5-Isopropylidene-3-ethyl rhodanine induce growth inhibition followed by apoptosis in leukemia cells

Abstract

5-Isopropylidene-3-ethyl rhodanine II was prepared by conventional and Microwave assisted synthesis. For the first time, we found that rhodanine II treatment led to cytotoxicity in leukemic cell line, CEM by inducing apoptosis.

Introduction

Rhodanine derivatives are attractive compounds due to their biological activities. They are anticonvulsant, antibacterial, antiviral and antidiabetic in nature [1] (a), [1] (a)(b). Rhodanine derivatives have also been reported as inhibitors of Hepatitis C Virus (HCV) protease [2], uridine diphospho-N-acetylmuramate/l-alanine ligase [3], bacterial β-lactamase and Mur ligases [4], [5]. Recently, substituted rhodanines were investigated for tau aggregation inhibitor properties [6]. Rhodanines are classified as nonmutagenic [7] and a long-term study on the clinical effects of the rhodanine-based Epalrestat for antidiabetic demonstrated that it is well tolerated [8]. The use of the rodanine analogs as anti-leukemia agents has also been reported in literatures [9], [10], [11], [12], [13], [14], [15]. Rhodanine derivatives were found to have marked mildew-proofing activity. It is interesting to note that the new mildew-proofing agents contain the structure

present in many plant fungicides (tetramethylthiuram disulphide and the salts of dithiocarbamic acid), as well as a carbonyl group conjugated with an ethylenic linkage, found in another class of fungicides [16]. Due to various possibilities of chemical derivatization of the rhodanine ring, rhodanine-based compounds will probably remain a privileged scaffold in drug discovery. Therefore, the synthesis of these compounds is of considerable interest.

The rhodanine moiety has been synthesized by various methods such as addition of isothiocyanate to mercaptoacetic acid followed by acid catalyzed cyclisation, or the reaction of ammonia or primary amines with carbon disulfide and chloroacetic acid in the presence of bases [17], [18].

Arylidenerhodanines are frequently identified as potent hits in high throughput screening against various prokaryotic and eukaryotic targets. Condensation of aromatic aldehydes at the nucleophilic C-5 active methylene has been performed using piperidinium benzoate in refluxing toluene or sodium acetate in refluxing glacial acetic acid [17], [18]. Recently, Sim et al. [19] reported the synthesis of 5-arylalkylidene rhodanines in 60–82% yields by heating the reactants suspended in toluene at 110 °C for 3 days. Sing et al. [20] reported the condensation of rhodanine with an aldehyde (0.1 mmol) by heating in anhydrous EtOH (200 mL) for 6 h at 80 °C. Zhang Alloum et al. reported the successful synthesis of some 5-arylalkylidene rhodanines on solid inorganic supports in dry media under microwave irradiation [21], [22]. Jian-Feng Zhou et al. have reported the synthesis of bis(benzylidene)cycloalkanones by the aldol condensation in an aqueous medium under phase-transfer catalysis and microwave irradiation [23] and synthesis of 5-arylalkylidene rhodanines by the aldol condensation of aromatic aldehydes with rhodanine using tetrabutylammonium bromide (TBAB) as phase-transfer catalyst in an aqueous medium under microwave irradiation.

Alternatively, the alkylidene rhodanines were prepared by the condensation of 3-3-carboxyethylrhodanines with oxo-compounds unrelated to aromatic aldehydes and tested for possible antimetabolic activity [24]. Rhodanine, Ketone, and NH₄OAc were refluxed in toluene for 3 days to prepare the alkylidene rhodanin derivatives. Obviously, these methods involve long reaction times, high temperatures, use large quantities of organic solvents and some give unsatisfactory yields. Due to these drawbacks the number of available reports on the investigation of alkylidene rhodanines was very few. This prompted us to synthesise few rhodanine derivatives and their corresponding oxygen (2-thio-2,4-oxazolidine derivatives) and nitrogen (thiohydantions) analogs. Besides we show that the newly synthesized isopropylidene rhodanine derivatives induced cytotoxicity in leukemic cells in a dose- and time-dependent manner. The results are encouraging, which makes them a promising starting point for further synthesis and optimization by QSAR studies.