Organic Chemistry International

Organic Chemistry International / 2008 / Article

Research Letter | Open Access

Volume 2008 |Article ID 209830 | https://doi.org/10.1155/2008/209830

Ying Yang, Wen-Jun Mao, Huan-Qiu Li, Tao-Tao Zhu, Lei Shi, Peng-Cheng Lv, Hai-Liang Zhu, "Synthesis and Biological Evaluation of 7-O-Modified Formononetin Derivatives", Organic Chemistry International, vol. 2008, Article ID 209830, 4 pages, 2008. https://doi.org/10.1155/2008/209830

Synthesis and Biological Evaluation of 7-O-Modified Formononetin Derivatives

Academic Editor: Alexander Greer
Received15 Jul 2008
Accepted27 Sep 2008
Published18 Dec 2008

Abstract

Three series of novel formononetin derivatives were synthesized, in which formononetin and heterocyclic moieties were separated by 2-carbon, 3-carbon, and 4-carbon spacers. The chemical structures of these compounds were confirmed. All the derivatives were screened for antiproliferative activities against Jurkat cell line and HepG-2 cell line. In this paper, compounds prepared were also screened for their antibacterial activity of six bacterial strains. Compound 3b exihibited promising antibacterial activity against B. subtilis with minimal inhibitory concentration (MIC) value of 0.78  𝜇 g/mL, and compound 5e showed significant antiproliferative activities against Jurkat cell growth with I C 5 0 of 1 . 3 5 × 1 0 4 𝜇 g/mL. The preliminary investigation of structure-activity relationships (SARs) was also discussed based on the obtained experimental data.

1. Introduction

Isoflavonoids are a broad class of polyphenolic secondary metabolites that are abundant in plants [1, 2] and in various common foods such as apples, onions, tea, and red wine [3, 4]. Isoflavonoids also have a potent activity against protein tyrosine kinase (PTK) [5]. Because of such a broad range of pharmacological properties, they receive considerable therapeutic importance. Protein tyrosine kinases (PTKs) have been intensively investigated because of their role in the transduction of proliferative signals in mammalian cells. Many transmembrane growth factor receptors possess intracellular PTK activity, with initiation of this activity following external binding of a growth factor, being the first step in the cellular signal transduction pathway which controls mitogenesis and cell proliferation [6, 7]. Therefore, selective interruption of signal transduction in tumor cells by specific inhibitors of PTK activity has recently emerged as a major new approach for the design of tumor-specific drugs [8, 9].

Formononetin (1, shown in Scheme 1), a kind of isoflavonoid, is reported to have many biological activities including antiproliferative, antioxidant, antidiabetic, antiestrogenic, antibacterial, antiangiogenic effects, and so on [1014]. Formononetin is also a potent aryl hydrocarbon receptor agonist in vitro [14]. The versatile biological activities of formononetin prompt us to prepare a new series of its derivatives and evaluate their biological significance. Herein, we describe the synthesis of formononetin derivatives in which formononetin and heterocyclic moieties were linked by spacers,and investigate the effects of the size of the spacers and substitution patterns of the heterocyclic moieties. All of the compounds were assayed for their antiproliferative activities against a panel of two human tumor cell lines (Jurkat and HepG-2) by applying the MTT colorimetric assay. The results of this study may be useful to researchers attempting to gain more understanding of the PTK inhibitory activity of isoflavonoid derivatives.

209830.scheme.001

To our knowledge, this is the first report on the screening of 7-O-modified formononetin derivatives for their antimicrobial and antiproliferative activities.

2. Results and Discussions

2.1. Chemical Synthesis

Compounds 2a–c were the key intermediates for the synthesis of the compounds investigated. They were prepared from alkylation of 7-OH group by using 1,2-, 1,3-, or 1,4-dihaloalkanes in the presence of K2CO3 in anhydrous DMF [15]. The synthesis of compounds 3a–f, 4a–e, and 5a–f was accomplished according to the general pathway illustrated in Scheme 1. To increase the antimicrobial properties of formononetin, formononetin derivatives in which the formononetin ring system was linked to the alkylamines by different spacers at C-7 position were investigated, with a view to modify their lipophilicity. Literature survey revealed that the compounds containing alkyl amino side chains showed better activities against the test bacteria than those containing aromatic ring amino side chains [15]. To further optimize this activity, seventeen compounds reported in this paper contain alkyl amino groups. Reaction of 2a–c with different cyclic and noncyclic alkylamines yielded 3a–f, 4a–e, and 5a–f, respectively, which were all first reported. All of the synthesized compounds gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structures.

2.2. Biological Evaluation and Discussion
2.2.1. Antiproliferative Activities [16]

The antiproliferative activities of these compounds were evaluated against a panel of two human tumor cell lines (Jurkat and HepG-2) by applying the MTT colorimetric assay. The observed IC50’s are listed in Table 1. From the results of the in vitro antiproliferative MTT tests of the prepared compounds, it followed that in series 1, most of the prepared compounds showed good antiproliferative activities. Among them compounds 3b and 3d exhibited strong activities on Jurkat cell growth. Also, compounds 3b and 3c had stronger activities on HepG-2 cell line than the positive control 5-UF. In series 2, compounds 4a, 4b, and 4e displayed remarkable antiproliferative activities on Jurkat cell, while they just showed moderate activities against HepG-2 cell. In series 3, compound 5e displayed significant antiproliferative activities on Jurkat cell growth, and compound 5d showed promising inhibitory activities on HepG-2 cell growth.


