European Journal of Medicinal Chemistry 87 (2014) 814e833

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European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents Vivek Asati, Debarshi Kar Mahapatra, Sanjay K. Bharti* Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495009, Chhattisgarh, India

a r t i c l e i n f o

a b s t r a c t

Article history: Received 5 May 2014 Received in revised form 22 August 2014 Accepted 10 October 2014 Available online 12 October 2014

A variety of substituents on the thiazolidine-2,4-dione(TZD) nucleus have provided a wide spectrum of biological activities by the using of different mechanism on various target sites. PPARg ligands have recently been demonstrated to affect cell proliferation, differentiation and apoptosis of different cell types. Currently, some of the TZDs are designed for the treatment of human cancers expressing high levels of PPARg because it is assumed that activation of PPARg mediates their anticancer activity. Another site for TZDs is survival signaling pathways under growth factor loops have been implicated in cancer development, progression, and metastasis. The Raf/MEK/ERK, Wnt and PI3K/Akt signalling cascades are the most commonly up-regulated in human cancers. In the present review, various derivatives of thiazolidine-2,4diones its SAR and different signaling pathways involved to produce anticancer activity been highlighted. © 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Thiazolidine-2,4-dione ERK PI3K Antiproliferative activity Signaling pathways Kinases

1. Introduction Cancer is the second leading cause of death after the heart diseases across the globe which affected 8.2 million lives in the year 2012 [1,2]. Among the various types of malignant tumors reported so far breast cancer is the second most prominent reason for deaths among the women [3]. Colorectal cancer is the third leading cause of death in United States with 50% patients lost their lives in the year 2010 [1]. Despite the huge efforts to implement novel chemotherapeutic strategies for the treatment of different types of cancer, this disease remains one of the major concerns worldwide. Consequently, there is an urgent need to find unexplored classes of substances with selective action against cancer cells. The regulation of the cell proliferations and apoptotic pathways associated with cell death is known as an important approach to understand a great variety of medical illnesses, including cancer [4,5]. Therefore, the identification of cell-cycle regulators and apoptotic stimuli to combat cancer cells represents an attractive strategy to the discovery and development of potential antitumor agents [6,7]. Heterocyclic compounds play an important role in cancer therapy, where TZDs have been reported to be a potential scaffold which derived from five membered thiazole system comprising of three carbon atoms, one nitrogen atom, and one sulfur atom with * Corresponding author. E-mail addresses: [email protected], vivekasati_pharma@yahoo. com (V. Asati), [email protected] (S.K. Bharti). http://dx.doi.org/10.1016/j.ejmech.2014.10.025 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

two double bonded oxygen on 2 and 4 position is of considerable interest in different areas of medicinal chemistry [8]. Literature survey revealed that TZD is one of the important novel heterocyclic ring system has therapeutic importance and when combined with other heterocyclic rings produce wide range of biological activities such as anti-diabetic [9], anti-inflammatory [10], anti-oxidant [11], anti-tubercular [12], anti-microbial [13], anticonvulsant [14] and cytotoxic activities [15]. For the exploration of novel and highly active therapeutic compounds the combination of two pharmacophores into a single molecule is an interesting, effective and mostly used direction in modern medicinal chemistry. When two pharmacophores of different orientation binds with different molecular targets or with two distinct sites on the same molecular target could be beneficial for the treatment of cancer [16,17]. In addition to the above, TZDs are implicated in cancer development, progression, and metastasis, among which the Raf/MEK/extracellular signal regulated kinase (ERK) [18], phosphatidylinositol 3-kinase (PI3K)/ Akt [18], Wnt signal transduction pathways [19] and peroxisome proliferator-activated receptors (PPARs) [20] signalling cascades are the most commonly up-regulated in human cancers.

2. PPARs In the field of molecular biology, the peroxisome proliferatoractivated receptors (PPARs) are an important group known as nuclear receptor proteins that function as transcription factors regulating the expression of genes [21e23]. PPARs play essential roles in

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

the regulation of cellular differentiation, development, and metabolism of carbohydrate, lipid, protein as well as tumor genesis [24] of higher organisms (Fig. 1) [25,26]. TZDs are potential agonist of the nuclear PPARs act on different up-regulated proteins of signaling transduction pathway like Raf, PI3K which induces antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for downregulation of carcinogenesis (Fig. 2) [27]. Scientists have classified PPARs in three categories, on the basis of its tissue distribution, namely PPAR-a, PPAR-b, and PPAR-g. PPARalpha, the first identified PPAR family member is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and muscle. PPAR-g, on the other hand, is expressed at high levels in adipose tissue. All PPARs isoforms require heterodimerization with the retinoid X receptor (RXR) (Fig. 3) for optimal DNA binding and transcriptional activity [28,29]. Upon ligand binding, the complex of PPAR and RXR binds to specific recognition sites on DNA, the peroxisome proliferator response elements (PPREs) and regulates transcription of specific genes [30e35]. A PPRE, consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has been identified in the upstream regulatory sequences of genes related to metabolic pathways [36]. The PPAR-g and RXR complex, along with other coactivators for transcription formed heterodimer complex, activate transcription of target genes [37]. This complex [38] is associated with a multicomponent co-repressor complex, which physically interacts with the PPAR receptor through silencing mediator for retinoid and thyroid hormone receptors (SMRT). Co-activator complex contains histone acetylase activity, which initiates chromatin remodeling [39] and proceeds for active transcription (Fig. 4). PPARs are activated by dietary fatty acids and eicosanoids [40] and when they gets activated performs different physiological functions, based on their divergent patterns of tissue-specific expression, physiological consequences and different ligandbinding specificities (Table 1) [41e44]. PPAR-g is an important molecule for adipocyte differentiation and is over-expressed in adipose tissue [45,46]. In addition to adipose tissue, PPAR-g has also been detected in a wide variety of cancer cells [47e51]. In cancer cells, PPAR-g activation by its high

