NMR) or absence (DEPT 13C NMR) of the corresponding signals as well as the electron density of the substituted quinoline moiety. Due to the bispyridin-2-ylmethyl or bisquinolin-2-ylmethyl substitution, the signals of the corresponding pyridine or quinoline moieties displayed nearly double intensities and thus could be readily assigned to the corresponding carbon atoms. Thus, we assigned resonances at 159.76 ppm to C-2′′, ~123.0 ppm to C-3′′, ~136.7 ppm to C-4′′, ~122.5 ppm to C-5′′, ~149.2 ppm to C-6′′ for the pyridine-2-methyl substituted analogues (9 and 11) based on the electron density of the substituted pyridine moiety. By the same reasoning, we could assign the C-13 signals for analogues 10 and 12; that is, resonances at ~160.7 ppm to C-2′′, ~121.5 ppm to C-3′′, ~136.6 ppm to C-4′′, ~126.6 ppm to C-5′′, ~128.2 ppm to C-6′′, ~129.0 ppm to C-7′′, ~129.8 ppm to C-8′′, ~147.4 ppm to C-9′′, and ~127.4 ppm to C-10′′. ­Finally, the remaining resonance signals for C-3, -4, -5, -7, and -8 were not clearly defined due to the substituents’ ­effect at the 2- and 6-positions (analogues 712). Based on both the estimated electronic effect of substituents and the electron density of the quinoline moiety, we assigned resonances at ~124 ppm to C-3, ~136.5–136.8 ppm to C-4, ~106.6–106.9 ppm to C-5, ~119.3 ppm to C-7, and ~131 ppm to C-8. Similarly, the C-13 resonance signals for analogues 1619 were assigned and are summarized in Table [1].

Table 1 Assignment of 13C NMR Spectra of Compounds 712 and 1419 a

7

8

9

10

11

12

14

15

16

17

18

19

C-2

158.30

158.31

152.05

162.88

C-3

124.06

123.81

123.97

124.01

124.09

124.10

101.17

98.81

95.50

98.63

95.47

98.70

C-4

136.50

136.74

136.75

136.83

136.78

136.80

151.11

152.15

C-5

106.61

106.82

106.85

106.90

106.78

106.81

122.58

122.67

122.35

122.76

122.31

122.55

C-6

148.20

148.21

128.10

127.36

124.91

127.39

125.51

127.50

C-7

121.63

119.43

119.30

119.29

119.27

119.25

129.93

129.28

129.71

129.23

129.70

129.30

C-8

131.81

131.10

131.02

131.06

131.00

131.03

131.32

131.18

130.29

131.31

130.20

131.26

C-9

142.40

142.42

147.47

147.66

C-10

130.72

130.76

119.61

121.87

C6-2′

67.50

67.43

67.48

67.49

71.29

71.25

C6-3′

39.79

40.82

37.20

37.21

37.20

37.22

C6-8′

28.66

28.67

28.66

28.69

C4-2′

68.61

68.17

61.51

68.47

59.19

71.86

C4-3′

39.60

39.61

37.06

37.34

37.06

37.34

C4-8′

28.68

28.69

27.71

28.69

C2-1′

164.31

164.32

165.01

164.19

C2-3′

52.89

40.88

39.87

39.86

41.33

41.31

53.03

42.15

41.92

39.61

45.66

41.21

C2-4′

39.81

53.17

53.61

53.19

53.63

41.37

53.17

53.49

53.21

53.52

C2-6′

59.97

61.03

59.98

61.04

59.96

61.06

59.97

61.07

C-2′′

159.76

160.69

159.77

160.68

C-3′′

123.05

121.48

123.06

121.49

123.06

121.51

123.07

121.51

C-4′′

136.75

136.62

136.78

136.63

136.80

136.64

136.81

136.64

C-5′′

122.50

126.56

122.53

126.58

122.52

126.56

122.54

126.57

C-6′′

149.19

128.17

149.20

128.18

149.19

128.15

149.20

128.17

C-7′′

129.02

129.01

129.02

129.02

C-8′′

129.83

129.84

129.83

129.84

C-9′′

147.40

147.39

C-10′′

127.39

127.38

a The atom labeling of the analogues is illustrated by analogues 10 and 16 with the 4- or 6-substituted quinoline-2-carbonyl as the parent structure, 2-, 4-, or 6-substituents being labeled by 2-n′, 4-n′ or 6-n′, respectively, and the secondary aromatic substituent (on the N) being labeled by C-n”.

In conclusion, we have synthesized four PaPy2QH derivatives in an attempt to develop ligands that could be used as metal ion nitrosyl complexes for application in prostate cancer treatment. In the first stage of this work, we characterized the final unchelated ligands as well as all the novel intermediates and conducted preliminary spectroscopic studies on the ligands. Most of these compounds displayed excellent fluorescence intensities, with the exception of 16 and 17, which showed low fluorescence excitation and emission intensities. On the other hand, both 18 and 19 showed extremely high excitation and emission intensities, even at very low concentration, making them potentially useful as imaging agents in biological systems and therefore worthy of further investigation. Based on previous studies by several groups, the formation of manganese complexes may significantly enhance their spectroscopic intensity and cause a redshift of their maximum absorption. In the next stage, work will focus on the biological conjugation and in vitro and in vivo measurements.

All reactions were carried out in oven-dried glassware under a N2 atmosphere, unless otherwise stated. All reagents or solvents purchased commercially were used directly without further purification. Reactions were monitored by analytical thin-layer chromatography (TLC) on silica gel F254 glass plates and visualized under UV light (254 and 365 nm). Temperatures were recorded using a regular thermo­meter without correction. Flash column chromatography was performed on silica gel (200–300 mesh). Melting points were measured using the capillary method without correction. 1H NMR spectra were recorded with a Bruker Avance III 400 MHz NMR spectrometer at r.t. Chemical shifts were recorded as parts per million (ppm) downfield to tetramethylsilane (TMS). The following abbreviations are used for multiplicity of NMR signals and descriptions: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; dt, double triplet; dq, double quartet; br. broad; pyr, pyridine moiety; qui, quinoline moiety; N-sub pyr, N-substituted pyridine-2-methyl moiety; N-sub qui, N-substituted quinoline-2 methyl moiety. 13C NMR or DEPT- 13C-NMR) spectra were recorded with a Bruker Avance III 400 MHz NMR spectrometer (100 MHz).


