Subscriber access provided by Universiteit Utrecht
Article
Facile Diversity-Oriented Synthesis of Polycyclic Pyridines and Their Cytotocicity Effects in Human Cancer Cell Lines Limi Goswami, Shyamalee Gogoi, Junali Gogoi, Rajani Kumar Baruah, Romesh Boruah, and Pranjal Gogoi ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00192 • Publication Date (Web): 15 Mar 2016 Downloaded from http://pubs.acs.org on March 15, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Combinatorial Science is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 16
ACS Combinatorial Science
1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Facile Diversity-Oriented Synthesis of Polycyclic Pyridines and Their Cytotocicity Effects in Human Cancer Cell Lines Limi Goswami,a Shyamalee Gogoi,a‡ Junali Gogoi,a‡ Rajani K. Baruah,b Romesh C Boruah,a and Pranjal Gogoia* a
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India b Analytical Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785006, India
ABSTRACTS: A three-component cascade method has been developed for the direct synthesis of polysubstituted pyridines. This strategy provides a very convenient route to pyridines using a variety of β-bromoα,β-unsaturated aldehydes, 1,3-diketones and ammonium acetate without any additional catalyst or metal salt under mild conditions. A variety of β-ketoesters and 4-hydroxycoumarin were also used instead of 1,3-diketones for the diverse synthesis of polycyclic pyridines. One of the synthesised pyridine has been unambiguously established by single crystal XRD study. All the synthesized pyridine derivatives were evaluated for their antiproliferative properties in vitro against human cancer cell lines (HeLa, Me180 and ZR751). Compounds 4{4,1} and 4{2,4} were showed significant cytotoxicity in human breast cancer cell line (ZR751) and cervical cancer cell line (Me180) respectively and few other compounds were found to have moderate activities.
KEYWORDS: Pyridine, halovinyl aldehyde, cascade reaction, antitumor activity
ACS Paragon Plus Environment
ACS Combinatorial Science
Page 2 of 16
2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
INTRODUCTION Pyridine is one of the most important heterocyclic core units found in various natural products and pharmaceuticals.1 They are widely associated in materials and surfaces, supramolecular structures, polymers and in catalysis as building blocks for the synthesis of chiral ligand.2 They play a vital role in the biologically active natural substances including vitamin B6, nicotine, or oxido-reductive NADP-NADPH coenzymes. In pharmaceuticals, they have been synthesized for different applications such as anticancer, anti-inflammatory, antidepressant, acetylcholinesterase inhibitor, HIV protease inhibitor etc.1d,3 Interestingly, more than hundred currently marketed drugs contain this privileged unit, which remains in high demand after their synthesis.4 Notable examples of them are Lavendamycin5a (anti cancer), Streptonigrin5b (anti cancer), MRZ-86765c (mGluR5 receptor antagonist) and Bay 60-5521 (CETP inhibitors)5d having pyridine as central core unit (Figure 1). Considering, the importance of pyridine moieties in pharmaceutical and chemical domains, a concise and environment friendly synthetic route to highly substituted pyridine libraries is highly desirable.6 On the other hand, multicomponent reactions (MCRs) are very much attractive in organic synthesis because this synthetic strategy helps to construct complex structural motif via the formation of carbon-carbon and carbon-heteroatom bond in one-pot and single step.7 This approach has addressed the synthetic efficiency by minimizing waste, reaction time, energy, cost and rapidly generate library of compounds for new medicine. However, the MCRs, especially when they are not metal-catalyzed, are well accepted as “environmentally benign” processes. Multicomponent synthesis of pyridine is known and several methods have been developed to achieve this important structural unit.8 In this regards, multi-component Hantzsch reaction,9 Chichibabin reaction,10 Bohlmann-Rahtz,11 Kröhnke pyridine synthesis12 are the well known approaches to achieve this structural unit. Additionally Mannich, Michael addition, VilsmeierHaack based reactions are also used for the synthesis of polysubstituted pyridines.13 Although, most of the reported methods are simple and practical, they have some limitations such as use of catalyst, activator, transition-metal, limited substrate scope, harsh reaction conditions etc. To overcome these limitations as well as to achieve structurally diverse pyridines for drug discovery programme, several other miscellaneous methods have been developed and desirable to get novel pyridines.14
Figure 1. Representative pyridine bearing bioactive compounds ACS Paragon Plus Environment
Page 3 of 16
ACS Combinatorial Science
3 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
RESULTS AND DISCUSSION Recently, we have reported the synthesis of 2-aminopyridines from β-halo-α,β-unsaturated aldehydes via Knoevenagel condensation under microwave irradiation.15 In addition, we have been working
on
β-halo-α,β-unsaturated
aldehydes
as
a
versatile
synthon
for
various
heterocycles/carbocycles.16 We now report this synthon for the synthesis of some novel polysubstituted pyridines using β-bromo-α,β-unsaturated aldehydes 1{1-11}, 1,3-dicarbonyls 2{18} and ammonium acetate 3 (Figure 2). a) β-Bromo-α,β-unsaturated aldehydes 1{1-11}
b) 1,3-Dicarbonyls 2{1-8} O
O
O
O
O
2{1} O
O
O OEt
2{6}
O
2{2}
2{3}
O
O
O
2{5}
O
2{4}
OH
O O O
2{7}
O
2{8}
Figure 2. Various β-Bromo-α,β-unsaturated aldehydes and 1,3-dicarbonyls used in the synthesis of pyridines. Initially, we chose 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde 1{1}, 5,5-dimethyl-1,3cyclohexanedione 2{1} and ammonium acetate 3 as starting materials to examine the synthesis of pyridine 4{1,1} (Table 1). The reaction was performed using equimolar ratio of the reactants at 80 o
C for 10 h in acetonitrile, and the product 4{1,1} was obtained, albeit in only 25% yield. To
improve the yield, the amount of ammonium acetate was increased and subsequently, the product 4{1,1} was obtained in moderate yield (Table 1; entry 2 and 3). Further optimization of the ACS Paragon Plus Environment
ACS Combinatorial Science
Page 4 of 16
4 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
reaction, various solvents DMF, DMSO, water, dioxane and toluene were also screened at different reaction temperatures (Table 1; entries 4-8). Among them, the solvent DMF gave excellent result at 120 oC (Table 1; entry 8). Additionally, this multicomponent reaction was also carried out under solvent-free conditions, however ammonium acetate was required in excess amount (5 equivalents with respect to 1{1}) to achieve comparable yield (Table 1; entry 10).
