1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel

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1,3-dipolar cycloaddition reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties Prakash Rambhau Mali, Prashishkumar Kisan Shirsat, Navnath Bapurao Khomane, V Lakshama Nayak, Jagadeesh Babu Nanubolu, and Harshadas Mitaram Meshram ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00044 • Publication Date (Web): 17 Aug 2017 Downloaded from http://pubs.acs.org on August 19, 2017

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ACS Combinatorial Science

1,3-dipolar cycloaddition reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties Prakash R. Mali,a,b Prashishkumar K. Shirsat,a,b Navnath Khomane,a,b Lakshama Nayak,a Jagadeesh Babu Nanuboluc and H. M. Meshram*,a a

Medicinal chemisty and Biotechnology division, CSIR-Indian Institute of Chemical Technology Hyderabad, India

b c

Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.

Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, India.

KEYWORDS:1,3-dipolar cycloaddition, amino acid, but-2-ynedioates, N-substituted oxindole derivatives, Microwave assisted, Aqueous medium, Cytotoxic properties Supporting Information Placeholder ABSTRACT: The multicomponent reaction between isatin, amino acid, but-2-ynedioates and phenacyl bromide has been developed using microwave irradiation under catalyst and base free conditions in aqueous medium. This synthetic protocol is useful for the synthesis of various functionalized spirooxindole derivatives. This MCR exhibits a broad substrate scope with excellent yields and shorter reaction time. Additionally the synthesized spirooxindole derivatives were evaluated for their anticancer activity against three human cancer cell lines; MCF-7 (breast), A549 (lung) and Hela cervical. Most of the compounds showed moderate to potent cytotoxic activity against the tested cell lines.

Introduction Cancer is a major health concern showing an alarming increase in the number of patients throughout the world due to increasing longevity. According to the statistics, cancer is the second leading cause of human mortality after cardiovascular disease.1-4 Old drugs like Indomethacin (GI50 64.3 mM, COX 2-inhibitor) and Doxorubicin (GI50 0.096 mM, topo II inhibitor) created some hope for extending life of cancer patients.5-9 There are several current chemotherapeutic drugs available having various restrictions and drawbacks like difficulties in isolation, undesirable side effects, complexity in synthesis and multidrug resistance.10 Therefore, to overcome these problems there is a critical need to develop and improve new chemotherapeutic agents which are better than previous ones. There are several spirooxindoles which are found in nature, some with better activity (Figure 1). Due to their biologically active properties, we are interested in the synthesis of spirooxindoles derivatives.11 Herein we report an efficient, simple, environmentally benign and ecofriendly route toward spirooxindoles by using water as an easily available green solvent. The present synthetic, multi-component reaction (MCR) strategy is useful for the synthesis of libraries of novel spirooxindoles.12

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Figure 1: Some biologically active pharmaceutical drugs or lead compounds with spirooxindole scaffold. Due to the simplicity of preparation, the imine generated from isatin with α-amino acids or amines are often chosen as important 1,3-dipolar intermediates to react with different dipolarophiles. In this context, Wang et al. reported mesityl oxide dienone13, Perumal and co-workers reported 1,3-dipolar cycloaddition reaction of isatin, phenylglycine, proline and thiaproline with β-nitro styrenes. 14 Subsequently, catalytic 1,3-dipolar cycloaddition was also reported using diazooxindoles as the starting material.15 Sun and co-workers reported the 1,3-dipolar cycloaddition reaction of amino acids, isatin and but2-ynedioates in methanol gave an unprecedented spiro product.16 Shi et al. reported the three-component reaction of isatin, an amino-ester and alkynes in the presence of Bronsted acids.17 Recently, Kumar and co-workers reported the multicomponent 1,3-dipolar cycloaddition strategy for the synthesis of dihydrothiophenone-engrafted dispiro hybrid heterocycles.18 Recently, interest in microwaves in organic synthesis has increased because of faster reaction times, better yields, higher purities and greater operational simplicity over conventional heating.19 To the best of our knowledge, there is no previous report for the synthesis of spirooxindole derivatives using isatin, but-2- ynedioates, amino acids and phenacyl bromide. Scheme 1: synthesis of oxindole derivatives under microwave irradiation in aqueous medium.