#

6-Hydroxyquinoline-2-carboxylic Acid (5)

6-Hydroxyquinoline-2-carboxylic acid was prepared as described by Sarmiento et al.[31] To a 50 mL reaction bottle was added 6-methoxyquinoline (1.00 g, 6.28 mmol) and 1,2-dichloroethane (10 mL), the mixture stirred until it became a clear solution and then 85% 3-chloro­benzoperoxoic acid (7.53 mmol) in 1,2-dichloroethane (10 mL) was added dropwise. The mixture was stirred at 40 °C for 12 h and then transferred to a separatory funnel, washed with 10% Na2SO3, 10% K2CO3 and saturated brine, and dried over sodium sulfate. The solid was filtered off, solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography, eluting with EtOAc­/MeOH (30:1) to give 2 as a white solid (0.91 g, 82.7% yield, 98.5% purity); mp 106–107 °C (lit.[35] 102–104 °C).

To a 50 mL reaction bottle was added 2 (0.25 g, 1.43 mmol), 1,2-dichloroethane (10 mL), trimethylsilyl cyanide (0.16 g, 1.57 mmol), and dimethylcarbamic chloride (0.15 g, 1.43 mmol). The solution was stirred at 60 °C for 3 h, cooled to r.t., poured into 10% aqueous sodium carbonate, extracted and washed with saturated brine, and dried over sodium sulfate. After filtering, the solvent was removed and the crude product was recrystallized from EtOAc to give 3 as a pale-yellow solid (0.22 g, 84.6% yield, 98.7% purity); mp 174–176 °C (lit.[36] 175–176 °C). 1H NMR (DMSO-d 6): δ = 8.49–8.51 (d, 1 H), 8.02–8.04 (d, 1 H), 7.96–7.98 (d, 1 H), 7.55–7.58 (dd, 1 H), 7.51–7.52 (d, 1 H), 3.95 (s, 3 H).

A solution of 3 (1.50 g, 8.14 mmol) in concentrated hydrochloric acid (20 mL) was heated to reflux for 4 h. The mixture was cooled to r.t. and the yellow solid was filtered, washed with water, and recrystallized from EtOAc to give 6-methoxyquinoline-2 carboxylic acid 4 as a white solid (1.46 g, 88.5% yield, 97.3% purity); mp 183–185 °C; ESI-MS: m/z [M + 1]+ calcd for C11H9NO3: 203.20; found: 204.06.

A solution of 4 (1.00 g, 4.90 mmol) in 48% HBr (20 mL) was heated to reflux for 4 h. The mixture was cooled to r.t. and the solid was filtered and recrystallized from EtOH to give 6-hydroxyquinoline-2-carboxylic acid 5 as a white solid (0.70 g, 84.3% yield, 98.2% purity). 1H NMR (DMSO-d 6): δ = 10.41 (s, 1 H), 8.29–8.31 (d, 1 H), 7.99–8.02 (m, 2 H), 7.41–7.44 (dd, 1 H), 7.22–7.23 (d, 1 H); ESI-MS: m/z [M + 1]+ calcd. for C10H7NO3: 189.17; found: 190.03.


#

6-Hydroxyquinoline-2-carboxylic Acid Methyl Ester (6)

A solution of 5 (5.00 g, 26.43 mmol) and p-toluenesulfonic acid monohydrate (0.10 g, 0.60 mmol) in MeOH (50 mL) was heated to reflux for 6 h. The mixture was concentrated in vacuo and the crude product was recrystallized from EtOAc to afford methyl 6-hydroxyquinoline-2-carboxylate 6 as a white solid (4.20 g, 76.3% yield, 98.8% purity); mp 196–197 °C. 1H NMR (DMSO-d 6): δ = 10.46 (s, 1 H), 8.30–8.32 (d, 1 H), 7.99–8.03 (m, 2 H), 7.41–7.44 (dd, 1 H), 7.23–7.24 (d, 1 H), 3.93 (s, 3 H); ESI-MS: m/z [M + 1]+ calcd. for C11H9NO3: 203.20; found: 204.03; Anal. Calcd (%) for C11H9NO3: C 65.02, H 4.46, N 6.89; found: C 64.88, H 4.37, N 6.74.


#

Methyl 6-{2-[(tert-Butoxycarbonyl)amino]ethoxy}quinoline-2-carboxylate (7)

N-Boc-aminoethylbromide was prepared according to a modified procedure reported by Chauhan et al.[37] A solution of di-tert-butyl dicarbonate (12.60 g, 57.73 mmol), triethylamine (10 mL) and EtOH (40 mL) was added dropwise to a solution of aminoethylbromide hydrochloride (10.00 g, 48.81 mmol) in EtOH (40 mL) at 0 °C under stirring. The mixture was stirred at r.t. overnight, then concentrated in vacuo, water (100 mL) was added, and the mixture extracted with EtOAc (2 × 100 mL). The combined extracts were washed with aq. ammonium, saturated brine, dried over sodium sulfate and filtered. The solvent was removed in vacuo to give N-Boc-aminoethylbromide as a colorless oil (10.5 g) that was used directly in the following reaction without further purification.

To a flask was added 6 (3.00 g, 14.76 mmol), DMF (25 mL), K2CO3 (8.30 g, 59.04 mmol), and N-Boc-aminoethylbromide (6.70 g, 29.52 mmol). The mixture was stirred at 80 °C for 5 h, then cooled to r.t. and poured into water, extracted with EtOAc (3 × 100 mL), washed with saturated brine, and dried over sodium sulfate. After filtering and removal of solvent, the crude product was purified by silica gel chromatography eluting with petroleum ether/EtOAc (1:3) to afford 6-{2-[(tert-butoxycarbonyl)amino]ethoxy}quinoline-2-carboxylic acid methyl ester 7 as a white solid (4.6 g, 86.8% yield, 98.5 % purity); mp113–114 °C. 1H NMR (DMSO-d 6): δ = 8.40–8.42 (d, 1 H), 8.05–8.09 (m, 2 H), 7.48–7.50 (m, 2 H), 7.10–7.13 (t, 1 H), 4.13–4.16 (t, 2 H), 3.94 (s, 3 H), 3.39–3.42 (t, 2 H), 1.39 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 136.50, 131.81, 124.06, 121.63, 106.61, 67.50 (-O-CH2-CH2-NH-), 52.89 (OCH3), 39.79 (-NH-CH2-CH2-O-), 28.66 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C18H22N2O5: 346.38; found: 347.16. Anal. Calcd (%) for C18H22N2O5: C 62.42, H 6.40, N 8.09; found: C 62.35, H 6.28, N 7.91.


