Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity

doi:10.1016/j.ejmech.2009.03.023

European Journal of Medicinal Chemistry

Volume 44, Issue 8, August 2009, Pages 3340-3344

https://doi.org/10.1016/j.ejmech.2009.03.023 Get rights and content

Abstract

A new series of chiral 1,3,4-thiadiazoles derivatives possessing γ-substituted butenolide moiety were synthesized and evaluated for in vitro anticancer properties. All the compounds showed good anticancer activities against Hela cell lines. Of all the studied compounds, compound 9e exhibited the best inhibitory activity with an IC₅₀ of 0.9 μM. After being treated with 0.1 μg/mL compound 9e for 24 h, the growth inhibition rate of Hela cell lines was 59.2%.

Graphical abstract

In the present study, a new series of chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety were synthesized and evaluated for their in vitro anticancer activity.

Introduction

The identification of new compounds for the treatment of cancer is an important undertaking in pharmaceutical research. 1,3,4-Thiadiazole derivatives have received much attention due to their versatile biological properties [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. In particular, a few differently substituted 1,3,4-thiadiazoles have been found to exhibit anticancer activities [14], [15], [16], [17], [18]. Besides, γ-substituted butenolide moiety represents a biological important entity that is present in natural products such as dysidiolide [19], andirolactone [20] and vallapin [21]. Dysidiolide and its derivatives have been found to possess varying anticancer properties [22], [23], [24].

In view of these above mentioned facts and an attempt to achieve new compounds with better anticancer properties, we designed and synthesized a new series of hybrid 1,3,4-thiadiazoles derivatives possessing γ-substituted butenolide moiety (Fig. 1) to evaluate their in vitro anticancer properties. To the best of our knowledge, the synthesis and anticancer activities of these compounds have not been reported so far.

Section snippets

Chemistry

The enantiomerically pure γ-substituted butenolides 4 were prepared by the procedure shown in Scheme 1 [25], [26]. Mucobromic acid 2 was easily accessible by the treatment of furfural 1 with Br₂/H₂O. The enantiomerically pure γ-substituted butenolides 4 were obtained via acetalization of mucobromic acid 2 by employing (−)-menthol and (+)-borneol as a chiral auxiliary, respectively and followed by resolution of the resulting diastereomers.

The 5-substituted-2-mercapto-1,3,4-thiadiazoles 8 were

Conclusion

In summary, a series of new chiral 1,3,4-thiadiazoles derivatives possessing γ-substituted butenolide moiety have been synthesized and their in vitro anticancer activity against cervical cancer cells has been evaluated. All the target compounds exhibited good anticancer activities. Compound 9e with an IC₅₀ of 0.9 μM was found to be the most active. This might have relationship with the hydrophile ability of nitro group on the benzene ring. Further studies of SAR of these compounds and the

Chemistry

Thin-layer chromatography (TLC) was carried out on silica GF254 plates (Qingdao Haiyang Chemical Co., Ltd, China). All the melting points were determined on a WRS-1B digital melting point apparatus and are uncorrected. IR spectra were recorded on an FTIR-8400S spectrometer as KBr discs. ¹H NMR and ¹³C NMR spectra were obtained with a Bruker Avance III 400 MHz spectrometer in chloroform-d (CDCl₃) and tetramethylsilane (TMS) was used as an internal standard. Diffraction measurement was made on a

Acknowledgements

We thank Major State Basic Research Development Program of China (2007CB21602), National Natural Science Foundation of China (20702044), Key Project of Chinese Ministry of Education (203143), and Natural Science Foundation of Ningxia Province of China (NZ0606) for financial support. We also thank a reviewer for his invaluable suggestions on our work.

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Short communicationSynthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Chemistry

Acknowledgements

Bioorg. Med. Chem.

Il Farmaco

Il Farmaco

Il Farmaco

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Chin. Chem. Lett.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Pharm. Sci.

Phytochemistry

Bioorg. Med. Chem.

Short communication
Synthesis of new chiral 2,5-disubstituted 1,3,4-thiadiazoles possessing γ-butenolide moiety and preliminary evaluation of in vitro anticancer activity