Table 1. Optimization studies for the synthesis of pyridine 4{1,1}
Entry
Reagent systema
1 2 3 4 5 6 7 8 9 10
NH4OAc (1 mmol),CH3CN NH4OAc (2 mmol),CH3CN NH4OAc (3 mmol),CH3CN NH4OAc (3 mmol),water NH4OAc (3 mmol), DMSO NH4OAc (3 mmol), dioxane NH4OAc (3 mmol), toluene, NH4OAc (3 mmol), DMF NH4OAc (3 mmol) NH4OAc (5 mmol)
a
Reaction conditions Yield (%)b 80 oC/10h 80 oC/7h 80 oC/6h 100 oC/6h 120 oC/6h 100 oC/7h 110 oC/7h 120 oC/6h 120 oC/4h 120 oC/4h
25 41 52 53 87 79 45 93 51 77
solvent (4 mL); b isolated yield of 4{1,1}
After the optimization of the reaction conditions, various polycyclic pyridines were synthesized from β-bromo-α,β-unsaturated aldehydes using our optimized conditions (Table 2). The requisite β-bromo-α,β-unsaturated aldehydes were efficiently synthesized from their corresponding carbonyl compounds using Vilsmeier reaction.16b,17 As illustrated in Table 2, a variety of β-bromo-α,β-unsaturated aldehydes 1{1-11} were treated with 5,5-dimethyl-1,3cyclohexanedione 2{1} and ammonium acetate 3 in DMF at 120 oC (Table 2; 4{1,1}-4{11,1}). All the β-bromo-α,β-unsaturated aldehydes were well tolerated to the reaction conditions and participated in the cascade process affording to the desired products in the yields ranging from 49% to 95%. β-Bromo-α,β-unsaturated aldehydes embodied with various tetralones were smoothly participated in the tandem reaction to provide the corresponding pyridines in excellent yields (4{1,1}-4{3,1}, Table 2). In addition, six-, seven- and eight-membered cyclic β-bromo-α,βunsaturated aldehydes were also investigated (4{4,1}-4{7,1}, Table 2). The yields of expected pyridine products from the corresponding six- and eight-membered β-bromo-α,β-unsaturated aldehydes were comparative, whereas the seven-membered β-bromo-α,β-unsaturated aldehyde gave low yield of product (4{6,1}, Table 2). ACS Paragon Plus Environment
Page 5 of 16
ACS Combinatorial Science
5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Table 2. Synthesis of polysubstituted pyridines a,b
4{1,1}; 93%
4{2,1}; 90%
4{3,1}; 95%
4{4,1}; 79%
4{5,1}; 83%
4{6,1}; 49%
4{7,1}; 88%
4{8,1}; 82%
4{9,1}; 69%
4{10,1}; 73%
4{11,1}; 70%
4{2,2}; 89%
4{3,2}; 92%
4{6,2}; 45%
4{8,2}; 80%
4{10,2}; 71%
4{1,4}; 69%
4{2,4}; 74%
4{3,4}; 88%
4{7,4}; 77%
4{1,5}; 55%
4{2,5}; 57%
4{3,5}; 63%
4{1,6}; 74%
4{2,6}; 80%
4{3,6}; 87%
4{6,6}; 41%
4{1,7}; 75%
4{2,7}; 77%
4{3,7}; 83%
4{8,7}; 65%
4{3,3}; 62%
4{1,2}; 90%
4{7,2};85%
4{10,3}; 59%
4{8,4}; 74%
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), and NH4OAc (3 mmol), DMF (4 mL); b isolated yield
ACS Paragon Plus Environment
ACS Combinatorial Science
Page 6 of 16
6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Chromane and coumarin derived β-bromo-α,β-unsaturated aldehydes were also employed as substrates under the optimized conditions and gave the desired pyridines 4{8,1} and 4{9,1} in 82% and 69% yields respectively. Interestingly, steroidal β-bromo-α,β-unsaturated aldehydes derived from dehydroisoandrosterone 3-acetate and estrone underwent the cascade process to gave the corresponding D-ring annelated pyridines 4{10,1} and 4{11,1} in good yields. Next, the optimized tandem reaction was tested with other 1,3-diketone compounds, and the results are summarized in Table 2. Readily available 1,3-cyclohexanedione 2{2} was employed to react with various β-bromo-α,β-unsaturated aldehydes and ammonium acetate to afford various pyridines. 