#

6-(2-(tert-Butoxycarbonyl)aminoethoxy)-N-(2-aminoethyl)quinoline-2-carboxamide (8)

A solution of 7 (0.92 g, 2.66 mmol), ethylenediamine (3.20 g, 53.20 mmol), and MeOH (20 mL) was stirred at r.t. for 7 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloro­methane (50 mL), washed with water (3 × 50 mL), dried over anhydrous ­sodium sulfate, filtered and solvent removed in vacuo. The crude product was purified by silica gel chromatography, eluting with chloro­form/methanol (20:1) to give 8 as a pale-yellow solid (0.88 g, 88% yield, 97% purity); mp 120–121 °C. 1H NMR (DMSO-d 6): δ = 8.87–8.90 (t, 1 H), 8.39–8.41 (d, 1 H), 8.10–8.12 (d, 1 H), 8.01–8.04 (m, 1 H), 7.48–7.50 (m, 2 H), 7.10–7.13 (t, 1 H), 4.12–4.15 (t, 2 H), 3.41–3.44 (m, 6 H), 2.80–2.83 (t, 2 H), 1.39 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 136.74, 131.10, 123.81, 119.13, 106.82, 67.43 (-O-CH2-CH2-NH-), 40.88 (-NH-CH2-CH2-NH2), 40.82 (-NH-CH2-CH2-O-), 39.81 (-NH-CH2-CH2-NH2), 28.67 (-C(CH3)3); ESI-MS: m/z [M + 2]+ calcd for C19H26N4O4: 374.44; found: 376.20; Anal. Calcd (%) for C19H26N4O4: C 60.95, H 7.00, N 14.96; found: C 61.03, H 6.87, N 14.84.


#

6-[2-(tert-Butoxycarbonyl)aminoethoxy]-N-(2-{[di(pyridin-2-yl)methyl]amino}ethyl)quinoline-2-carboxamide (9)

A solution of 8 (0.61 g, 1.63 mmol), EtOH (10 mL), 10 M NaOH (0.65 mL, 6.52 mmol), and 2-chloromethylpyridine hydrochloride (0.59 g, 3.60 mmol) was stirred at 70 °C for 4 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate and filtered. After removal of solvent, the crude product was purified by silica gel chromatography, eluting with chloroform/methanol (20:1) to afford 9 as a colorless semi-solid (0.77 g, 85% yield, 97.7% purity), 1H NMR (DMSO-d 6): δ = 8.95–8.97 (t, 1 H), 8.47–8.48 (d, 2 H), 8.41–8.43 (d, 1 H), 8.07–8.09 (d, 1 H), 8.04–8.06 (d, 1 H), 7.50–7.60 (m, 6 H), 7.18–7.21 (m, 2 H), 7.10–7.13 (m, 1 H), 4.14–4.17 (t, 2 H), 3.85 (s, 4 H), 3.51–3.54 (m, 2 H), 3.40–3.43 (t, 2 H), 2.73–2.76 (t, 2 H), 1.39 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 149.19 (2Cs, N-sub pyr), 136.75 (2Cs of N-sub pyr + 1C of qui), 131.02 (1C, qui), 123.97 (1C, qui), 123.05 (2Cs, N-sub pyr), 122.50 (2Cs, N-sub pyr), 119.30 (1C, qui), 106.85 (1C, qui), 67.48 (-O-CH2-CH2-NH-), 59.97 (-N(CH2–2-pyr)2), 53.17 (-NH-CH2-CH2-N(CH2–2-pyr)2), 39.87 (-NH-CH2-CH2-N(CH2–2-pyr)2), 37.20 (-NH-CH2-CH2-O-), 28.66 (-C(CH3)3); ESI-MS: m/z [M + 2]+ calcd for C31H36N6O4: 556.67; found: 558.28; Anal. Calcd (%) for C31H36N6O4: C 66.89, H 6.52, N 15.10; found: C 66.74, H 6.36, N 14.89.


#

6-[2-(tert-Butoxycarbonyl)aminoethoxy]-N-(2-{[di(quinolin-2-yl)methyl]amino}ethyl)quinoline-2-carboxamide (10)

A solution of 8 (4.50 g, 12.02 mmol) in EtOH (40 mL), 10 M NaOH (5 mL, 48.08 mmol), and 2-chloromethylquinoline hydrochloride (5.66 g, 26.44 mmol) was stirred at 70 °C for 5 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (100 mL), washed with brine, dried over anhydrous sodium sulfate and filtered. After removal of solvent, the crude product was recrystallized from EtOAc to afford 10 as a white solid (6.87 g, 87.0% yield, 98% purity); mp 145–146 °C. 1H NMR (DMSO-d 6): δ = 8.92–8.94 (t, 1 H), 8.40–8.42 (d, 1 H), 8.11–8.13 (d, 2 H), 8.01–8.06 (m, 2 H), 7.95–7.97 (m, 2 H), 7.80–7.86 (m, 4 H), 7.67–7.70 (m, 2 H), 7.51–7.57 (m, 4 H), 7.11–7.13 (m, 1 H), 4.16–4.19 (t, 2 H), 4.06 (s, 4 H), 3.54–3.57 (t, 2 H), 3.40–3.44 (m, 2 H), 2.83–2.86 (t, 2 H), 1.39 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 136.83 (1C, qui), 136.62 (2Cs, N-sub qui), 131.06 (1C, qui), 129.83 (2Cs, N-sub qui), 129.02 (2Cs, N-sub qui), 128.17 (2Cs, N-sub qui), 126.56 (2Cs, N-sub qui), 124.01 (1C, qui), 121.18 (2Cs, N-sub qui), 119.29 (1C, qui), 106.90 (1C, qui), 67.49 (-O-CH2-CH2-NH-), 61.03 (-NH-CH2-CH2-N(CH2–2-qui)2), 53.61 (-NH-CH2-CH2-N(CH2–2-qui)2), 39.86 (-NH-CH2-CH2-N(CH2–2-qui)2), 37.21 (-NH-CH2-CH2-O-), 28.69 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C39H40N6O4: 656.79; found: 657.30. Anal. Calcd (%) for C39H40N6O4: C 71.32, H 6.14, N 12.80; found: C 70.07, H 5.92, N 12.73.