In the continuation of our ongoing research20 using water as a green solvent herein we report the synthesis of substituted spirooxindole derivatives by using the microwave irradiation technique in water as a solvent staring from isatin, but-2ynedioates, amino acids and phenacyl bromide. Results and discussion As an extension of our investigation on microwave assisted synthesis of isatin based spiro compounds, our initial studies were directed towards examining the feasibility of our procedures and the optimization of the reaction conditions. By systematically varying key reaction conditions to effect the MCRs between isatins (1), but-2-ynedioates (2) and amino acids (3) as model substrates, we were able to determine the best reaction conditions. The effects of solvents, time and temperature were examined and the results are listed in (Table 1). Initially, when the reaction was performed in water, it did not furnish any desired product, even after 24 hours. When the same experiment was carried out under microwave irradiation at 50 oC for 15 minutes traces of product was detected. The further increase in the temperature to 70 oC afforded the expected required spirooxindole 4{1,1,1} in 40% yield. To further improve the yield of the product, the reaction was performed under microwave irradiation in different solvents, temperatures and times.


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Figure 2: X-ray ORTEP diagram for compounds 4{2,1,1} and 6{2,2,5,1}. The reaction was examined in water, methanol, ethanol, DCM, THF, DMF, acetonitrile, DMSO, toluene and 1,4-dioxane at various temperatures and times which resulted in the formation of compound 4{1,1,1} ( Table 1). It was observed that in 1,4dioxane (Table 1, Entry 1) and toluene (Table 1, Entry 2) the reaction did not proceed and in case of methanol as a solvent lower yield of the product was obtained (Table 1, Entry 8). Finally it was observed that when water was used as solvent gave the best results for the same reactions.

O

O

O

Cl

O

O

F

O

MeO

O

N H 1{1}

O

N H 1{2}

O

O

N H 1{3}

O

N H 1{4}

N H 1{5}

O O 2N

O

O

O

O

N Ph

N H

1{6}

OEt

OMe

EtO

MeO O

1{7}

Chemset 1 Diversity reagents {1-7}

O

2{1}

2{2}


HO

N H 3{1}

COOH

N H

COOH

H 2N

H2 N

COOH

H 2N

H 2N

COOH

COOH

3{6}

3{5}

3{4}

COOH

3{3}

3{2}

Chemset 3 Diversity reagents {1-6} O

O

O Br

Br

Br

Ph 5{2}

5{1}

5{3} O

O

O Br

Br

Br MeO

Cl 5{4}

5{5}

5{6}


Figure 3: Chemsets: Isatins Chemset 1, but-2-ynedioates Chemset 2, amino acid Chemset 3 and phenacyl bromide Chemset 4.



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Then the same reaction screened at different temperatures 50, 70, 80, 100 and 110 oC under microwave irradiation in water. It was observed that lowering the temperature (Table 1, Entry 14) resulted in low yield where as increase in temperature (Table 1, Entry 9) did not improve the yield of product. From the screening results the optimal condition was found to be it Entry 11 (Table 1).

Table 1. Optimization of reaction conditions for three and four component oxindole synthesis of 4{1,1,4}a and 6{1,1,4,1}aa

Entry

a

Temp (o c)

Solvent

Time (mins)

Yieldb (%)b

Comp

Comp

Comp

Comp

Comp

Comp

Comp

Comp

4{1,1,4}

6{1,1,4,1}

4{1,1,4}

6{1,1,4,1}

4{1,1,4}

6{1,1,4,1}

4{1,1,4}

6{1,1,4,1}

1

1,4-dioxane

Water

80

70

20

20

_

27

2

Toluene

Water

100

90

15

15

_

40

3

DMF

Water

110

100

15

15

20

91

4

THF

Water

80

110

20

15

15

85

5

Ethanol

Methanol

90

100

20

15

30

60

6

DMSO

Ethanol

110

90

18

15

20

20

7

DCM

1,4-dioxane

60

60

10

15

28

_

8

Methanol

DMF

80

70

15

15

55

_

9

Water

DMSO

110

90

15

15

70

_

10

Water

DCM

100

100

10

10

80

_

11

Water

Toluene

80

110

10

10

89

_

12

Water

_

80

_

15

_

75

_

13

Water

_

70

_

20

_

40

_

14

Water

_

50

_

15

_

26

_

Reaction conditions: Isatin (1 mmol), amino acids (1.2 mmol) and but-2-ynedioates (1 mmol) in water (2 mL) in

microwave at 80 °C for 10 mins. bIsolated yield of pure product. aa

Reaction conditions: Isatin (1 mmol), amino acids (1.2 mmol), but-2-ynedioates (1 mmol) and phenacyl

bromide (1 mol) in water (2 mL) in microwave at 100 °C for 15 mins.