1,3-Cyclohexanedione shows more or less similar results with 5,5-dimethyl-1,3cyclohexanedione 2{1} (Table 2; 4{1,2}, 4{2,2}, 4{3,2}, 4{6,2}, 4{7,2}, 4{8,2} and 4{10,2}). However, when 1,3-cyclopentanedione 2{3} was used, the desired product was obtained in moderate yield (~60%) (Table 2; 4{3,3} and 4{10,3}). On the other hand, 1,3-indanedione 2{4} was found to be a suitable 1,3-dicarbonyl and produced the respective pyridines in good yields (Table 2; 4{1,4}, 4{2,4}, 4{3,4}, 4{7,4}, 4{8,4}). Acyclic 1,3-diketones pentane-2,4-dione 2{5} was also employed in the reaction to afford pyridines 4{1,5}, 4{2,5} and 4{3,5} in 55%, 57% and 63% yields respectively. Further, another two β-ketoesters such as ethyl acetoacetate 2{6} and benzyl acetoacetate 2{7} also turned out be excellent substrates in the present protocol to afford substituted pyridines in good yields (Table 2; 4{1,6}, 4{2,6}, 4{3,6}, 4{6,6}, 4{1,7}, 4{2,7}, 4{3,7}, and 4{8,7}). The structures of all products 4 were characterized by IR, 1H-NMR,
13
C-
NMR spectral. The structure of 4{3,1} was further confirmed by X-ray diffraction analysis. The molecular structure of 4{3,1} is shown in Figure 3.
Figure 3. Crystal structure of 4{3,1} To further examine the scope of this three component cascade reaction, 4-hydroxycoumarin 2{8} was considered as 1,3-diketone analogue to synthesize structurally diverse coumarin fused pyridines (Table 3). Consequently, β-bromo-α,β-unsaturated aldehydes derived from various tetralones and chromane were treated with 2{8} and ammonium acetate under the optimized conditions. Coumarin fused pyridines 4{1,8}, 4{2,8}, 4{3,8}, 4{8,8} were obtained in good yields and these structurally diverse pyridines might have some potential applications in pharmaceutical ACS Paragon Plus Environment
Page 7 of 16
ACS Combinatorial Science
7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
industries. The above results clearly demonstrate the versatility of the reaction in obtaining the pyridines with various functionalities. Table 3. Synthesis of coumarin fused pyridines a,b
4{1,8}; 72% a
4{2,8}; 75%
4{3,8}; 77%
4{8,8}; 65%
Reaction conditions: 1 (1 mmol), 2{8} (1 mmol), and NH4OAc (3 mmol), DMF (4 mL); b isolated yield
At present the exact reaction mechanism is not clear. Initially, it was assumed that the reaction proceeds via enamine, which undergoes addition-elimination followed by cyclization and condensation with β-bromo-α,β-unsaturated aldehyde to form the pyridine products (Path B, Scheme 2). However, the expected pyridine product was not observed in the crystal structure. Based on the crystal structure, a plausible reaction mechanism is proposed as in scheme 2. The in situ generated “ammonia” from ammonium acetate reacts with β-bromo-α,β-unsaturated aldehyde 1 to form aminoaldehyde I, which reacts with 1,3-diketone to form another intermediate II. The enamine intermediate II undergoes cyclization to form the pyridine products. Scheme 2. Proposed mechanism
The synthesized polycyclic pyridine derivatives were tested for anticancer potential in human breast (ZR751) and cervical (HeLa and Me180) cancer cell lines using MTT assay.18 The effect of the tested compounds on proliferation of cancer cell lines is presented in Table 4. As shown in Table 4, the compounds 4{2,4}, 4{8,1} and 4{11,1} exhibited promising growth inhibition against cervical cancer cell line ME180, at exposure of 260 µM for 24 h, with inhibition percentage of ACS Paragon Plus Environment
ACS Combinatorial Science
Page 8 of 16
8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
81.67%, 78.64% and 78.64 % respectively. Whereas, the compound 4{4,1} showed significant growth inhibition (89.80%) against breast cancer cell line ZR751.