#

6-(2-Aminoethoxy)-N-(2-{[di(pyridin-2-yl)methyl]amino}ethyl)quinoline-2-carboxamide (11)

A solution of 9 (2.00 g, 3.60 mmol), dichloromethane (5 mL), and trifluoroacetic acid (6 mL, 34.28 mmol) was stirred at r.t. for 8 h. The mixture was concentrated in vacuo and the residue dissolved in dichloromethane (50 mL), washed with 2 M NaOH, saturated brine, dried over anhydrous sodium sulfate and filtered. After removal of solvent, the crude product was purified by silica gel chromatography, eluting with chloroform/methanol (20:1) to give 11 as a white solid (1.64 g, 92.0% yield, 98.2% purity); mp 65–66 °C. 1H NMR (DMSO-d 6): δ = 8.96–8.98 (t, 1 H), 8.47–8.48 (d, 2 H), 8.41–8.43 (d, 1 H), 8.03–8.09 (m, 2 H), 7.55–7.60 (m, 5 H), 7.47–7.48 (d, 1 H), 7.18–7.21 (dd, 2 H), 4.10–4.12 (t, 2 H), 3.86 (s, 4 H), 3.50–3.55 (q, 2 H), 2.97–3.00 (t, 2 H), 2.74–2.77 (t, 2 H), 1.64 (b, 2 H). 13C NMR (DMSO-d 6): δ = 164.31 (C=O), 159.76 (2Cs, N-sub pyr), 158.30 (1C, qui), 149.20 (2Cs, N-sub pyr), 148.20 (1C, qui), 142.40 (1C, qui), 136.78 (2Cs, N-sub pyr), 131.00 (1C, qui), 130.72 (1C, qui), 124.09 (1C, qui), 123.06 (2Cs, N-sub pyr), 122.53 (2Cs, N-sub pyr), 119.27 (1C, qui), 106.78 (1C, qui), 71.29 (-O-CH2-CH2-NH2), 59.98 (-CH2-N(CH2-pyr)2), 53.19 (-NH-CH2-CH2-N(CH2-pyr)2), 41.33 (-NH-CH2-CH2-N(CH2-pyr)2), 37.20 (-O-CH2-CH2-NH2); ESI-MS: m/z [M + 1]+ calcd for C26H28N6O2: 456.55; found: 457.22; Anal. Calcd (%) for C26H28N6O2: C 68.40, H 6.18, N 18.41; found: C 68.25, H 6.03, N 18.33.


#

6-(2-Aminoethoxy)-N-(2-((di(quinolin-2-yl)methyl)amino)ethyl)quinoline-2-carboxamide (12)

A solution of 10 (5.00 g, 7.61 mmol), dichloromethane (25 mL), and trifluoroacetic acid (12 mL, 68.56 mmol) was stirred at r.t. for 8 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (100 mL), washed with 2 M NaOH, saturated brine, dried over anhydrous sodium sulfate and filtered. After removal of solvent, the crude product was recrystallized from EtOAc to give 12 as a white solid (4.0 g, 95.0% yield, 98.0% purity); mp 155–156 °C. 1H NMR (CDCl3): δ = 8.86–8.88 (m, 1 H), 8.20–8.30 (m, 2 H), 8.01–8.04 (m, 3 H), 7.93–7.96 (m, 2 H), 7.83–7.86 (m, 2 H), 7.63–7.70 (m, 4 H), 7.45–7.53 (m, 3 H), 7.18–7.20 (m, 1 H), 4.18–4.21 (t, 2 H), 4.16 (s, 4 H), 3.70–3.71 (b, 2 H), 3.23–3.26 (m, 2 H), 3.00 (br, 2 H), 2.07 (br, 2 H). 13C NMR (DMSO-d 6): δ = 164.32 (C=O), 160.69 (2Cs, N-sub qui), 158.31 (1C, qui), 148.21 (1C, qui), 147.40 (2Cs, N-sub qui), 142.42 (1C, qui), 136.80 (1C, qui), 136.63 (2Cs, N-sub qui), 131.03 (1C, qui), 130.76 (1C, qui), 129.84 (2Cs, N-sub qui), 129.01 (2Cs, N-sub qui), 128.18 (2Cs, N-sub qui), 127.39 (2Cs, N-sub qui), 126.58 (2Cs, N-sub qui), 124.10 (1C, qui), 121.49 (2Cs, N-sub qui), 119.25 (1C, qui), 106.81 (1C, qui), 71.25 (-O-CH2-CH2-NH2), 61.04 (-CH2-N(CH2-qui)2), 53.63 (-CH2-N(CH2-qui)2), 41.31 (-NH-CH2-CH2-N(CH2-qui)2), 37.22 (-O-CH2-CH2-NH2). ESI-MS: m/z [M + 1]+ calcd for C34H32N6O2: 556.67; found: 557.24; Anal. Calcd (%) for C34H32N6O2 H2O: C 71.06, H 5.96, N 14.62; found: C 69.92, H 5.83, N 14.53.


#

Methyl 4-Hydroxyquinoline-2-carboxylate (13)

A solution of 4-hydroxyquinoline-2-carboxylic acid (20.00 g, 96.54 mmol) and 2 drops of concentrated sulfuric acid in MeOH (50 mL) was heated at reflux for 12 h. The mixture was concentrated in vacuo, extracted with EtOAc, washed with saturated Na2CO3, saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the crude product was recrystallized from EtOAc to afford 13 as a white solid (19.0 g, 93.0% yield, 98.1% purity); mp 221–222 °C. 1H NMR (DMSO-d 6): δ = 8.11–8.13 (d, 1 H), 7.99–8.01 (d, 1 H), 7.74–7.78 (t, 1 H), 7.42–7.45 (t, 1 H), 6.76 (s, 1 H), 3.99 (s, 3 H); ESI-MS: m/z [M + 1]+ calcd for C11H9NO3: 203.20; found: 204.06.