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With the optimised conditions in hand, initially we tested the effect of the different substituents on the aromatic ring of isatin. The electron-donating substrates, such as 5,7-dimethyl isatin, 5-methoxy isatin afforded the desired products in high yields (Table 2, products 4{4,1,1}, 4{5,1,3}, whereas isatin containing halogen group resulted in moderate yields of the products (Table 2, entries 4{2,1,1}, 4{3,1,1}, 4{2,2,1}, 4{3,2,1}, 4{2,1,3}, 4{3,1,3}, 4{3,2,3}, 4{2,1,4}, 4{3,2,4}, 4{2,2,4}, 4{3,1,4}, 4{3,1,5}, 4{2,1,5}, 4{2,2,5}, 4{3,2,5}, 4{1,1,5} and 4{1,1,6}). The reaction of N-protected isatin proceeds smoothly to give the desired product in high yield (Table 2, entries 4{6,2,3}, 4{6,2,4}) as compared to isatin having free N-H group. Subsequently, we investigated the scope of variety of amino acids, in which we found that the reaction of isatin with phenyl alanine and but-2-ynedioates afforded a better yield compared to other amino acids such as proline, isoleucine, valine, and glycine. The reaction conditions for the synthesis of the four-component, novel oxindole derivatives optimised through the different temperature, solvent and time. For this isatin (1), but-2-ynedioates (2), amino acid (3) and phenacyl bromide (5) was chosen as model substrates. Water was found to be best solvent for the synthesis of N-alkylated oxindole derivatives (Table 1, Entry 3). The reaction, in other solvents such as 1,4-dioxane, DMF, DMSO, DCM, Toluene (Table 1, Entry 7-11) did not proceed. Whereas, use of protic solvents, such as methanol or ethanol, resulted in lower yields (Table 1, Entry 5, 6). The cyclised product was confirmed with the spectral data (IR, NMR, Mass, HRMS). Further both structures 4{2,1,1} and 6{2,2,5,1} were confirmed by X-ray crystallography (Figure 2). Table 2: Scope of isatins, amino acids and but-2-ynedioates amines for the synthesis of tetrahydrospiro[indoline-3,3pyrrolizine] 1,2dicarboxylate



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Furthermore, to optimise the reaction temperature, we carried out the reactions at different temperature ranging from 70 °C – 110 °C in water as solvent (Table 1, entries 1-4). The optimal temperature for the reaction was found to be 100 °C (Table 1, Entry 3) for 15 min. Lowering the temperature gave a lower yield (Table 1, entry 1). Therefore, and optimal reaction condition was obtained when water used as the solvent. With the optimised reaction conditions we investigated the scope of reaction with respect to isatin derivatives having both electron-donating and electron-withdrawing groups. It was observed that isatin bearing electron-withdrawing substituent’s gave higher yields (Table 3. comp. 6{3,1,4,2}, 6{7,1,5,4}). Phenacyl bromide containing aryl group with electron-withdrawing substituent’s gave considerably higher yields than those with electron-donating groups (Table 3. comp. 6{1,1,5,6}, 6{1,1,3,5}, 6{1,1,1,5}). When the reaction was performed using Nalkylated isatin, it did not furnish any desired product. We observed that only those isatin having free nitrogen gave the desired products. From this we conclude amino acid containing nitrogen substitution not take place in this reaction. In case of different amino acids, proline gave the highest yield as compare to other amino acids Table 3 comp. 6{1,1,1,1}, 6{1,1,1,3}, 6{1,1,1,4}, 6{1,1,1,5}, 6{1,1,1,2} all results are summarised in (Table 3). Table 3: Substrate scope for synthesis of n-substituted oxindole derivative

Plausible mechanism A plausible mechanism for this three-component reaction is proposed and illustrated in Figure 4. Initially, the condensation reaction of α-amino acid (3) with isatin (1) furnishes the imine intermediate (figure 4:1-3i) by eliminating CO2. Later on the 1,3-dipolar cycloaddition reaction (figure 4: 1-3ii) takes place between the imine intermediate and but-2-ynedioates (2) to form product 4. Finally, it cyclizes to form spiro compound 4. In the case of four-component reaction, the spiro compound further reacts with phenacyl bromide (5) and results in the formation of desired product 6.