Table 4: Growth inhibition (%) of different cancer cell lines when treated with test compounds at 24 h exposure. Sl.No Sample ID Conc. (µM) HeLa 1
2
3
4
5
6
7
8
9
10
11
12
13
14
4{1,1}
4{2,1}
4{3,1}
4{4,1}
4{5,1}
4{6,1}
4{7,1}
4{8,1}
4{9,1}
4{10,1}
4{11,1}
4{1,2}
4{2,2}
4{3,2}
% of inhibition Me180
Zr751
130
NI
19.88 ± 1.31
31.56 ± 1.18
260
2.90 ± 1.33
27.31± 1.08
38.66 ± 1.32
130
8.82 ± 1.47
15.35 ± 1.71
37.58 ± 1.19
260
20.87 ± 0.93
25.04 ± 1.29
45.29 ± 1.57
130
45.00 ± 3.51
39.23 ± 0.06
NI
260
69.71 ± 1.33
56.78 ± 0.57
NI
130
14.44 ± 0.43
59.70 ± 1.57
39.87 ± 0.42
260
32.30 ± 0.18
73.98 ± 1.04
89.80 ± 0.09
130
NI
24.68 ± 1.18
13.97 ± 1.18
260
11.07 ± 0.76
45.75 ± 1.20
59.33 ± 1.27
130
19.36 ± 1.01
21.06 ± 1.04
46.86 ± 1.32
260
24.26 ± 0.79
67.69 ± 0.39
69.00 ± 1.08
130
16.11 ± 3.33
18.44 ± 1.37
47.39 ± 2.58
260
18.49 ± 0.13
58.71± 0.29
54.63 ± 2.17
130
1.85 ± 2.33
60.54 ± 0.25
25.60 ± 3.07
260
12.19 ± 2.41
78.64 ± 0.07
43.06 ± 2.39
130
7.57 ± 0.51
6.42 ± 2.77
27.62 ± 1.57
260
11.06 ± 1.81
30.77 ± 2.03
34.22 ± 1.77
130
NI
37.76 ± 0.91
56.22 ± 1.46
260
NI
46.81 ± 0.57
62.26 ± 1.28
130
NI
68.68 ± 0.40
60.11 ± 0.97
260
10.81± 1.23
78.64 ± 0.05
66.93± 0.13
130
27.32 ± 4.53
NI
NI
260
30.05 ± 2.79
12.37 ± 2.54
NI
130
35.77 ± 0.57
41.20 ± 1.90
NI
260
69.67 ± 0.07
45.71 ± 2.57
NI
130
16.82 ± 0.29
27.05 ± 1.32
13.75 ± 1.17
260
20.32 ± 0.23
37.54 ± 0.22
42.85 ± 1.38
ACS Paragon Plus Environment
Page 9 of 16
ACS Combinatorial Science
9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4{6,2}
4{7,2}
4{8,2}
4{10,2}
130
NI
65.62 ± 0.07
NI
260
NI
NI
16.99 ± 3.39
130
NI
NI
49.61 ± 0.29
260
NI
NI
51.77 ± 0.79
130
43.13 ± 0.56
12.32 ± 3.13
NI
260
47.44 ± 0.32
33.56 ± 2.69
NI
130
16.18 ± 0.25
48.54 ± 0.87
14.55 ± 1.83
260
19.01 ± 0.35
56.62 ± 1.10
38.27 ± 1.40
NI
NI
ND
NI
NI
ND
130
NI
30.43 ± 0.76
22.55 ± 1.15
260
9.77 ± 1.21
37.21 ± 1.07
42.64 ± 1.57
130
41.33 ± 0.11
56.08 ± 0.77
NI
260
47.33 ± 1.31
57.88 ± 0.37
NI
130
41.61± 1.70
65.62 ± 0.43
NI
260
49.79 ± 1.54
81.67 ± 0.57 NI
130
NI
NI
NI
260
3.04 ± 1.30
24.42 ± 1.26
NI
130
ND
ND
ND
260
ND
ND
ND
130
NI
46.64 ± 0.87
NI
260
NI
65.34 ± 0.35
NI
130
29.95 ± 3.20
23.47 ± 2.37
NI
260
34.81 ± 2.17
42.42 ± 2.21
NI
130
33.44 ± 1.10
23.72 ± 2.64
19.37 ± 1.38
260
34.77 ± 0.79
24.10 ± 2.46
23.37 ± 1.59
130
12.52 ± 3.510 23.85 ± 1.69
35.49 ± 2.75
260
20.35 ± 3.70
34.84 ± 2.77
40.42 ± 1.18
130
28.46 ± 1.09
18.61 ± 1.83
7.68 ± 3.31
260
31.31 ± 0.77
33.84 ± 1.37
8.71 ± 3.10
130
NI
17.88 ± 2.25
18.39 ± 2.67
260
10.94 ± 1.21
43.89 ± 2.67
33.54 ±2.19
130
26.72 ± 1.57
15.76 ± 1.87
19.54 ± 1.12
260
28.16 ± 0.99
27.11 ± 1.71
32.21 ± 1.43
130
36.77 ± 1.76
22.05 ± 2.20
16.77 ± 2.30
4{3,3}
4{10,3}
4{1,4}
4{2,4}
4{3,4}
4{7,4}
4{8,4}
4{1,5}
4{2,5}
4{3,5}
4{1,6}
4{2,6}
4{3,6}
4{6,6}
ACS Paragon Plus Environment
ACS Combinatorial Science
Page 10 of 16
10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
33
4{1,7}
34
4{2,7}
35
4{3,7}
36
4{8,7}
37
4{1,8}
38
4{2,8}
39
4{3,8}
40
4{8,8}
260
59.6 ± 1.39
35.11 ± 1.67
40.00 ± 2.19
130
11.14 ± 3.18
59.77 ± 1.26
NI
260
11.75 ± 3.37
68.98 ± 1.43
NI
130
NI
NI
NI
260
NI
21.61± 2.97
NI
130
2.6 ± 4.30
32.37 ± 2.50
NI
260
6.8 ± 3.50
65.28 ± 1.39
NI
130
NI
8.35 ± 2.56
NI
260
NI
24.69 ± 2.07
NI
130
35.35 ± 1.20
35.30 ± 2.11
ND
260
39.24 ± 1.34
46.52 ± 1.79
ND
130
6.11 ± 2.37
2.51 ± 3.87
ND
260
7.98 ± 1.79
6.35 ± 3.50
ND
130
51.00 ± 1.03
50.30 ± 2.23
ND
260
56.34 ± 2.34
53.43 ± 2.54
ND
130
53.47 ± 1.37
39.34 ± 1.55
ND
260
55.32 ± 0.57
53.60 ± 1.37
ND
41
Cis-platin
130
98.99 ± 0.79
78.73 ± 0.07
_
42
Paclitaxel
130
_
_
83.77 ± 0.18
