Microwave-assisted Synthesis of New 1 , 3-thiazolidin-4-ones and Evaluation of Their Anticancer Efficacy

An efficient method for the synthesis of thiazolidinones from the microwave-assisted, three-component mixture of an aromatic aldehyde, a 2-amino-4H-benzothiopyrano[4,3-d]thiazole and meraptoacetic acid is described. The transformation of the amino group of 2-amino-4H-[1]benzothiopyrano[4,3-d]thiazoles into a thiazolidinone ring has not been reported to date. In vitro their anticancer activity was evaluated by MTT method. The results of bioactivities evaluation showed the compound 4 exhibited the best anticancer activity and its IC50 was 5.76 μM, 6.19 μM, 6.67 μM against gastric cancer cells (SGC-7901), cervical cancer cells (Hela) and lung cancer cells (A-549), respectively.


Introduction
Thiazoles are one of the most intensively investigated classes of aromatic five membered hetrocycles.Thiazole derivatives find a variety of applications ranging from anti-fungal and anti-bacterial through to CNS regulators of commercially successful diuretics.All these facts were driving force to develop novel thiozole derivatives with wide structural varation.

Anticancer Activity in Vitro
The anticancer activities of target compounds were evaluated in vitro gastric cancer cells (SGC-7901), cervical cancer cells (Hela) and lung cancer cells (A-549) by measuring cell viability according to the MTT method described in the literature with cisplatin as the positive control.The cells were seeded in RPMI 1640 medium (100 μL) in a 96-well plate at a concentration of 6000-7000 cells per well.After culturing for 12 h at 37 °C and 5% CO 2 , cells were incubated with various concentrations of the samples for 24 h.Twenty microliter of MTT (5 mg/mL) was added and incubated with the cells for 4 h.The formazan product was dissolved by adding dimethyl sulfoxide (DMSO, 100 μL) to each well, and the plates were read at 570 nm.All measurements were performed in triplicate and each experiment was repeated at least three times.IC 50 values were determined as the drug and sample concentration at 50% inhibition of the cell growth.

Microwave-assisted synthesis thiazolidin-4-ones
Generally, 1,3-thiazolidin-4-ones derivatives can be synthesized by a three-component condensation of a primary amine, an aldehyde, and mercaptoacetic acid.The dehydration process is the rate determining step of the reaction which is usually performed, the reaction is usually performed in refluxing toluene with dehydrating agents for 2-48 hours, but the yields were generally not satisfactory, Thus either a catalyst or a dehydrating agent or a Dean and Stark' was usually used to promote reaction.The applications of some new synthetic methods, such as microwave-assisted synthesis, and reagents, such as ionic liquids (Zhang, Xinying, 2009), and KSF clay (Dandia, A., 2006), have been recently explored for improving the synthesis of the 1,3-thiazolidin-4-ones.We now reported a new method for one-pot synthesis of a series of new 1,3-thiazolidin-4-ones using DCC as a dehydrating agent under microwave heating in a sealed vessel (Scheme 1).
This new method resulted in increased yields with shorter reaction times in comparison with the conventional routes which typically affords yields in the range 10%-65%.As to different substitutions of aromatic aldhydes R 2 -CHO, their reactivity was: R 2 =aryl with electron withdrawing > aryl with no substitution > aryl with electron donating.The yields were good when aromatic aldhydes with electron withdrawing, such as -NO 2 and -Cl, and it was more than 85%; when R 2 =4-nitrophenyl, the yield was the best.When aromatic aldhydes with electron donating, mainly because electron donating groups increased the electron density reducing the reactivity of carbonyl, so the reactivity lower, the yield decreased.In this report, we also studied the effects of different substituents on 4H-thiochromeno[4,3-d]thiazol-2-amines.The results showed that different R and R 1 had no significant impact on the yield of 1,3-thiazolidin-4-one.
In conclusion, during the microwave-assisted synthesis of 1,3-thiazolin-4-ones, the electron density of aldhydes had great impact on the reactivity.Generally speaking, the reactivity was higher when aromatic aldhydes with electron withdrawing, and the yield was also good; when electron donating on aromatic ring, the reactivity was lower, so the yield decreased.

Study for anticancer activity
Anticancer activities were tested against gastric cancer cells (SGC-7901), cervical cancer cells (Hela) and lung cancer cells (A-549) and using cisplatin as positive control (Table 1).Most of the compounds had good anticancer activities.R 2 had significant impact on the anticancer activity.The R 2 with deactivating groups, such as R 2 =4-nitrophenyl and 4-chlorophenyl (compounds 3c and 3f) had better anticancer activiy than that had activating groups or no substitutions.When R 2 was maintained, different R and R 1 had no significant impact on the anticancer activity.Moreover it was worth noting that the anticancer activity was better when R 2 was heterocyclic than R 2 was benzene ring's.In addition, the further molecular modifications on 1,3-thiazolidin-4-one brought us better result and methylene at C-5 position of 1,3-thiazolidin-4-one showed the best anticancer activity.
In summary, a series of new 1,3-thiazolidin-4-ones synthesized under microwave-assisted with DCC as dehydrating agent were reported.In microwave-assisted synthesis conditions, the yields of the new compounds were better than conventional method and the reaction time in 10 minutes.Most of the new compounds had anticancer activity, compound had the best anticancer activity when a furan-2-yl was at C-2 position and a methylene was at C-5 position, so it may be noted that different heteroaryl substituents at C-2 position and methylene at C-5 position of 1,3-thiazolidin-4-ones deserve further consideration from the point of structure-activity optimization.Further structure-activity optimization and other biological studies of 1,3-thiazolidin-4-ones are undertook in the laboratory.Chemistry, 19, 334-339. Zhang, X. Y., Li, X. Y., Li, D. F., Qu, G., Wang, J. J., Loiseau, P. M., & Fan, X. S. (2009).Ionic liquid mediated and promoted eco-friendly preparation of thiazolidinoneand pyrimidine nucleoside-thiazolidinone hybrids and their antiparasitic activities.Bioorganic & Medicinal Chemistry Letter,19,[6280][6281][6282][6283][6284][6285][6286][6287]

Table 1 .
. Anticancer activity of compounds synthesized Scheme 1.The synthesis route of target compound