#

Methyl 4-{2-[(tert-Butoxycarbonyl)amino]ethoxy}quinoline-2-carboxylate (14)

To a solution of 13 (10.00 g, 49.22 mmol) in DMF (50 mL) was added K2CO3 (27.00 g, 195.3 mmol) and N-Boc-aminoethylbromide (17.00 g, 75.86 mmol). The mixture was stirred at 80°C for 12 h and then cooled to r.t., poured into ice-water, extracted with EtOAc (3 × 100 mL), washed saturated brine and dried over anhydrous sodium sulfate. After filtration and removal of solvent, the crude product was recrystallized from EtOAc to afford 14 as a white solid (14.31 g, 84.0% yield, 98.9 % purity); mp 81–82 °C. 1H NMR (CDCl3): δ = 8.24–8.27 (m, 2 H), 7.77–7.81 (m, 1 H), 7.61–7.65 (m, 1 H), 7.58 (s, 1 H), 5.03 (br, 1 H), 4.35–4.38 (m, 2 H), 4.09 (s, 3 H), 3.74–3.76 (br, 2 H), 1.48 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 131.32, 129.93, 128.10, 122.58, 101.17, 68.61 (-O-CH2-CH2-NH-), 53.13 (OCH3), 39.60 (-NH-CH2-CH2-O-), 28.68 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C18H22N2O5: 346.38; found: 347.17; Anal. Calcd (%) for C18H22N2O5: C 62.42, H 6.40, N 8.09; found: C 62.27, H 6.13, N 7.93.


#

4-[2-(tert-Butoxycarbonyl)aminoethoxy]-N-(2-aminoethyl)quinoline-2-carboxamide (15)

A solution of 14 (14.00 g, 40.42 mmol), ethylenediamine (48.60 g, 808.65 mmol), and MeOH (100 mL) was stirred at r.t. for 6 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (150 mL), washed with water (3 × 100 mL), saturated brine and dried over anhydrous sodium sulfate. After filtration and removal of solvent, the product was recrystallized from dichloromethane to give 15 as a white solid (14.60 g, 96.0% yield, 98.7% purity); mp 137–138 °C. 1H NMR (DMSO-d 6): δ = 8.90–8.93 (t, 1 H), 8.30–8.32 (d, 1 H), 8.05–8.07 (d, 1 H), 7.82–7.86 (m, 1 H), 7.62–7.66 (m, 1 H), 7.55 (s, 1 H), 7.17–7.20 (t, 1 H), 4.29–4.32 (t, 2 H), 3.49–3.51 (m, 2 H), 3.36–3.41 (m, 2 H), 2.77–2.80 (t, 2 H), 1.39 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 131.18, 129.28, 127.36, 122.27, 98.81, 68.47 (-O-CH2-CH2-NH-), 42.15 (-NH-CH2-CH2-NH2), 41.37 (-NH-CH2-CH2-NH2), 39.61 (-NH-CH2-CH2-O-), 28.69 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C19H26N4O4: 375.44; found: 375.20; Anal. Calcd (%) for C19H26N4O4: C 60.95, H 7.00, N 14.96; found: C 60.72, H 6.86, N 14.74.


#

4-[2-(tert-Butoxycarbonyl)aminoethoxy]-N-(2-{[di(pyridin-2-yl)methyl]amino}ethyl)quinoline-2-carboxamide (16)

A solution of 15 (9.00 g, 24.04 mmol), water (40 mL), NaOH (3.80 g, 95.00 mmol), and 2-chloromethylpyridine hydrochloride (8.70 g, 53.04 mmol) was stirred at 70 °C for 6 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (100 mL), washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the crude product was purified by silica gel chromatography, eluting with chloroform/methanol (20:1) to afford 16 as a white solid (10.0 g, 74.7% yield, 98.3% purity); mp 131–133 °C. 1H NMR (CDCl3): δ = 8.95–8.98 (br, 1 H), 8.55–8.58 (m, 2 H), 8.28–8.30 (d, 1 H), 8.09–8.11 (d, 1 H), 7.78–7.82 (m, 1 H), 7.50–7.63 (m, 6 H), 7.09–7.12 (m, 2 H), 5.03 (br, 1 H), 4.35–4.38 (t, 2 H), 3.96 (s, 4 H), 3.74–3.75 (br, 2 H), 3.63–3.67 (m, 2 H), 2.88–2.91 (m, 2 H), 1.48 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 149.19 (2Cs, N-sub pyr), 136.80 (2Cs, N-sub pyr), 130.29 (1C, qui), 129.71 (1C, qui), 124.91 (1C, qui), 123.06 (2Cs, N-sub pyr), 122.52 (2Cs, N-sub pyr), 122.35 (1C, qui), 95.50 (1C, qui), 67.51 (-O-CH2-CH2-NH-), 59.96 (-N(CH2–2-pyr)2), 53.17 (-NH-CH2-CH2-N(CH2–2-pyr)2), 41.92 (-NH-CH2-CH2-N(CH2–2-pyr)2), 37.06 (-NH-CH2-CH2-O-), 27.71 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C31H36N6O4: 556.67; found: 557.30; Anal. Calcd (%) for C31H36N6O4: C 66.89, H 6.52, N 15.10; found: C 66.94, H 6.34, N 14.89.