Each value is the mean ± SD (n = 3). NI: no inhibition (at 230 µM or 260 µM), ND: not determined (precipitation was observed after addition of compounds). Data were analyzed by one way ANOVA analysis supplemented with Tukey-Kramer multiple comparisons test. Furthermore, we have analyzed our synthesized pyridine library by Drug Likeness Tool (DruLiTo), utilizing drug likeness parameters like Lipinski’s rule and Ghose filter. The values of significant molecular descriptors of three potent molecules, viz. 4{4,1}, 4{2,4} and 4{11,1} are showing in the table 5, which show that all of them possess drug like character as defined by Lipinski’s rule (see supporting information for entire library). Table 5. Drug- likeness-DruLito results of 4{4,1}, 4{2,4} and 4{11,1}. Com. Name
MW LogP AlogP HBA HBD TPSA AMR nRB nAtom
nAcidic Group
RC
nRigid nArom Bond Ring nHB
SAlerts
4{4,1} 229.32 1.965
0.454
2
0
29.43 67.34
0
36
0
3
19
1
2
0
4{2,4} 313.36 1.598
1.278
3
0
38.66 100.15
1
39
0
5
27
3
3
0
4{11,1} 443.59 4.717
2.02
4
0
55.73 133.73
2
66
0
6
36
2
4
2
DruLiTo results. MW: Molecular weight; Logp: compound's hydrophilicity; AlogP: Ghose-Crippen-Viswanadhan octanol-water partition coefficient; HBA: Hydrogen bonding acceptor; HBD: Hydrogen bonding donor; TPSA: The polar surface area prediction, AMR: Molecular refractivity, nRB: Number of Rotational Bonds; nAtom: number of atoms; nAcidic Group: number of acidic groups; RC: rotational bond count, nRigid Bond: number of rigid bond, nAromRing: number of aromatic rings; nHB: number of hydrogen bond, SAlarts: structure alerts.
ACS Paragon Plus Environment
Page 11 of 16
ACS Combinatorial Science
11 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
CONCLUSION In conclusion, we have developed an efficient three-component cascade reaction for the synthesis of polycyclic pyridines. This synthetic protocol is advantageous because of merits such as additional catalyst and metal-free, simplicity in operation, cost efficiency and it can be used for the synthesis of fused steroidal and coumarin derived pyridines. Our protocol will facilitate the generation of libraries of compounds of potential biological significance in medicinal chemistry and drug discovery. Derivatives of 4{4,1} could be highly promising small molecule for future drug development against human breast cancer.
EXPERIMENTAL PROCEDURES All the β-bromo-α,β-unsaturated aldehydes were efficiently synthesized from their corresponding carbonyl compounds using Vilsmeier reaction.16b,17 1H NMR and 13C NMR spectra were recorded at ambient temperature on a Bruker Avance 500 MHz NMR spectrometer (125 MHz for
13
C).
NMR chemical shifts are reported on the δ scale (ppm) downfield from tetramethylsilane (δ=0.0 ppm) using the residual solvent signal at δ=7.26 ppm (1H) or δ=77 ppm (13C) as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). IR spectra were recorded on a spectrophotometer using CHCl3. Column chromatography was performed with silica gel 60 (100-200 mesh). MTT [3-(4,5Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide] and cell culture chemicals were purchased from Sigma-Aldrich Inc., St Louis, MO, USA. A.
Typical experimental procedure for the synthesis of 4
A mixture of β-bromo-α,β-unsaturated aldehyde (1 mmol), 1,3-diketone (1 mmol), and NH4OAc (3 mmol) in DMF (4 mL) was stirred at 120 oC for 6 hours in a preheated oil bath. After being cooled to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3x20 mL). The combined organic fraction was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc/hexanes) to afford the corresponding product 4{1,1}-4{8,8}. B.
Experimental procedure for the synthesis of 4aa under solvent-free conditions.
