Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192 IJPRBS Available Online at www.ijprbs.com 179 NOVEL 2,4-THIAZOLIDINEDIONE ANALOGUES AS CYTOTOXIC AGENTS: SYNTHESIS AND BIOLOGICAL SCREENING DHAVAL G. SHAH 1 , LAXMAN J. PATEL 2 1. Food & Drugs Laboratory, Vadodara, Gujarat, India. 2. Faculty of Pharmacy, Ganpat University, Kherva, Mahesana, Gujarat, India. Accepted Date: 24/06/2016; Published Date: 27/06/2016 Abstract: Synthesis of novel Thiazolidinedione derivatives was performed from reaction of N- benzoyl substituted aryl alkyl halide with N-substituted 2, 4-thiazolidinedione derivatives and screened for their in vitro cytotoxic activity by MTT assay. The cell lines used were MCF 7 (Breast cancer cell), HELA (Cervical cancer cell line), HEK (Normal epidermal kidney cell line) HEP (Laryngeal cancer cell line) MDA MB 468 (Brest cancer cell line). Result of screening on cell line showed moderate to good cytotoxic activity for all the compounds. Compound DGS27 (IC50 = 3.63 μM, HEP), DGS27 (IC50 = 1.07 μM, HEK), DGS7 (IC50 = 1.09 μM, HELA), DGS7 (IC50 = 1.989 μM, M468) and DGS7 (IC50 = 2.5 μM, MCF7) was found to be most active compared to standard Methotrexate (IC50 = 0.22 μM HEP, IC50 =0.072 μM HEK, IC50 = 0.102 μM HELA, IC50 = 0.152 μM M468, IC50 = 0.100 μM MCF7). Structure activity relationship of synthesized analogs suggested that the attachment of electron withdrawing groups like Chloro at R2 position and Acetyl group at R1 gave better cytotoxic activity. Activity by Hydrogen and Acetyl substitution at R1 position linked with N substituted 2, 4 - Thiazolidinedione scaffold gave better activity in the order of H > CH2COOH. Our findings may impart new direction to medicinal chemists and biochemists for further investigations of 2, 4- Thiazolidinedione containing cytotoxic agents. Keywords: 2,4 - Thiazolidinedione, Cytotoxic, MTT assay INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE PAPER-QR CODE Corresponding Author: MR. DHAVAL G. SHAH Access Online On: www.ijprbs.com How to Cite This Article: Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192
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Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192 IJPRBS
Available Online at www.ijprbs.com 179
NOVEL 2,4-THIAZOLIDINEDIONE ANALOGUES AS CYTOTOXIC AGENTS:
SYNTHESIS AND BIOLOGICAL SCREENING
DHAVAL G. SHAH1, LAXMAN J. PATEL2
1. Food & Drugs Laboratory, Vadodara, Gujarat, India.
2. Faculty of Pharmacy, Ganpat University, Kherva, Mahesana, Gujarat, India.
Accepted Date: 24/06/2016; Published Date: 27/06/2016
Abstract: Synthesis of novel Thiazolidinedione derivatives was performed from reaction of N-benzoyl substituted aryl alkyl halide with N-substituted 2, 4-thiazolidinedione derivatives and screened for their in vitro cytotoxic activity by MTT assay. The cell lines used were MCF 7 (Breast cancer cell), HELA (Cervical cancer cell line), HEK (Normal epidermal kidney cell line) HEP (Laryngeal cancer cell line) MDA MB 468 (Brest cancer cell line). Result of screening on cell line showed moderate to good cytotoxic activity for all the compounds. Compound DGS27 (IC50 = 3.63 µM, HEP), DGS27 (IC50 = 1.07 µM, HEK), DGS7 (IC50 = 1.09 µM, HELA), DGS7 (IC50 = 1.989 µM, M468) and DGS7 (IC50 = 2.5 µM, MCF7) was found to be most active compared to standard Methotrexate (IC50 = 0.22 µM HEP, IC50 =0.072 µM HEK, IC50 = 0.102 µM HELA, IC50 = 0.152 µM M468, IC50 = 0.100 µM MCF7). Structure activity relationship of synthesized analogs suggested that the attachment of electron withdrawing groups like Chloro at R2 position and Acetyl group at R1 gave better cytotoxic activity. Activity by Hydrogen and Acetyl substitution at R1 position linked with N substituted 2, 4 - Thiazolidinedione scaffold gave better activity in the order of H > CH2COOH. Our findings may impart new direction to medicinal chemists and biochemists for further investigations of 2, 4- Thiazolidinedione containing cytotoxic agents.
