Facile Diversity-Oriented Synthesis of Polycyclic Pyridines and Their

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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

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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

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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

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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


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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

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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



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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

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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


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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


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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}



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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.


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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


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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

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Facile Diversity-Oriented Synthesis of Polycyclic Pyridines and Their

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