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affinity ligands can inhibit cell proliferation and differentiation [52,53]. Thus PPAR-g is involved not only in lipid metabolism but also in cellular proliferation of cancer cells. Therefore, it was suggested that PPAR-g is a possible molecular target for TZDs in cancer treatment. Although a lot of evidence has established that PPAR-g activation induces growth arrest in cancer cells, the molecular mechanism of the growth inhibition by PPAR-g ligands is not well understood. Some researchers have recently demonstrated that the cyclin-dependent kinase inhibitor may be a crucial molecule in the cell growth inhibition by PPAR-g ligands in human cancer cells [52e55]. Among the proposed mechanisms for the antitumor effect of TZDs including apoptosis induction, cell cycle arrest, and differentiation has been extensively reported. Interestingly, some of the observed anticancer therapies for the most common types of cancers including lung, breast, and colon and will explore the principal of PPAR-g-dependent and -independent mechanisms by which TZDs exert their antitumor effects [56e59]. An emerging view related with TZDs are that some antitumor effects produced by them are totally or partially PPAR dependent, whereas others are PPAR independent [60e62]. The aim of this review is to examine the current evidence about the molecular mechanisms by which thiazolidinediones augment cellular differentiation, inhibit cellular proliferation, and induce apoptosis. 3. Wnt signal transduction pathways Wnt/b-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes [63,64]. Wnt proteins which are recognized as secreted glycoproteins bind to the Frizzled receptors and LRP5/6 co-receptors (Fig. 5), and through stabilizing the critical mediator beta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. However, Wnt binding also acts through b-catenin-independent, noncanonical pathways, such as the planar cell polarity (PCP) and Ca2þ dependent pathways. Deregulation of the canonical Wnt/b-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of b-catenin, has been implicated

Fig. 1. Role of PPARg activation in different metabolic processes.

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Fig. 2. Signaling pathway of PPARs represented different target proteins for thiazolidinedione.

Fig. 3. Role of lipid metabolism in PPARs activation and heterodimerization with retinoid X receptor for optimal DNA binding.

in colorectal tumorigenesis. Oncogenic mutations of beta-catenin have been observed in small fraction in non-colon cancers and it have been observed that elevated levels of beta-catenin protein are the cause for most common forms of human malignancies,

indicating that activation of this pathway may play an important role in tumor development [65]. It was observed that when PPARg interact with Wnt/b-catenin signaling likely plays a key role in tumorigenesis. b-catenin

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Fig. 4. Role of histone acetylation in transcription through PPARg and RXR heterodimer complex.

inactivates after phosphorylation by GSK-3b and suppresses tumor cell proliferation. Two drugs rosiglitazone (RGZ) and GW9662, that are thiazolidinedione derivatives, inhibit the growth of Raji cells (human lymphoma cell line) by inducing apoptosis and arresting cell cycle, which is dependent on PPARg ligand mediated activity [66]. Another thiazolidinedione derivative, troglitazone was found, not only involved in TGF-b1-induced phosphorylation of Akt and glycogen synthase kinase (GSK)-3b, but also inhibit nuclear translocation of b-catenin, phosphorylation of Smad2 and Smad3 and upregulation of the EMT-associated transcription factor SNAI1. These results demonstrate inhibitory actions of troglitazone on

TGF-b1-induced EMT via a PPARg-independent mechanism likely through inhibition of b-catenin-dependent signaling downstream of TGF-b1, supporting a role for interactions between TGF-b and Wnt/b-catenin signaling pathways in EMT [67,68]. 4. Ras/Raf/MEK/ERK and PI3K/Akt signaling pathway A variety of extracellular factors such as growth factors, adhesion molecules and differentiation factors as well as tumorpromoting factors utilize the Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (Ras/Raf/MEK/ERK),

Table 1 Physiological functions of isoforms of peroxisome proliferator-activated receptor [41e44]. Isoform

А В

G

Tissue distributiona

Physiological role

Liver

Kidney

Intestine

Spleen

Fat

þþþþ þþ 

þþ þþ þ/

þþþþ þþþ þþ

þ þþ þþþ

  þþþþ

Where þþþþ indicate large area distribution and  indicate negligible distribution. a Tissue distribution is based on in situ hybridization of rat tissue.