These observations are not surprising if one considers the central role of HDACs as key
regulators of chromatin structure and posttranslational modifiers of numerous key proteins in
any cell type and tissue. Thus, the question arises whether future drug development in the field
should focus on selective targeting of individual HDAC family members, which possess a critical
oncogenic function in cancer cells but have no such function in normal cells. Here, we discuss
the potential of individual HDACs as drug targets in cancer therapy. To this aim, it was reviewed
the role of individual HDACs not only in cancer, but also in normal physiology and development
in order to understand the potential side effects associated with their inhibition
Thiazolidine-2,4-diones (TZD) are the derivatives of thiazolidine, which belongs to an important
group of heterocyclic compounds. TZD and rhodanine analogs have been recognized as the
privileged templates in drug design and discovery and numerous compounds containing the
TZD ring have been developed as potential anticancer agents. More interestingly, some TZD
analogs such as the anti-diabetic drug troglitazone have been shown to exhibit anticancer
activities through the inhibition of the HDAC inhibitor..
Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192 IJPRBS
Available Online at www.ijprbs.com 181
MATERIAL AND METHODS:
Melting points of all synthesized compounds were determined in open capillaries using Veego
melting point apparatus, Model VMP-D (Veego India ltd., Mumbai, India) and were
uncorrected. Infrared spectra were recorded using KBr pellets on SHIMADZU-FT-IR 8400S
instrument. Mass spectra were recorded on PerkinElmer LC–MS PE Sciex API/65
Spectrophotometer. The 1H NMR spectra were recorded on Brucker Avance-300 (300 MHz)
model spectrophotometer in CDCl3 using DMSO as solvent and TMSi as internal standard with 1H resonant frequency of 300 MHz. The TLC was performed on precoated alumina silica gel 60
F254 (Merck). The mobile phase was benzene:methanol (9:1) and detection was made using UV
light. The resulting compounds were purified by recrystallization using suitable solvent. The
elemental analyses were done on elementar Vario EL 3 Carlo erba 1108 and were well in
accordance with the structures assigned to the compound. Synthetic grade chemicals procured
from SD fine chemicals, Baroda, India were used for the synthesis of the target compounds. All
the compounds were prepared according to the literature procedures with some minor
modifications[11,12] General synthetic procedures used for the preparation of the target
compound are as follows:
Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192 IJPRBS
Available Online at www.ijprbs.com 182
SYNTHETIC PATHWAY
R2=
1) 2,3-dichlorobenzoyl
2) 2,4-dicholorobenzoyl
3) 4-nitrobenzoyl
4) Benzoyl
5) 4-chlorobenzoyl
6) 2-chlorobenzoyl
R1=
a) -H
b) -CH2COOH
c) -CH2COOC2H5
d) -CH2CH2COOCH3
e) -CH2CH2COOC2H5
Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Dhaval G. Shah, IJPRBS, 2016; Volume 5(3): 179-192 IJPRBS
Available Online at www.ijprbs.com 183
Synthesis of 2,4-thiazolidinedione (Microwave)(1A)
Add Chloracetic acid 56.5 gm (0.6 mol) in 60 ml of water andthiourea 45.6 gm (0.6 mol) in 60 ml
of water were mixed and transferred in 250 ml round bottom flask.The mixture was stirred for
15 minute and cooled which yields white precipitates. To the content of the flask 60 ml of conc.
HCl was added slowly from dropping funnel.The mixture was refluxed for 15 min at 750watt at
microwave. On cooling the content of the flask solidified into a cluster of white needles. The
product was filtered. The product was purified by recrystallization from ethyl alcohol
Synthesis of 3- aryl substituted 2,4-thiazolidinedione (microwave)(2A-2F)
Add 2,4 –thiazolidinedione (0.01 mole) in 20 mL of 5% aqueous sodium hydroxide in a well-
corked flask. Add Substituted benzoyl chloride (0.01 mole) about 0.5 mL at a time, with
constant shaking. Add 10 ml Ethanol to flask and reflux for 5-7 min at 750 watt in Microwave.
Filter off the solid derivative, wash with a little cold water and recrystalize from ethanol.