#

4-[2-(tert-Butoxycarbonyl)aminoethoxy]-N-(2-{[di(quinolin-2-yl)methyl]amino}ethyl)quinoline-2-carboxamide (17)

A solution of 15 (5.33 g, 14.23 mmol), water (20 mL), NaOH (2.30 g, 57.50 mmol), and 2-chloromethylquinoline hydrochloride (6.70 g, 31.30 mmol) was stirred at 70 °C for 6 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (100 mL), washed with saturated brine and dried over anhydrous sodium sulfate. After the removal of the solid and the solvent, the crude material was purified by silica gel column and eluted with ethyl acetate/25% ammonium hydroxide (v/v = 200:1) to afford 17 as a white solid (7.1 g, 76.0% yield, 98.5% purity); mp 78–79 °C. 1H NMR (CDCl3): δ = 8.91 (br, 1 H), 8.31–8.33 (d, 1 H), 8.06–8.10 (m, 3 H), 7.94–7.96 (m, 2 H), 7.81–7.88 (m, 3 H), 7.63–7.69 (m, 6 H), 7.46–7.50 (m, 2 H), 5.05 (br, 1 H), 4.34–4.37 (t, 2 H), 4.16 (s, 4 H), 3.75–3.76 (br, 2 H), 3.68–3.70 (br, 2 H), 2.99–3.01 (t, 2 H), 1.49 (s, 9 H). DEPT-13C (DMSO-d 6): δ = 136.64 (2Cs, N-sub qui), 131.31 (1C, qui), 129.83 (2Cs, N-sub qui), 129.23 (1C, qui), 129.02 (2Cs, N-sub qui), 128.15 (2Cs, N-sub qui), 127.39 (1C, qui), 126.56 (2Cs, N-sub qui), 122.76 (1C, qui), 121.51 (2Cs, N-sub qui), 98.63 (1C, qui), 68.47 (-O-CH2-CH2-NH-), 61.06 (-N(CH2-2-qui)2), 53.49 (-CH2-N(CH2-2-qui)2), 39.61 (-CH2-CH2-N(CH2-2-qui)2), 37.34 (-NH-CH2-CH2-O-), 28.69 (-C(CH3)3); ESI-MS: m/z [M + 1]+ calcd for C39H40N6O4: 656.79; found: 657.29; Anal. Calcd (%) for C39H40N6O4: C 71.32, H 6.14, N 12.80; found: C 71.27, H 5.96, N 12.67.


#

4-(2-Aminoethoxy)-N-(2-((di(pyridin-2-yl)methyl)amino)ethyl)quinoline-2-carboxamide (18)

A solution of 16 (10.00 g, 17.96 mmol), dichloromethane (50 mL), and trifluoroacetic acid (15 mL) was stirred at r.t. for 10 h. The mixture was concentrated in vacuo and the residue was added with dichloromethane (100 mL), washed with 2 N NaOH, saturated brine, and dried over anhydrous sodium sulfate. After removal of the solvent, the crude material was purified by silica gel column and eluted with ethyl acetate/25% ammonium hydroxide (v/v = 200:1) to give 18 as a white solid (7.4 g, 90.0% yield, 98.1 % purity); mp 155–156 °C. 1H NMR (CDCl): δ = 8.92–8.93 (br, 1 H), 8.47–8.49 (m, 2 H), 8.29–8.31 (d, 1 H), 7.92–7.94 (d, 1 H), 7.73–7.77 (m, 1 H), 7.58–7.65 (m, 4 H), 7.51–7.55 (m, 1 H), 7.41–7.44 (m, 1 H), 7.19–7.22 (m, 2 H), 4.89–4.92 (m, 1 H), 3.85 (s, 4 H), 3.67–3.71 (m, 2 H), 3.48–3.52 (m, 2 H), 3.42–3.46 (m, 2 H), 2.71–2.74 (m, 2 H). 13C NMR (DMSO-d 6): δ = 165.01 (C=O), 159.77 (2Cs, N-sub pyr), 152.05 (1C, qui), 151.11 (1C, qui), 149.20 (2Cs, N-sub pyr), 147.47 (1C, qui), 136.81 (2Cs, N-sub pyr), 130.20 (1C, qui), 129.70 (1C, qui), 125.51 (1C, qui), 123.07 (2Cs, N-sub pyr), 122.54 (2Cs, N-sub pyr), 122.31 (1C, qui), 119.61 (1C, qui), 95.47 (1C, qui), 59.97 (2Cs, -CH2-N(CH2-pyr)2), 59.19 (-O-CH2-CH2-NH2), 53.21 (-CH2-N(CH2-pyr)2), 45.66 (CO-N-CH2-CH2-N), 37.06 (-CH2-NH2); ESI-MS: m/z [M + 2]+ calcd for C26H28N6O2: 456.55 found: 458.21; Anal. Calcd (%) for C26H28N6O2 H2O: C 65.80, H 6.37, N 17.71; found: C 65.64, H 6.29, N 17.82.


#

4-(2-Aminoethoxy)-N-(2-((di(quinolin-2-yl)methyl)amino)ethyl)quinoline-2-carboxamide (19)

A solution of 17 (1.00 g, 1.50 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was stirred at r.t. for 6 h. The mixture was concentrated in vacuo and the residue was added with dichloromethane (25 mL), washed with 2 N NaOH, saturated brine, and dried over anhydrous sodium sulfate. The crude material was purified by silica gel column and eluted with ethyl acetate/25% ammonium hydroxide (v/v = 200:1) to give 19 as a white solid (0.73 g, 86.0% yield, 98.0% purity); mp148–149 °C. 1H NMR (CDCl3): δ = 8.94 (br, 1 H), 8.33–8.35 (m, 1 H), 8.07–8.12 (m, 3 H), 7.95–7.97 (m, 2 H), 7.82–7.7789 (m, 3 H), 7.65–7.70 (m, 6 H), 7.46–7.50 (m, 2 H), 4.33–4.36 (t, 2 H), 4.17 (s, 4 H), 3.68–3.72 (m, 2 H), 3.28–3.31 (t, 2 H), 2.99–3.02 (t, 2 H), 1.66 (br, 2 H). 13C NMR (DMSO-d 6): δ = 164.19 (C=O), 162.88 (1C, qui), 160.68 (2Cs, N-sub qui), 152.15 (1C, qui), 147.66 (1C, qui), 147.39 (2Cs, N-sub qui), 136.64 (2Cs, N-sub qui), 131.26 (1C, qui), 129.84 (2Cs, N-sub qui), 129.30 (1C, qui), 129.02 (2Cs, N-sub qui), 128.17 (2Cs, N-sub qui), 127.50 (1C, qui), 127.38 (2Cs, N-sub qui), 126.57 (2Cs, N-sub qui), 122.55 (1C, qui), 121.87 (1C, qui), 121.51 (2Cs, N-sub qui), 98.70 (1C, qui), 71.86 (-O- C H2-CH2-NH2), 61.07 (2Cs, -CH2-N( C H2-qui)2), 53.52 (- C H2-N(CH2-qui)2), 41.21 (N- C H2-CH2-N(CH2-qui)2), 37.34 (- C H2-NH2); ESI-MS: m/z [M + 1]+ calcd for C34H32N6O2: 556.67; found: 557.25. Anal. Calcd (%) for C34H32N6O2 H2O: C 71.06, H 5.96, N 14.62; found: C 70.89, H 6.02, N 14.57.