Lipid metabolism, regulation of inflammation Embryo implantation Adipocyte differentiation, regulation of inflammation

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Fig. 5. Wnt signal transduction pathways.

that represents an ubiquitous signaling module for the linkage of extracellular signals to the cytoplasmic and nuclear effectors and regulates cell behavior such as cellular proliferation, differentiation, survival and apoptosis [69e71]. It is one of the major growth regulating factor signaling pathways in which Interleukin 6 (IL6)

IGF-1, VEGF, SDF-1

IL-6

BAFF, APRIL

PI3K

JAK 2

Grb2

Grb2 SOS

TRAF

PI3K

SOS

PDK-1

NIK

Ras

Akt

IKK

Raf

STAT3

triggers Ras/Raf/MEK/ERK mediated proliferation; induces JAK2/ STAT3 signaling promoting cell survival; and activates PI3K/Akt signaling, thereby promoting anti-apoptosis and drug resistance in Myeloma cells. IGF1, VEGF, and SDF-1a activate ERK and PI3K/Akt signaling cascades. TNFa family members BAFF and APRIL trigger

mTOR

FKHR

GSK3β

IκB

NFκB

MEK

ERK

H N

O

R

O

S

Thiazolidine-2,4-diones

Proliferation Anti-apoptosis Cell cycle regulation Cell adhesion & migration Fig. 6. Raf/MEK/ERK and PI3K/Akt signaling pathway.

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NFkB activation, thereby promoting anti-apoptosis and drug resistance in Myeloma cells (Fig. 6) [72,73]. Recently, thiazolidine2,4-dione analogs were found as a potential anticancer agent via the inhibition of the Raf/MEK/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades, were synthesized and biologically characterized [18]. 5. Anticancer activity of thiazolidine-2,4-diones TZDs act as agonist of the nuclear receptor PPARg. These synthetic compounds are known for a long time to possess anticancer activity and numerous studies have been performed to understand their mechanism of action. The mechanism that is responsible mainly related to a PPARg-independent manner. The PPARg-independent changes including ionic changes (intracellular pH and Ca2þ), reactive oxygen species (ROS) production, Mitogen Activated Protein Kinases (MAPK) activation, endoplasmic reticulum stress and proteasomal degradation [74,75]. Novel function of troglitazone and ciglitazone in targeting energy restriction provides a mechanistic basis to account for their PPARg-independent effects on a broad spectrum of signaling targets. This is proposed that glycolytic inhibition also plays an important role for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells. This is based on the efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose in suppressing carcinogenesis in animal models. Thiazolidinedione analogs through these agents produce different cellular responses characteristic of energy restriction, including transient induction of Sirt1 (silent information regulator 1) expression, activation of the intracellular fuel sensor, AMP-activated protein kinase, and endoplasmic reticulum stress, the interplay among which culminated in autophagic and apoptotic death [76]. Subsequently, it was proposed that, substituted 5-arylidene and 3-benzylidene groups in TZDs play an important role in its activity through specific interactions with key residues located in the site of the PPARg structure, which correlate the hypothesis that these molecules are potential ligands of PPARg. The analysis of the docking results, which takes into account the hydrophilic and hydrophobic interactions between the ligands and the target, explained why the 3-(2-bromobenzyl)-5-(4-methanesulfonylbenzylidene)-thiazolidine-2,4-dione (1) compound has the best activity and the best docking score [10]. Br

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have different mechanism of action with a broad spectrum of activity against numerous cancer cell lines. In which N-3-substituted5-arylidene thiazolidine-2,4-diones, bearing the bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion (2, 3 and 4) showed good activity against proliferation of human myeloid leukemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis. The mechanism behind the apoptosis is related to activation of multiple caspases and also associated with the release of cytochrome C from the mitochondria (Fig. 7) [77].

R

2. R = CF 3

O

3. R = Cl

N

4. R = F O

S O

H2C

NH Br

Synthesized compound like (Z)-5-(2,4 dihydroxybenzylidene) thiazolidine-2,4-dione (5) plays a crucial role in UV-induced melanogenesis, which is known to be related to the induction of tyrosinase enzyme. This compound inhibit sodium nitroprusside (SNP, an NO donor)-induced NO generation, dose-dependently and suppressed tyrosinase activity and melanin synthesis induced by single nucleotide polymorphism (SNP) in B16F10 melanoma cells. The effect of compound on signaling pathway showed by two techniques, first related with the guanosine cyclic 30,50monophosphate (cGMP) activities and second related with the gene expressions of tyrosinase and microphthalmia-associated transcription factor (MITF). The compound (5) was a promising anti-melanogenic agent in which enhancement of tyrosinase gene expression via the cGMP pathway is a probable primary mechanism of NO-induced melanogenesis [78].

HO

O

O

N H S

NH

O

S HO

O 5

SO2CH 3 1

The thiazolidine-2,4-diones scaffold have recently been proposed for hybridization with different bioactive molecules which

A series of novel (Z)-[(2H-chromen-3-yl)methylene]azolidinones bearing thiazolidine-2,4-dione (6), rhodanine or hydantoin scaffolds were synthesized as potential anticancer agents. It is proposed that N-substitution of azolidinone moiety cannot improve the activity but S/NH replacement (thiazolidine-2,4-dione/ hydantoin) and S/O alteration (rhodanine/thiazolidine-2,4-dione) enable to modulate the growth inhibitory activity against A549 (human alveolar basal epithelial adenocarcinoma), K562 (human

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Fig. 7. Release of cytochrome C from the mitochondria after apoptotic signals and induction of caspase 9.