A mixture of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde (1 mmol), 5,5-dimethyl-1,3cyclohexanedione (1 mmol) and NH4OAc (5 mmol) was stirred at 120 oC for 4 hours in a ACS Paragon Plus Environment
ACS Combinatorial Science
Page 12 of 16
12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
preheated oil bath. After being cooled to room temperature, the reaction mixture was purified on a silica gel column chromatography (15% EtOAc/hexanes) without any work-up to give the pyridine 4{1,1} (0.214 g; 77% yield). General procedure for in Vitro evaluation of anticancer activity: The proliferation effect of compounds on cancer cells were determined by MTT assay. Briefly, cancer cells were plated at a density of 3 ×104 cells/well in 96-well culture plates and incubated for 24 h. The cells were then exposed to test compounds (130 and 260 µM) or equivalent amount of DMSO (vehicle control) for 24 h. After incubation, the contents were replaced with 100 µl of MTT dissolved in serum-free medium (1.2 mM) after which the plates were further incubated for 3 h. The contents were then replaced with equal amounts of DMSO to solubilise the formazan grains formed by viable cells. Finally, the absorbance was taken at 570 nm using a multi-well plate reader (Thermo, Multiskan spectrum). The percent inhibition was calculated by using the formula: [(Absorbance of solvent control – Absorbance of test sample) / Absorbance of solvent control] × 100.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at www.pubs.acs.org. General methods, synthetic procedures, characterization data and copies of 1H and 13C NMR spectra of all products.
AUTHOR INFORMATION Corresponding Author Fax: +913762370011. E-mail:
[email protected] Author Contributions ‡
J.G. and S.G. contributed equally to this work.
ACKNOWLEDGEMENTS We acknowledge the CSIR, New Delhi, for financially supporting us with CSIR-ORIGIN (CSC0108) project. We are grateful to the Director, CSIR-North East Institute of Science and Technology, Jorhat, India for the interest in this work and facilities. We thank Dr. Jagat C Borah and his group for testing anticancer potential of synthesized compounds. We also acknowledge Mr. Bharat G. Somkuwar for analyzing our library by Drug Likeness tool. ACS Paragon Plus Environment
Page 13 of 16
ACS Combinatorial Science
13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
REFERENCES (1)
(a) Jones, G. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; McKillop, A. Eds.; Pergamon: Oxford, 1996, Vol. 5, p 167; (b) Michael, J. P. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 2005, 22, 627-646; (c) Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J. Total synthesis of the thiopeptide promothiocin A. J. Am. Chem. Soc. 2000, 122, 3301-3313; (d) Baumann, M.; Baxendale, I. R. An overview of the synthetic routes to the best selling drugs containing 6membered heterocycles. Belistein J. Org. Chem. 2013, 9, 2265-2319; (e) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257−10274.
(2)
(a) Functional Organic Materials: Syntheses, Strategies and Applications; Muller, T. J. J.; Bunz, U. H. F. Eds.; Wiley-VCH: Weinheim, 2007; (b) Lehn, J. –M. Supramolecular Chemistry-Concepts and Perspectives; VCH: Weinheim, 1995; (c) Kang, N. –G.; Changez, M.; Lee, J. –S. Living anionic polymerization of the amphiphilic monomer 2-(4vinylphenyl)pyridine. Macromolecules 2007, 40, 8553-8559; (d) Fu, G. C. Asymmetric catalysis with “planar-chiral” derivatives of 4-(dimethylamino)pyridine. Acc. Chem. Res. 2004, 37, 542-547.
(3) (a) Lacerda, R. B.; de Lima, C. K. F.; da Silva, L. L.; Romeiro, N. C.; Miranda, A. L. P.; Barreiro, E. J.; Fraga, C. A. M. Discovery of novel analgesic and anti-inflammatory 3arylamine-imidazo[1,2-a]pyridine symbiotic prototypes. Bioorg. Med. Chem. 2009, 17, 7484; (b) Vacher, B.; Bonnaud, B.; Funes, P.; Jubault, N.; Koek, W.; Assie, M. -B.; Cosi, C.; Kleven, M. Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J. Med. Chem. 1999, 42, 1648-1660; (c) O’Hagan, D. Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids. Nat. Prod. Rep. 2000, 17, 435-446; (d) Horiuch, M.; Murakami, C.; Fukamiya, N.; Yu, D.; Chen, T.-H.; Bastow, K. F.; Zhang, D.-C.; Takaishi, Y.; Imakura, Y.; Lee, K.-H. Tripfordines A−C, sesquiterpene pyridine alkaloids from Tripterygium wilfordii, and structure anti-HIV activity relationships of Tripterygium alkaloids. J. Nat. Prod. 2006, 69, 1271-1274. (4)
Goetz, A. E.; Garg, N. K. Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model. Nature Chem. 2013, 5, 54-60 and references cited therein.