#

Spectroscopic Measurements

Solutions of the analogues were prepared in chloroform and diluted to a final concentration of 0.1 μM for all measurements. UV absorption spectra were recorded with a Meipuda UV-650 spectrophoto­meter (Shanghai, China). Fluorescence intensity spectra were measured with a Perkin–Elmer LS 55 fluorescence spectrometer.


#
#

Supporting Information

  • References

  • 1 Sharma JN. Al-Omran A. Parvathy SS. Inflammopharmacology 2007; 15: 252
  • 2 Loscalzo J. Circ. Res. 2013; 113: 100
  • 3 Vincent SR. Prog. Neurobiol. (Oxford, U. K.) 2010; 90: 246
  • 4 Bogdan C. Nat. Immunol. 2001; 2: 907
  • 5 Riddell DR. Owen JS. Vitam. Horm. (London, U. K.) 1999; 57: 25
  • 6 Nathan CF. Hibbs JB. Curr. Opin. Immunol. 1991; 3: 65
  • 7 Blaise GA. Gauvin D. Gangal M. Authier S. Toxicology 2005; 208: 177
  • 8 Brüne B. Cell Death Differ. 2003; 10: 864
  • 9 Simeone AM. Collela S. Krahe R. Johnson MM. Mora E. Tari AM. Carcinogenesis 2006; 27: 568
  • 10 Choudhari SK. Chaudhary M. Bagde S. Gadbail AR. Joshi V. World J. Surg. Oncol. 2013; 11: 118
  • 11 Xu W. Liu LZ. Loizidou M. Ahmed M. Charles IG. Cell Res. 2002; 12: 311
  • 12 Huerta-Yepez S. Vega M. Jazirehi A. Garban H. Hongo F. Cheng G. Bonavida B. Oncogene 2004; 23: 4993
  • 13 Donia M. Maksimovic-Ivanic D. Mijatovic S. Mojic M. Miljkovic D. Timotijevic G. Fagone P. Caponnetto S. Al-Abed Y. McCubrey J. Stosic-Grujicic S. Nicoletti F. Cell Cycle 2011; 10: 492
  • 14 Adams C. McCarthy HO. Coulter JA. Worthington J. Murphy C. Robson T. Hirst DG. J. Gene Med. 2009; 11: 160
  • 15 Frederiksen LJ. Siemens DR. Heaton JP. Maxwell LR. Adams MA. Graham CH. J. Urol. 2003; 170: 1003
  • 16 Stewart GD. Nanda J. Katz E. Bowman KJ. Christie JG. Brown DJ. McLaren DB. Riddick AC. Ross JA. Jones GD. Habib FK. Biochem. Pharmacol. 2011; 81: 203
  • 17 Royle JS. Ross JA. Ansell I. Bollina P. Tulloch DN. Habib FK. J. Urol. 2004; 172: 338
  • 18 Baritaki S. Huerta-Yepez S. Sahakyan A. Karagiannides I. Bakirtzi K. Jazirehi A. Bonavida B. Cell Cycle 2010; 9: 4931
  • 19 Siemens DR. Heaton JP. Adams MA. Kawakami J. Graham CH. Urology. 2009; 74: 878
  • 20 Mascharak PK. Indian J. Chem., Sect. A: Inorg., Bio-inorg., Phys., Theor. 2012; 51: 99
  • 21 Miller MR. Megson IL. Br. J. Pharmacol. 2007; 151: 305
  • 22 Huerta S. Chilka S. Bonavida B. Int. J. Oncol. 2008; 33: 909
  • 23 Wang PG. Xian M. Tang X. Wu X. Wen Z. Cai T. Janczuk AJ. Chem. Rev. 2002; 102: 1091
  • 24 Pavlos CM. Xu H. Toscano JP. Curr. Top. Med. Chem. 2005; 5: 637
  • 25 Eroy-Reveles AA. Leung Y. Beavers CM. Olmstead MM. Mascharak PK. J. Am. Chem. Soc. 2008; 130: 4447
  • 26 Hitomi Y. Iwamoto Y. Kodera M. Dalton Trans. 2014; 2161
  • 27 Ghosh K. Eroy-Reveles AA. Avila B. Holman TR. Olmstead MM. Mascharak PK. Inorg. Chem. 2004; 43: 2988
  • 28 Patra AK. Mascharak PK. Inorg. Chem. 2003; 42: 7363
  • 29 Eroy-Reveles AA. Hoffman-Luca CG. Mascharak PK. Dalton Trans. 2007; 5268
  • 30 Patra AK. Rose MJ. Murphy KA. Olmstead MM. Mascharak PK. Inorg. Chem. 2004; 43: 4487
  • 31 Sarmiento RM. R. Nettekoven MH. Taylor S. Plancher JM. Richter H. Roche O. Bioorg. Med. Chem. Lett. 2009; 19: 4495
  • 32 Yoshikawa K. Kobayashi S. Nakamoto Y. Haginoya N. Komoriya S. Yoshino T. Nagata T. Mochizuki A. Watanabe K. Suzuki M. Kanno H. Ohta T. Bioorg. Med. Chem. 2009; 17: 8221
  • 33 Song SY. Lu HL. Wang GF. Yang YQ. Huang YS. Res. Chem. Intermed. 2016; 42: 4433
  • 34 Waghmodea SB. Mahalea G. Patila VP. Renalsonb K. Singhb D. Synth. Commun. 2013; 43: 3272
  • 35 Hwang H. Kim J. Jeong J. Chang S. J. Am. Chem. Soc. 2014; 136: 10770
  • 36 Dale L. Boger DL. Panek JS. J. Am. Chem. Soc. 1985; 107: 5745
  • 37 Chauhan K. Datta A. Adhikari A. Chuttani K. Kumar SA. Mishra AK. Org. Biomol. Chem. 2014; 12: 7328