chronic myelogenous leukemia), MCF-7 (human breast adenocarcinoma), and MOLT-4 (human acute lymphoblastic leukemia) cancer cell lines [79]. O

Where X= O,N; Y = S N

R1

Y O

R2

X

R3

R1 = H, Br, OMe

compound which exhibited distinctive selectivity of CNS and renal cancer, resultant compound exhibited different cytostatic and cytotoxic activities toward H1299 cells for further developing potential application as anticancer drugs [81,82]. Novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized and evaluated for in vitro anticancer activity within DTP

R2 = H, Me R

R3 = H, Me, Et, CH2CO 2H S

6 O

Thiazolidinediones (TZDs) showed relationship with endotrophin and cisplatin resistance, this is due to COL6A3 (collagenVIa3) levels are increased in response to cisplatin exposure in tumors. Endotrophin, which is mainly secreted from stromal adipocytes in the tumor microenvironment, confers a high degree of cisplatin resistance by enhancing epithelialemesenchymal transition, fibrosis and angiogenesis. Endotrophin is a cleavage product of collagenVIa3 (COL6A3) and the effects of endotrophin can be bypassed, either through use of COL6 null mice or by administering TZDs in wild-type mice (leading to a downregulation of endotrophin). The proposed data suggested that endotrophin levels are a strong prognostic marker for the effectiveness of the combination therapy of TZDs with cisplatin, and neutralization of endotrophin activity dramatically improves the therapeutic response to combination therapy. Treatment with an endotrophin neutralizing monoclonal antibody in combination with cisplatin very effectively inhibits tumor growth of mammary cancer stem cells MMTV-PyMT model [80]. Fragment-based drug design strategies also take a novel point for further development of potential anticancer drugs like 2-thiosubstituted anthra[1,2-d]imidazole-6,11-diones (7 and 8) were synthesized in this effort and evaluated for human telomerase reverse transcriptase (hTERT) repressing activities, cell proliferations, and NCI 60-cell panel assay. All compounds were moderate selectivity toward leukemia cancer except one

NH x

N 7. R =

N

8. R = -CH 2-CH 3 O

NCI protocol (NCI's Developmental Therapeutics Program). Some compounds found to be the most active (9 and 10), which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with minimum growth percent on cell line like HL-60(TB) (Leukemia), SF-295 (CNS Cancer) and SF-295 (CNS Cancer). The mechanism that involved for anticancer activity by compound 9 was Dihydroorotate dehydrogenase inhibitor an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine, DNA/RNA antimetabolite, Dihydrofolate reductase inhibitor, Reversible binding inhibitor of the human kinesin Eg5; a molecular motor protein that is essential in mitosis, antimitotic agent, RNA/DNA antimetabolite and compound 10 was RNA/DNA antimetabolite, Microtubule polymerization inhibitor, DNA antimetabolite [83].

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O

O

R

NH N

S

N

O H5C2O

9. R =

O OH

S

10. R =

N

NH 2

O

ph(p-OCH3)

15

naphthalen-2-yl

Nuclear factor-kappaB (NF-kB) regulates various genes involved in cancer; suggest drugs that suppressing or inhibiting NF-kB may possess anticancer activity. In this way thiazolidin-4-ones (11, 12 and 13) were synthesized and docked into active site of NF-kB and evaluated for anti-inflammatory and anticancer activity. The compound 11, 12 and 13 are most active compounds against Human breast carcinoma cell line (BT-549), Human cervical adenocarcinoma cell line (HeLa), human colon adenocarcinoma cell line (COLO-205) and human kidney adenocarcinoma cell line (ACHN) [84].

Troglitazone-induced inhibition of cell growth played an important role in human pancreatic cancer cells through activated protein kinases (MAPKs), extracellular signal-related kinase (ERK), c-Jun N-terminal protein kinase (JNK), and p38 MAPK. All these kinases produce tumor cell inhibition but troglitazone (16) specifically inhibit the phosphorylation of ERK1/2 and mitogen-activated protein kinase (MEK)1/2 in human pancreatic cancer cells [87] (Fig. 8). S

CH3 H3C

O

O

CH3 O

O

N H

x HO

11. R =

H3C

x

O O

16

H3C

H3C

N H

N R

12. R = S S

13. R =

x

2,4-thiazolidinedione group may be utilized successfully to inhibit histone deacetylase (HDAC) activity with future potential for lead optimization by chemical derivatization of active compound, N-(6-(2,4-dioxothiazolidin-3-yl)hexyl) benzenesulfonamide (14). It was demonstrated that these compounds showed cytotoxicity that parallels their ability to inhibit HDACs activity in human cancer cell line HepG2 [85].