(5)
(a) Hassani, M.; Cai, W.; Holley, D. C.; Lineswala, J. P.; Maharjan, B. R.; Ebrahimian, G. R.; Seradj, H.; Stocksdale, M. G.; Mohammadi, F.; Marvin, C. C.; Gerdes, J. M.; Beall, H. D.; Behforouz, M. Novel lavendamycin analogues as antitumor agents: synthesis, in vitro ACS Paragon Plus Environment
ACS Combinatorial Science
Page 14 of 16
14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
cytotoxicity, structure metabolism, and computational molecular modeling studies with NAD(P)H: quinone oxidoreductase 1. J. Med. Chem. 2005, 48, 7733–7749; (b) Harding, M. M.; Long, G. V.; Brown, C. L. Solution conformation of the antitumor drug streptonigrin. J. Med. Chem. 1993, 36, 3056–3060; (c) Rocher, J.-P.; Bonnet, B.; Bolea, C.; Lutjens, R.; Le Poul, E.; Poli, S.; Epping-Jordan, M.; Bessis, A.-S.; Ludwig, B.; Mutel, V. mGluR5 negative allosteric modulators over-view: A medicinal chemistry approach towards a series of novel therapeutic agents. Curr. Topics. Med. Chem. 2011, 11, 680–695; (d)
Mantlo, N. B.;
Escribano, A. Update on the discovery and development of cholesteryl ester transfer protein inhibitors for reducing residual cardiovascular risk. J. Med. Chem. 2014, 57, 1−17 and references cited there in. (6)
(a) Jiang, H.; Yang, J.; Tang, X.; Li, J.; Wu, W. Cu-catalyzed three-component cascade annulation reaction: an entry to functionalized pyridines. J. Org. Chem. 2015, 80, 8763-8771; (b) Thi Le, S.; Asahara, H.; Nishiwaki, N. An alternative synthetic approach to 3alkylated/arylated 5-nitropyridines. J. Org. Chem. 2015, 80, 8856-8858; (c) Bai, Y.; Tang, L.; Huang, H.; Deng, G-J. Synthesis of 2,4-diarylsubstituted-pyridines through a Rucatalyzed four component reaction. Org. Biomol. Chem. 2015, 13, 4404-4407; (d) Kim, D-S.; Park, J-W.; Jun, C-H. Pyridine synthesis by reactions of allyl amines and alkynes proceeding through a Cu(OAc)2 oxidation and Rh(III)-catalyzed N-annulation sequence. Chem.Commun. 2012, 48, 11334-11336; (e) Sim, Y-K.; Lee, H.; Park, J-W.; Kim, D-S.; Jun, C-H. A method for the synthesis of pyridines from aldehydes, alkynes and NH4OAc involving Rh-catalyzed hydroacylation and N-annulation. Chem. Commun. 2012, 48, 11787-11789.
(7)
(a) Bugaut, X.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. 1,3-DIcarbonyls in Multicomponent Reactions. In Multicomponent Reactions; Zhu, J.; Wang, Q.; Wang, M. Eds.; Wiley-VCH: Weinheim, Germany, 2014, Cap. 5, pp. 109-158; (b) Janvier, P.; Sun, X.; Bienaymé, H.; Zhu, J. Ammonium Chloride-Promoted Four-Component Synthesis of Pyrrolo[3,4-b]pyridin-5-one. J. Am. Chem. Soc. 2002, 124, 2560-2567; (c) Fayol, A.; Zhu, J. Synthesis of furoquinolines by a multicomponent domino process. Angew. Chem. Int. Ed. 2002, 41, 3633-3635.
(8)
(a) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-free multicomponent synthesis of pyridines. Chem. Rev. 2014, 114, 10829-10868; (b) Alex Raja, V. P.; Tenti, G.; Perumal, S.; Menéndez, J. C. A heavy metal- and oxidant-free, one-pot synthesis of pyridines and fused pyridines based on a Lewis acid-catalyzed multicomponent reaction. Chem. Commun. 2014, 50, 12270-12272.
(9)
(a) Evans, C. G.; Gestwicki, J. E. Enantioselective Organocatalytic Hantzsch Synthesis of Polyhydroquinolines. Org. Lett. 2009, 11, 2957-2959; (b) H. Xinwei; S. Yongjia; Y. Zhiyu; F. Mei; Z. Yao; H. Guang; W. Fuli.
FeCl3-Catalyzed Four-Component Nucleophilic
ACS Paragon Plus Environment
Page 15 of 16
ACS Combinatorial Science
15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Addition/Intermolecular Cyclization Yielding Polysubstituted Pyridine Derivatives. J. Org. Chem., 2014, 79, 8882–8888; (c) Dondoni, A.; Massi, A.; Aldhoun, M. Hantzsch-type threecomponent approach to a new family of carbon-linked glycosyl amino acids synthesis of Cglycosylmethyl pyridylalanines. J. Org. Chem. 2007, 72, 7677-7687; (d) Huang, Z.; Hu, Y.; Zhou, Y.; Shi, D. Efficient one-pot three-component synthesis of fused pyridine derivatives in ionic liquid. ACS Comb. Sci. 2011, 13, 45–49 and references cited therein. (10) (a) Snider, B. B.; Neubert, B. J. Syntheses of Ficuseptine, Juliprosine, and Juliprosopine by Biomimetic Intramolecular Chichibabin Pyridine Syntheses. Org. Lett. 2005, 7, 2715; (b) Jiang, B.; Wang, X.; Shi, F.; Tu, S-J.; Li, G. New multicomponent cyclization: domino synthesis of pentasubstituted pyridines under solvent-free conditions. Org. Biomol. Chem. 2011, 9, 4025–4028 and references cited therein. (11) (a) Bohlmann, F.; Rahtz, D. Uber eine neue Pyridinsynthese. Chem. Ber. 1957, 90, 22652272; (b) Bagley, M. C.; Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J. One-Pot Multistep Bohlmann-Rahtz Heteroannulation Reactions:Synthesis of Dimethyl Sulfomycinamate. J. Org. Chem. 2005, 70, 1389-1399; (c) Kantevari, S.; Patpi, S. R.; Addla, D.; Putapatri, S. R.; Sridhar, B.; Yogeeswari, P.; Sriram,