  • References

  • 1 Sharma JN. Al-Omran A. Parvathy SS. Inflammopharmacology 2007; 15: 252
  • 2 Loscalzo J. Circ. Res. 2013; 113: 100
  • 3 Vincent SR. Prog. Neurobiol. (Oxford, U. K.) 2010; 90: 246
  • 4 Bogdan C. Nat. Immunol. 2001; 2: 907
  • 5 Riddell DR. Owen JS. Vitam. Horm. (London, U. K.) 1999; 57: 25
  • 6 Nathan CF. Hibbs JB. Curr. Opin. Immunol. 1991; 3: 65
  • 7 Blaise GA. Gauvin D. Gangal M. Authier S. Toxicology 2005; 208: 177
  • 8 Brüne B. Cell Death Differ. 2003; 10: 864
  • 9 Simeone AM. Collela S. Krahe R. Johnson MM. Mora E. Tari AM. Carcinogenesis 2006; 27: 568
  • 10 Choudhari SK. Chaudhary M. Bagde S. Gadbail AR. Joshi V. World J. Surg. Oncol. 2013; 11: 118
  • 11 Xu W. Liu LZ. Loizidou M. Ahmed M. Charles IG. Cell Res. 2002; 12: 311
  • 12 Huerta-Yepez S. Vega M. Jazirehi A. Garban H. Hongo F. Cheng G. Bonavida B. Oncogene 2004; 23: 4993
  • 13 Donia M. Maksimovic-Ivanic D. Mijatovic S. Mojic M. Miljkovic D. Timotijevic G. Fagone P. Caponnetto S. Al-Abed Y. McCubrey J. Stosic-Grujicic S. Nicoletti F. Cell Cycle 2011; 10: 492
  • 14 Adams C. McCarthy HO. Coulter JA. Worthington J. Murphy C. Robson T. Hirst DG. J. Gene Med. 2009; 11: 160
  • 15 Frederiksen LJ. Siemens DR. Heaton JP. Maxwell LR. Adams MA. Graham CH. J. Urol. 2003; 170: 1003
  • 16 Stewart GD. Nanda J. Katz E. Bowman KJ. Christie JG. Brown DJ. McLaren DB. Riddick AC. Ross JA. Jones GD. Habib FK. Biochem. Pharmacol. 2011; 81: 203
  • 17 Royle JS. Ross JA. Ansell I. Bollina P. Tulloch DN. Habib FK. J. Urol. 2004; 172: 338
  • 18 Baritaki S. Huerta-Yepez S. Sahakyan A. Karagiannides I. Bakirtzi K. Jazirehi A. Bonavida B. Cell Cycle 2010; 9: 4931
  • 19 Siemens DR. Heaton JP. Adams MA. Kawakami J. Graham CH. Urology. 2009; 74: 878
  • 20 Mascharak PK. Indian J. Chem., Sect. A: Inorg., Bio-inorg., Phys., Theor. 2012; 51: 99
  • 21 Miller MR. Megson IL. Br. J. Pharmacol. 2007; 151: 305
  • 22 Huerta S. Chilka S. Bonavida B. Int. J. Oncol. 2008; 33: 909
  • 23 Wang PG. Xian M. Tang X. Wu X. Wen Z. Cai T. Janczuk AJ. Chem. Rev. 2002; 102: 1091
  • 24 Pavlos CM. Xu H. Toscano JP. Curr. Top. Med. Chem. 2005; 5: 637
  • 25 Eroy-Reveles AA. Leung Y. Beavers CM. Olmstead MM. Mascharak PK. J. Am. Chem. Soc. 2008; 130: 4447
  • 26 Hitomi Y. Iwamoto Y. Kodera M. Dalton Trans. 2014; 2161
  • 27 Ghosh K. Eroy-Reveles AA. Avila B. Holman TR. Olmstead MM. Mascharak PK. Inorg. Chem. 2004; 43: 2988
  • 28 Patra AK. Mascharak PK. Inorg. Chem. 2003; 42: 7363
  • 29 Eroy-Reveles AA. Hoffman-Luca CG. Mascharak PK. Dalton Trans. 2007; 5268
  • 30 Patra AK. Rose MJ. Murphy KA. Olmstead MM. Mascharak PK. Inorg. Chem. 2004; 43: 4487
  • 31 Sarmiento RM. R. Nettekoven MH. Taylor S. Plancher JM. Richter H. Roche O. Bioorg. Med. Chem. Lett. 2009; 19: 4495
  • 32 Yoshikawa K. Kobayashi S. Nakamoto Y. Haginoya N. Komoriya S. Yoshino T. Nagata T. Mochizuki A. Watanabe K. Suzuki M. Kanno H. Ohta T. Bioorg. Med. Chem. 2009; 17: 8221
  • 33 Song SY. Lu HL. Wang GF. Yang YQ. Huang YS. Res. Chem. Intermed. 2016; 42: 4433
  • 34 Waghmodea SB. Mahalea G. Patila VP. Renalsonb K. Singhb D. Synth. Commun. 2013; 43: 3272
  • 35 Hwang H. Kim J. Jeong J. Chang S. J. Am. Chem. Soc. 2014; 136: 10770
  • 36 Dale L. Boger DL. Panek JS. J. Am. Chem. Soc. 1985; 107: 5745
  • 37 Chauhan K. Datta A. Adhikari A. Chuttani K. Kumar SA. Mishra AK. Org. Biomol. Chem. 2014; 12: 7328

Zoom Image
Figure 1 Representative structures of some metal ion nitrosyl ligands
Zoom Image
Figure 2 Structures of the newly designed manganese nitrosyl ligands with an aminoethoxy link that is to attach to a carboxylic group on the gold nanoparticles
Zoom Image
Scheme 1 Synthesis of 6-aminoethoxy substituted analogues
Zoom Image
Scheme 2 Synthesis of 4-aminoethoxy substituted analogues