O S N X

Experimentally it has been proposed that troglitazone arrest cell cycle in G0/G1 phase and suppressed cell proliferation in a human eosinophilic leukemia cell line, EoL-1. This suppression correlated with the upregulation of mRNA for p21WAF1/CIP1 cyclindependent kinase (CDK) inhibitor. The inhibitory effects of troglitazone on cell proliferation and expression of p21 mRNA were observed in a human myelomonocytic cell line, U937, and a human myelomonoblastic cell line, KPB-M15 [88]. An important series of thiazolidine-2,4-dione derivatives, 3-(2aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione (17) and 2,5-disubstituted-thiazolidine-2,4-dione analogs (18) were identified as a dual inhibitor of the Raf/MEK/extracellular signalregulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades. This ring also shows anticancer activity to arrest cells in G0/G1 phase in human leukemia U937 cells. This dual inhibition property made for scientists to design new lead compounds that produce more active and less toxic compounds (Fig. 8) [89]. Biological activity of these analogs in human leukemia U937 cells established that steric interaction at the aromatic domain, the exocyclic double bond, and the H-bond interaction at the ethylamine domain are critical to the growth inhibition of cancer cells [18].

O

NH

O 17. R = Benzyl

R

14 Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) substrate-specific inhibitors of 3-(2-amino-ethyl)-5-(4-ethoxybenzylidene)-thiazolidine-2,4-dione (15) was synthesized and biologically evaluated in human leukemia U937 cells to define its pharmacophore activity and it was found that ethoxy group on 2position on the phenyl ring significantly improved functional activities of inhibiting cell proliferation and inducing apoptosis (Fig. 8) [86].

N S

18. R = Cyclohexyl NH2

O

The regulation of protein synthesis at the level of translation initiation induces cell apoptosis, may induce cell death and thus prevent the proliferation of tumor cells. A series of 20-benzyloxy50-substituted-5-benzylidene-thiazolidine-2,4-thione and dione derivatives (19, 20, 21 and 22) were synthesized and evaluated for

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anticancer activity in translation initiation specific assays. Several compounds were found to show inhibition of cell growth with low lM GI50, mediated by inhibition of translation initiation, which involves partial depletion of intracellular Ca2þ stores and extensive phosphorylation of eIF2a [90].

O Cl

N O

S

O

26

O Cl

NH

NH

S

S

R

S

N

H3C

S

S Cl

CH3

O

O

O

O

H3C

20

19

O O

27 Where X = O or S

O

O

O

O

NH S R

S O

NH

X

R 22

Analogs evaluated as translation initiation inhibitors. Recently 2,4-thiazolidinediones synthesized and characterized for their anticancer activity. Among the tested compounds using Brine Shrimp Lethality assay, compound (23), (24) and (25) exhibited significant inhibitory activity at ED50 value 4.00 ± 0.25 lg/mL and this level of activity was comparable to that of the reference drug podophyllotoxin with ED50 value 3.61 ± 0.17 lg/mL [91,92].

compound 27 showed good activity against human breast adenocarcinoma cell line [93]. Compounds containing the 1,3-thiazine-2,4-dione core showed antitumor activity due to the presence of S and N in their heterocyclic ring, has been showed that phenyl- and naphthyl-substituted thiazinediones (28 and 29) presented selective antitumoral activity against L1210 (murine lymphocytic leukemia), CCRF-CEM (human acute lymphoblastic leukemia), B16F10 (murine melanoma), MDAMB-231 (human breast cancer) and a non-tumoral cell line, Vero (kidney fibroblast). The mechanism behind this antitumor activity was related to caspase cascade activation, imbalance in intracellular Ca2þ and mitochondrial metabolism, and/or endoplasmic reticulum stress [94].

x

O 28. R = NH

R

x

O R

O

23. R = m-f-benzyl

NH

24. R = p-f-benzyl

S

O

S

O

29. R =

S 25. R =

x

Biologically active benzosuberones bearing 2,4-thiazolidenone moiety was synthesized as potential anticancer agents by Knoevenagel condensation with thiazolidenone derivatives in the presence of sodium acetate and glacial acetic acid and in vitro cytotoxicity of these compounds was evaluated against different human cancer cell lines (A549, HeLa, MDA-MB-231, MCF-7) and normal cell line, HEK293. Compound 26 showed good activity against HeLa, A549, MCF-7 and MDA-MB-231 cancer cell lines but

The biological activity of acridine, consist aromatic structure, is based on the intercalation within double-stranded DNA, thus interfering with cellular functions. Amsacrine is the best-known acridine which produces cytotoxic activity and when combined with TZD showed good activity against tumor growth. For taking consideration about both rings, a series of novel hybrid 5-acridin-9yl methylene-3-benzyl-thiazolidine-2,4-diones (30) were synthesized via N-alkylation and Michael reaction and evaluated for promising cytotoxic activity. On the basis of the positive interaction with the DNA showed that the modified acridine-thiazolidinedione could be promising key structures in anticancer drug development [95].

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6. Structure activity relationship of thiazolidine-2,4-diones O

N

Troglitazone have recently been reported for anticancer activity through inhibition of the Raf/MEK/ERK signal cascade, we have embarked on development of the thiazolidine-2,4-dione derivatives as potential substrate-specific ERK inhibitors (Fig. 10) [89].

N S R

O

6.1. SAR ▪ Structural extension of benzylidene in compound 35 to alkylidene shifted the biological target from ERK to their upstream activators.