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ACS Combinatorial Science O

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O O

O OR3 HN

OR3 N

O

O

NH2

1

3

OO

6

H2O

O

Ar

Br

Ar

OH

N H

O

5

N

H O

N H O OR3 HN

OR3 N H

CO2

OO

4 H

N O

1,3 dipolar cycloaddition reaction

H

N H

N H

1-3 i

O

N

OR3 O

O R3O

1-3 ii

O

OR3

R3O O

2

Figure 4: Plausible mechanism for the formation of pyrrolizine1, 2-dicarboxylate MTT assay method The anticancer activity of the compounds was determined using MTT assay [Biology-1]. 1×104 cells/well were seeded in 200 µl DMEM/MEM medium, supplemented with 10% FBS in each well of 96-well micro culture plates and incubated for 24 h at 37 °C in a CO2 incubator. All the compounds were added to the cells for 48 h. After 48 h of incubation, 20 µl MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) (5 mg/ml) was added to each well and the plates were further incubated for 4 h. Then the supernatant from each well was carefully removed, formazon crystals were dissolved in 200 µl of DMSO and absorbance at 570 nm wavelength was recorded. Cytotoxic activity: All the newly synthesized compounds 4{1,1,1}-4{6,2,4} were evaluated for their anticancer activity in three human cancer cell lines, A549 (lung), Hela (cervical) and MCF-7 (breast) by employing MTT assay.21 All the synthesized compounds showed good to potent activity against the tested cell lines. Among them compounds 4{1,2,1} and 4{1,2,5} showed significant activity against human lung cancer cell line, A549 with IC50 values 2.03 and 4.52 µM respectively when Doxorubicin is used as reference drug. Compound 4{1,2,5} was found to be more potent against MCF-7 cancer cell line having IC50 5.00 µM. 4{1,2,1} also showed good activity against Hela cancer cell line IC50 8.33 µM. Compounds 4{3,2,4} and 4{3,1,5} showed moderate activity against A549 cell line. The cycloadducts 4{1,1,1} and 4{1,1,2} also displayed moderate activity IC50 values 9.55 and 9.46 µM. Further compound results are summarized in (Table 4) and expressed its IC50 values respectively. Table 4: IC50 valuesa (in µM) for compounds in selected human cancer cell lines Compound

MCF-7b

A549c

4{1,1,1}

19.3

18.6

4{1,1,2}

9.4

4.8

16.6

4{1,1,3}

25.3

19.5

38.6

31.4

43.0

8.7

19.9

4{1,1,4} 4{1,1,5}

˃50 9.5


Helad ˃50


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4{1,1,6}

31.2

34.6

40.7

4{1,2,1}

3.3

2.0

8.3

4{1,2,4}

17.0

10.0

12.5

4{1,2,5}

5.0

4.5

4{2,1,1}

16.2

8.6

˃50 15.9

4{2,1,3}

˃50

˃50

˃50

4{2,1,4}

˃50

˃50

˃50

4{2,1,5} 4{2,2,1} 4{2,2,4} 4{2,2,5}

24.5 ˃50 22.0 ˃50

18.7

30.3

36.1

˃50

15.8

˃50

40.6

˃50

4{3,1,1}

14.5

16.9

17.0

4{3,1,3}

25.4

21.3

26.3

4{3,1,4}

24.9

18.3

27.8

4{3,1,5}

26.6

10.3

29.1

4{3,2,1}

˃50

54.1

4{3,2,3}

˃50

42.2

47.3

10.7

39.9

4{3,2,4} 4{3,2,5}

16.3 ˃50

˃50

4{4,1,1}

19.3

18.6

4{5,1,3}

20.6

29.2

4{6,2,3}

˃50

4{6,2,4}

˃50

˃50 27.7

˃50

˃50 ˃50 20.1 ˃50 ˃50

Doxorubicin

1.6

1.8

1.9

Sunitinib

25.4e

7.9f

˃30g

a

50% Inhibitory concentration after 48 h of drug treatment. b Human breast cancer. c human lung cancer. d Human cervical cancer. e, f, g IC50 values taken from the literature for comparison.22