CompoundsIC50 (μg/mL)
Jurkat1HepG-22

123.5273.03
2a 48.04>100.00
2b 0.214.14
2c 9.507.18
3a13.935.57
3b1.823.24
3c>100.002.67
3d3.708.14
3e12.217.15
3f 16.497.54
4a 0.416.14
4b 5.328.58
4c 16.4452.21
4d 18.085.90
4e 3.4957.82
5a 1.946.54
5b >100.007.52
5c 0.644.94
5d 1.271.49
5e 1.35×10-413.14
5f 7.1113.53

5-fluorouracil18.412.50

1Jurkat: Human T cell lymphoblast-like cell line.2HepG-2: Human hepatocellular liver carcinoma cell line.
2.2.2. Antibacterial Activities [17]

The antibacterial activities of the synthetic compounds were tested against B. subtilis, S. aureus and S. faecalis (Gram-positive bacteria), E. coli, P. aeruginosa, and E. cloacae (Gram-negative bacteria) by broth dilution method recommended by National Committee for Clinical Laboratory Standards (NCCLS) [18, 19]. Standard antimicrobial agents like penicillin and kanamycin were also screened under identical conditions for comparison. The minimal inhibitory concentration (MIC) values for the bacteria are listed in Table 2.


CompoundsMinimum inhibitory concentrations 0 𝑥 0 𝑓 𝑓 0 8 MICs 0 𝑥 0 𝑓 𝑓 0 9 (μg/mL)
Gram positiveGram negative
S. faecalisS. aureusB. subtilisE. coliP. aeruginosaE. cloacae

13.1225.0050.0050.0025.0050.00
2a3.126.253.126.251.5650.00
2b3.1250.0025.006.2525.001.56
2c3.123.1250.0012.5025.0012.50
3a3.126.2550.003.123.1225.00
3b1.5612.500.783.1250.003.12
3c3.126.256.2525.006.253.12
3d3.126.256.2512.503.126.25
3e3.121.5650.0025.0025.006.25
3f3.1212.5025.006.2550.0025.00
4a3.123.1250.006.2550.0050.00
4b3.1225.003.121.566.2512.50
4c3.1212.5025.006.256.2512.50
4d3.126.253.1212.503.1225.00
4e3.123.1250.001.5650.0050.00
5a3.121.566.2525.006.253.12
5b3.1212.501.5625.0050.0050.00
5c3.1250.001.566.256.2550.00
5d3.1250.0025.006.253.126.25
5e3.120.7812.506.2525.0025.00
5f3.1225.0050.0050.003.121.56

Penicillin1.561.561.566.256.253.12
Kanamycin3.121.560.393.123.121.56

Most compounds in series 1, which contained a 2-carbon spacer, displayed good activities against the test microorganisms. In this series, compound 3b showed pronounced activity against B. subtilis and S. faecalis with MIC values of 1.56 μg/mL and 0.78 μg/mL, respectively. In addition, compound 3e showed good activity against S. aureus.

A few compounds in series 2, which contain a 3-carbon spacer, exhibited great activities against the test microorganisms. In this series, compounds 4b, 4d, and 4e showed great activities against S. aureus, B. subtilis, and E. coli. Among them, 4b and 4e showed strong activities against E. coli with their MIC value (1.56 μg/mL) superior to the positive control kanamycin.

Similarly, several compounds in series 3, which contain a 4-carbon spacer, showed good activities against the test microorganisms. Among them, compounds 5a and 5e exhibited strong activities against S. aureus with their MIC values of 1.56 μg/mL and 0.78 μg/mL, respectively. Compounds 5b and 5c displayed great activities against B. subtilis. Also, compounds 5d and 5f showed strong activities against P. aeruginosa with the MICs (3.12 μg/mL), which were comparable to the positive control kanamycin.

3. Conclusion

To investigate the biological activities of formononetin derivatives, we had synthesized three series of formononetin derivatives. For all the compounds synthesized, antiproliferative and antibacterial activities against two cancer cell lines (Jurkat and HepG-2) and six bacterial strains (three Gram-positive bacterial strains: Bacillus subtilis, Staphylococcus aureus, and Streptococcus faecalis and three Gram-negative bacterial strains: Escherichia coli, Pseudomonas aeruginosa, and Enterobacter cloacae) were determined. From the bioassay results, it may be concluded that those containing long alkyl amino side chains exhibited better activities against gram-positive bacteria than those containing short ones, while it had the opposite rule for gram-negative. Specifically, the derivatives with dipropylamine moiety were more active than most of the other analog. In this study, we focused our attention on the structure-activity relationships. The work was of interest because this is a preliminary investigation of SAR, serving as the basis of further more detailed work.

Acknowledgment

Financial support by the National Natural Science Foundation of China (no. 30772627) is kindly acknowledged.

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Copyright © 2008 Ying Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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