Where R= CH3,Br, Cl, F

30

In continuation to on-going research programme the PIM kinases (PIM-1, 2, and 3) (proviral integration site for moloney murine leukemia virus) are found to be associated with apoptosis and cell cycle pathway (Fig. 9). PIM kinases are a family of three serine/ threonine kinases which constitute a small family of enzymes with a high degree of sequence and structural homology. The PIM kinases are primarily regulated by growth factor and cytokine signaling downstream of PTK/STAT activation. Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (31 and 32) have been identified as potent and highly selective inhibitors of the PIM kinases like PIM-1, PIM-2, and PIM-3. These inhibitors showed good antiproliferative activity in a megakaryoblastic leukemia cell line, MOLM-16, with GI50 values less than 100 nM [96,97].

H N

O

O

O N O CH3

35

H N

O

NH2

S

O

O

S

S N

N

NH2

NH2

R2

R2

32

31

Some researcher has proved thiazolidine-2,4-diones showed tyrosinase inhibitory activity. For this they designed and synthesized 5-(substituted benzylidene)thiazolidine-2,4-diones. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (33) and (Z)-5-(3-hydroxy-4 methoxybenzylidene)thiazolidine-2,4dione (34) exhibited much higher tyrosinase inhibitory activities, than kojic acid. After docking study of active compound with DOCK6, it has been proposed that multi-targeted tyrosine kinase inhibitors may produce antitumor properties, in patients with advanced malignancies. [98,99].

▪ Thiazolidine-2,4-dione compound, 3-(2-aminoethyl)-5-(3phenyl-propylidene)-thiazolidine-2,4-dione 36, as a novel lead structure for developing dual pathway inhibitors of the Raf/ MEK/ERK and PI3K/Akt pathways and anticancer agents. The compound contains several structural features that may contribute to its functional activities, such as the phenylpropylidene double bond which can act as a Michael addition reaction acceptor, the primary amine in the ethylamine tail for ionic interactions, and the aromatic ring for hydrophobic interactions.

O

O

HO NH

NH S

H3CO

HO 33

S

O

O 34

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▪ Compounds 37, 38, and 39 were designed along with 36 to shed light on its potential binding interaction features with receptor.

O N

NH2

S 39

O

Compound 40 showed three different parameters for their SAR analysis the phenyl ring, ethylamine tail, and spacer domain between the phenyl ring and thiazolidine-2,4-dione (Fig. 11) [86]. For phenyl ring it is observed that functional groups of varied lipophilicity, size and electronic properties were introduced to evaluate the effects on biological activities. Some changes in compound 41 by different substituents produced derivatives of thiazolidinedione showed multifarious activities given below:▪ Substitution on 4- and 3-positions with F, NO2 group abolished the inhibition of ribosomal S6 kinase 1 (Rsk1) phosphorylation indicating that electron withdrawing substituents are not favored at these two positions. ▪ 4-Cl substitution exhibited normal activity. ▪ H, 4-MeO, 3-EtO, 4-Me containing derivatives of compound 41 showed stearic effects and an oxygen atom at the 4-position on phenyl ring are important factor for activity. ▪ In the place of phenyl naphthalene and 2,3-dihydrobenzo[b] [1,4]dioxine-6 containing compounds showed better

inhibition of Elk-1 phosphorylation and p38 phosphorylation. This further indicates the importance of molecular size on target specificity. ▪ Shifting of the ethoxy substitution from 4 to 2-position on the phenyl ring exhibited better inhibition had minimal effects on the phosphorylation of ERK1/2 and enhanced inhibition on Elk1 phosphorylation. ▪ N-Dimethylation and N-acetylation (42 and 43) also abolished the inhibition of Rsk1 phosphorylation indicating that the primary amine is essential for biological activity. ▪ Saturation of the extra double bond of 44 and introduction of two addition hydroxyl groups completely abolished activities for Rsk1 and ERK1/2 except for weak inhibition of Rsk1 phosphorylation indicating that conjugation is especially important for the biological activity of 44.

▪ The spacer extended analog between phenyl ring and thiazolidine-2,4-dione 55 significantly inhibited phosphorylation of both Rsk1 and ERK1/2. These results also demonstrate that the benzylidene moiety of compound 40 is necessary for its interaction with ERK1/2 and molecular size is an important structural determinant for target specificity. ▪ Compound 40 inhibited the phosphorylation of Rsk1 and Elk1. It also inhibited the growth and survival of several cancer cell lines. In addition, small molecules containing the thiazolidine-2,4-dione moiety, such as the anti-diabetic drug troglitazone, have been recently reported to have anticancer activities. Structureeactivity relationship (SAR) studies of thiazolidine2,4-thione (45) and thiazolidine-2,4-dione (46) series represent the substituents on C-5 in the benzylidene or benzyl rings important for the Ca2þ release activity (Fig. 12) [90].

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

825

O

N

NH2

S

O

O 40

H3C

6.2. SAR

O N S

NH2

O 44

H

O

O

▪ Absence of substitution at C-5 results in the least potent analogs. ▪ In the thiazolidine-2,4-thione (45) series small lipophilic substituents at 5-position such as methyl, fluoro, chloro and bromo released Ca2þ from intracellular stores, caused phosphorylation of eukaryotic translation initiation factor 2a (eIF2a), were good inhibitors of cancer cell growth. ▪ Substitution of the 5-position with larger lipophilic groups such as t-butyl, phenyl, and p-t-butylphenyl produced compounds with unable to release Ca2þ from intracellular stores, while they still remained potent inducers of eIF2a phosphorylation.