Conclusion: In summary we have demonstrated a new, convenient, efficient, catalyst and base free reaction for the synthesis of novel spirooxindole derivatives using microwave irradiation in aqueous medium. This reaction has several advantages: (i) water is used as the reaction solvent; (ii) high atom economy; (iii) avoidance of catalyst; and (iv) broad substrate scope. Additionally, the synthesized compounds were evaluated for their anticancer activity against three human cancer cell lines, namely; MCF7 (breast), A549 (lung) and Hela (cervical). Most of the compounds showed significant anticancer activity against human lung cancer cell line, A549. Based on these observations, these compounds could be considered as important lead compounds for the potential application in anticancer chemotherapy. ACS Paragon Plus Environment

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Experimental General procedure for three components reaction: All microwave irradiation experiments were carried out in a dedicated CEM-Discover monomode microwave apparatus. A sealed 10 mL glass microwave vial containing mixture of isatin (1 mmol), amino acids (1.2 mmol) and but-2-ynedioates (1 mmol) in water (2 mL) was irradiated under microwave irradiation (150 W power) at 80 oC for 10 minutes. After completion of the reaction, (indicated by TLC) the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with brine solution, dried with anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography with a hexane-ethyl acetate (8 : 2) mixture to get the pure compounds. General Procedure for four components reaction: A sealed 10 mL glass tube containing mixture of isatin (1 mmol), amino acids (1.2 mmol), but-2-ynedioates (1 mmol) and phenacyl bromide (1 mmol) in water (2 mL) was irradiated under microwave irradiation (150 W power) at 100 oC for 15 minutes. After completion of the reaction, (indicated by TLC) the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with brine solution, dried with anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography with a hexane-ethyl acetate (9:1) mixture to get pure compounds. The isolated compounds were well characterized by IR, 1H NMR, 13C NMR and HRMS. ASSOCIATED CONTENT Supporting Information Copies of 1H and 13C NMR spectra of all new compounds. This material is available free of charge via the Internet at http:// pubs.acs.org. AUTHOR INFORMATION Corresponding Author Email: [email protected], Contact No: +91-40-2719- 1640 ORCID Harshadas Meshram: 0000-0002-5440-1542 Funding Sources This work was supported by UGC, New Delhi, and Council of Scientific & Industrial Research (CSIR), New Delhi under the XIIth Five Year Plan Project “Affordable Cancer Therapeutics (ORIGIN)” [Grant No. CSC0108] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS Prakash Mali is thankful to CSIR-UGC for the award of fellowship, The authors thank CSIR, New Delhi for financial support as part of XII five year plan program under the title ORIGIN (CSC 0108). REFERENCES 1. (a) Bach, P. B.; Jett, J. R.; Pastorino, U.; Tockman, M. S.; Swensen, S. J.; Begg, C. B. Computed tomography screening and lung cancer outcomes. JAMA. 2007, 297, 953-961. (b) Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer Statistics. CA: A Cancer Journal for Clinicians. 2014, 64, 9-29. 2. Gibbs, J. B. Mechanism-Based Target Identification and Drug Discovery in Cancer Research. Science. 2000, 287, 19691973. 3. Arve, L.; Voigt, T.; Waldmann, H. Charting Biological and Chemical Space: PSSC and SCONP as Guiding Principles for the Development of Compound Collections Based on Natural Product Scaffolds. Qsar Comb. Sci. 2006, 25, 449-456. 4. (a) Rajitha, G.; Janardhan, B.; Mahendar, P.; Ravibabu, V.; Sairengpuii, H.; Rajitha, Sadanandam, A.; Siddhardha, B. Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis, characterization and evaluation of anticancer and



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Table of contents

1. Text A one pot multi-component aqueous phase protocol is developed for the synthesis of functionalized spirooxindole derivatives by using microwave irradiation technique and the synthesized spirooxindole derivatives were evaluated for their anticancer activity against three human cancer cell lines. 2. Graphic

O Ar

O

R4

O

Br

R4

OR3

HN

OR3

R1 N

OO

° MW, 100 C

H2O, 15 min, When R2 = H

O Ar

R1

N R2

OH

O

R4

NH2

O

OR3

HN ° MW, 80 C

O

H2O, 10 min

O

R1

OR3 N R2

OO

OR3

R3O O

28 Examples

29 Examples

Catalyst f ree Broad substrate scope 57 Examples, up to 93% yield

Water as a green solvent Eco f riendly Anticancer activity


1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel

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