D. Facile Diversity-Oriented Synthesis and
Antitubercular Evaluation of Novel Aryl and Heteroaryl Tethered Pyridines and Dihydro-6Hquinolin-5-ones Derived via Variants of the Bohlmann-Rahtz Reaction. ACS Comb. Sci. 2011, 13, 427–435 and references cited therein. (12) (a) Fujimori, T.; Wirsching, P.; Janda, K. D. Preparation of a Kröhnke Pyridine Combinatorial Library Suitable for Solution-Phase Biological Screening. J. Comb. Chem., 2003, 5, 625–631; (b) Jiang, B.; Hao, W-J.; Wang, X.; Shi, F.; Tu, S-J. Diversity-Oriented Synthesis of Kröhnke Pyridines. J. Comb. Chem. 2009, 11, 846–850; (c) Prakasam, T.; Nandakumar, A.; Muralidharan, D.; Perumal, P. T. Simple and Convenient Approach to the Kröhnke Pyridine Type Synthesis of Functionalized Indol-3-yl Pyridine Derivatives Using 3Cyanoacetyl Indole. J. Comb. Chem. 2010, 12, 161–167. (13) (a) Sielemann, D.; Keuper, R.; Risch, N. Synthesis of Novel Functionalized Bi- and Oligopyridines. Eur. J. Org. Chem. 2000, 543-548; (b) Kelly, T. R.; Lebedev, R. L. Synthesis of Some Unsymmetrical Bridged Terpyridines. J. Org. Chem. 2002, 67, 2197-2205; (c) Nikolaus, R.; Esser, A. Ein neuartiger zugang zu kondensierten pyridinen. Synthesis 1988, 337; (d) Jagath Reddy, G.; Latha, D.; Thirupathaiah, C.; Srinivasa Rao, K. A facile synthesis of 2,3-disubstituted-6-arylpyridines from enaminones using montmorillonite K10 as solid acid support. Tetrahedron Lett. 2005, 46, 301–302; (e) Allais, C.; Constantieux, T.; Rodriguez, J. Use of β,γ-Unsaturated α-Ketocarbonyls for a Totally Regioselective Oxidative Multicomponent Synthesis of Polyfunctionalized Pyridines. Chem. Eur. J. 2009, 15, 12945– 12948; (f) Gangadasu, B.; Narender, P.; Bharath Kumar, S.; Ravinder, M.; Ananda Rao, B.; ACS Paragon Plus Environment
ACS Combinatorial Science
Page 16 of 16
16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Ramesh, Ch.; China Raju, B.; Jayathirtha Rao, V. Facile and selective synthesis of chloronicotinaldehydes by the Vilsmeier reaction. Tetrahedron 2006, 62, 8398–8403; (g) Gogoi, S.; Gogoi, S.; Boruah, R. C. A Rapid and Convenient Microwave-Promoted Synthesis of 3,5-Disubstituted 2-Chloropyridines and Their Conversion into Tetrazolo[1,5-a]pyridines. Synthesis 2013, 45, 219-224. (14) (a) Sha, F.; Huang, X. A Multicomponent Reaction of Arynes, Isocyanides, and Terminal Alkynes: Highly Chemo- and Regioselective Synthesis of Polysubstituted Pyridines and Isoquinolines. Angew. Chem. Int. Ed. 2009, 48, 3458 –3461; (b) Sha, F.; Wu, L.; Huang, X. Chemo- and Regioselective Assembly of Polysubstituted Pyridines and Isoquinolines from Isocyanides, Arynes, and Terminal Alkynes. J. Org. Chem. 2012, 77, 3754−3765. (c) Shi, Z.; Loh, T-P. Organocatalytic Synthesis of Highly Functionalized Pyridines at Room Temperature. Angew. Chem. Int. Ed. 2013, 52, 8584–8587; (d) Xiang, J-C.; Wang, M.; Cheng, Y.; Wu, A-X. Molecular Iodine-Mediated Chemoselective Synthesis of Multisubstituted Pyridines through Catabolism and Reconstruction Behavior of Natural Amino Acids. Org. Lett. 2016, 18, 24-27 and references cited therein. (15) Gogoi, J.; Gogoi, P.; Goswami, L.; Boruah, R. C. Microwave-Assisted Synthesis of Fused and Substituted 2-Aminopyridines from β-Halo α,β-Unsaturated Aldehydes. Synthesis 2015, 47, 1905-1912. (16) (a) Gogoi, P.; Bezbaruah, P.; Boruah, R. C. Ligand-free suzuki cross-coupling reactions: Application to β-Halo-α,β-unsaturated aldehydes. Eur. J. Org. Chem. 2013, 5032-5035; (b) Gogoi, J.; Gogoi, P.; Boruah, R. C. One-pot stereoselective synthesis of (Z)-β-ketoenamides from β-halo α,β-unsaturated aldehydes. Eur. J. Org. Chem. 2014, 3483-3490. (17) Shekarrao, K.; Kaishap, P. P.; Saddanapu, V.; Addlagatta, A.; Gogoi, S.; Boruah, R. C. Microwave-assisted palladium mediated efficient synthesis of pyrazolo[3,4-b]pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]quinazolines. RSC Adv. 2014, 4, 24001-24006. (18) Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods. 1983, 65, 55-63.
ACS Paragon Plus Environment