H

O

O

NH

NH

S

S

X=O

X=S H

R 45

46

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▪ In the thiazolidine-2,4-dione (46) series substitution at the 50 position with halogens, methyl, phenyl, p-t-butyl phenyl and methoxy group produced compounds have biological profile similar to that of the corresponding thiazolidine-2,4-thione analogs. ▪ The t-butyl containing thiazolidine-2,4-dione analog, displays good activities in all three assays, with the strongest eIF2a phosphorylation activity, t-Butyl thiazolidine-2,4-thione does not release Ca2þ from intracellular stores. ▪ The NO2 containing thiazolidine-2,4-dione analog, is devoid of Ca2þ release and eIF2a phosphorylation activities the corresponding NO2 in thiazolidine-2,4-thione is fully active in all three assays. ▪ Interestingly, while strong electronegative substituents retained the activities in all assays, the electron-donating substituents caused loss of activity in both Ca2þ depletion and phosphorylation of eIF2a assays. Novel benzosuberone bearing 2,4-thiazolidenone moieties showed as potential anticancer agents have been synthesized and evaluated for their in vitro cytotoxicity against A549, HeeLa, MDAMB-231 and MCF-7 cell lines [93]. O

▪ ▪



Series of TZD analogs of 50 were designed and synthesized showed that steric interaction at the aromatic domain, the exocyclic double bond, and the H-bond interaction at the ethylamine domain are critical for the growth inhibition of cancer cells [18].

R1

N S



MB-231 cell lines and compound containing R ¼ CH3, R1 ¼ CH3 showed most potent cytotoxicity against MCF-7. The compound 49 containing R ¼ CH3 showed significant activity against alveolar adenocarcinoma (A549), cervical cancer (HeLa), breast adenocarcinoma (MDA-MB-231) cell lines. While, the intermediate compound 47 containing R1 ¼ H, CH3 and Br showed moderate cytotoxicity against A549 cell line. The compound 47 containing R1 ¼ Cl was active against normal cell line, HEK293. That substitution at head group of benzosuberone ring played an important role in imparting the cytotoxicity to the compound. For example, compound 49 containing R ¼ CH3 bearing methyl substituent at head group of benzosuberone showed cytotoxicity against alveolar adenocarcinoma (A549), breast adenocarcinoma (MDAMB-231) and cervical cancer (HeLa) cell lines respectively. Finally electron donating group at the head group of benzosuberone and electron with-drawing as well as electron donating groups at the tail group of the compound 48 observed that compound with p-methyl (at tail group) was very active against MCF-7 cell line.

O

O

O

R

N

47

NH2

S O O

Cl

50

R1

R

O

N S R

O

O

N

Tail group

NH2

S

Head group

H3CO 2SHN

O

51

48

O O

Cl NH

R

N

S

NH2

S

OH R

O

H2NO 2S

52

O

49

N

6.3. SAR ▪ SAR study of all three basic structures (47, 48 and 49) of the compounds showed that alkyl-, methoxy-substituted compounds were more active for anticancer activity than halosubstituted compound. ▪ The compound 48 containing R ¼ H, R1 ¼ CH3 and R ¼ CH3, R1 ¼ H showed selective cytotoxicity against HeLa and MDA-

S

R

53 a- R=-CH 2OH

O c-

O R=

b- R=-COOH CH3

N

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

827

▪ All these results suggest to scientist for developing some novel thiazolidinediones derivatives that have multi target properties and more potent and effective analogs as anticancer agents.

O

N NH2

S O

54

It has been observed that the presence of either electronwithdrawing or electron releasing substituents on the phenyl ring reduced the cytostatic activity as compared with the unsubstituted derivatives [77].

O

O

R N

O

R

N NH2

O

N

S

O

O

S

55 O

Br NH

HN NH

H2C O

6.4. SAR ▪ Compounds 54 showed the essential role of the aromatic ring and the exocyclic double bond for optimal biological activity. ▪ Compound 55 does not show the inhibitory effects on the growth of U937 cells which further showed the critical role of the exocyclic double bond in compound 56 which is incorporated into benzene ring in compound 55. ▪ Analogs of compound 50 with cyclohexane ring containing compound produced enhanced activity due to non-planar nature with possible chair, boat, or other transitional conformations but compound with a cyclopropane ring exhibited decreased growth inhibition activity in U937 cells. ▪ Electron-donating substitutions on the phenyl ring exhibited comparable potency but electron-withdrawing substitutions on the phenyl ring exhibited decreased growth inhibition activity. ▪ Sulfonamide group substitution at the para-position in compounds 51 and 52 led to total loss of activity. This may suggest that protein interaction was not favored for the activity of thiazolidinedione. ▪ The bioisosteric replacement of phenyl ring with a pyridine or an indole ring showed the decreased potency of compounds. ▪ Primary amine also played an important role in activity that was proved by replacement of ethylamine with alcoholic (53-a), carboxyl (53-b) or tertiary amino (53-c) groups with total loss of activity but when it is replaced with OH group maintain the biological activity. ▪ These all result showed that H-bond rather than ionic bond interaction are an important target for biological activity while steric effects are not favored for this activity. ▪ The most important part of compound 50 with cyclohexane ring was related to antiproliferative activity in U937 cells and blockade of the Raf/MEK/ERK and PI3K/Akt signaling pathways and also produced antiproliferative activity through apoptotic effects in U937 (arrest in S-phase), M12 and DU145 cancer cells. That also inhibits some downstream substrate like p-4EBP1, pERK and p-Akt in DU145 cells.

56

Br 57

6.5. SAR ▪ Some compounds showed the same antiproliferative activity but they have substituents with opposite electronic effects in which one consist electron-releasing methyl group and another consist electron-withdrawing fluoro group. In the series of para-a-bromoacryloylamido analogs of compound 56:▪ Some compounds that showed greatest antiproliferative activity was N-3-methyl analog of thiazolidine-2,4-dione system, Increasing the size of the substituent, from methyl to t-butyl, replacement of methyl by a strong electron withdrawing trifluoromethyl. ▪ Some compounds that showed reduction in activity were increasing the length of the alkyl chain, Introduction of the weak electron-withdrawing fluorine atom, Moving the fluorine from para-to meta-position, changing para-chloro to meta-chloro, Replacement of the electron-withdrawing chlorine by the electron-releasing methyl group. ▪ Some compounds showed variable potencies was parasubstituted benzyl derivatives. In the series of meta-a-bromoacryloylamido analogs compound 57:▪ Compounds that showed reduction of the antiproliferative activity were para- and meta-isomeric derivatives, increasing the size of the halogen from fluorine to chlorine, substitution of the methyl with a bulkier t-butyl group.

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V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

Fig. 8. Cell proliferation and apoptotic pathways through different signaling substrate.

▪ Compounds showed unchanged activity were para- and metafluoro derivatives, Moving the chlorine atom from the para-to the meta-position, Replacement of p-fluoro by a weak electron releasing methyl group, replacing the p-methyl group by a ptrifluoromethyl moiety.

O N

R1

Y O 58

R2

X

R3

The structure activity relationships (SAR) analyses of thiazolidinediones indicate that the N-substitution with methyl, ethyl and carboxymethyl moieties produced inactive compounds [79]. The different substituents of thiazolidinediones are given in Table 2.

Table 2 Different substituted groups of thiazolidinediones at R1, R2, R3, X and Y position. Compounds

R1

R2

R3

X

Y

58s 58f 58a 58b 58h 58i 58l 58m

8-OMe H H H 6-Br 6-Br 6-Br 6-Br

H H H H H H Me Me

Et Et H H H H H H

O O O S O S O S

S S S S S S S S

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

829

Fig. 9. Role of PIM kinases in antiproliferative activity.

6.6. SAR ▪ Free imidic NH group is essential for cytotoxic activity. Exceptionally, N-ethyl derivative 58s bearing 8-methoxy group on chromene ring showed significant activity. ▪ By comparing the activities of 8-methoxy analog 58s with its unsubstituted counterpart 58f, revealed that the presence of methoxy group on the C-8 position of chromene ring confirm the highest cytotoxic activity of this compound. ▪ The comparison of thiazolidine-2,4-dione derivatives 58a, 58h and 58l with their rhodanine counterparts 58b, 58i and 58m, demonstrated that the replacement of O with S increases the activity. ▪ A similar result could be found by comparing the IC50 values of compounds 58i and 58m with a rhodanine structure.

▪ 6-bromo substitution led to increased cytotoxic activities of 58h and 58i compared to 58a and 58b, respectively, but the same substitution decreased the potency of 58j compared to 58c against all cell lines.

7. Concluding remarks A vast literature on diversity of TZD compounds through different mechanism in producing anticancer activity aimed to highlight in this review. Here focusing criteria for TZD compounds were related to PPARs dependant and independent pathway, Wnt signal transduction pathways, Raf/MEK/ERK and PI3K/Akt signaling pathway, DNAs and RNAs dependent interaction, PIM kinases inhibitor pathways in producing antiproliferative or apoptopic activity in various cell lines. TZD compounds have an important role

830

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

Fig. 10. SAR of thiazolidine-2,4-dione derivatives as Raf/MEK/ERK signal cascade inhibitor.

Fig. 11. SAR of thiazolidine-2,4-diones inhibited the phosphorylation of Rsk1 and Elk-1.

V. Asati et al. / European Journal of Medicinal Chemistry 87 (2014) 814e833

831

Fig. 12. SAR of thiazolidinediones and thiones that released Ca2þ from intracellular stores, caused phosphorylation of eIF2a and produces anticancer activity.

Patents of thiazolidine-2,4-diones as anticancer agent. S no.

Citing patent

Filing date

Publication date

Applicant

Title

1

WO2014068397A1

5 Nov 2013

8 May 2014

Commissariat A L'energie Atomique Et Aux Energies Atlternatives (Cea)

2

WO2009088992 A3

Jan 6, 2009

Oct 22, 2009

University Of Vermont And State Agricultural College

Combination of an anticancer agent such as a tyrosinekinase inhibitor and a stat5 antagonist, preferably a thiazolidinedione, for eliminating hematologic cancer stem cells in vivo and for preventing hematologic cancer relapse Ribonuclease and thiazolidinedione compounds and their use in methods to treat cancer

in treatment of diabetes and tumor progression but there are many problems still related to side effects and proper mechanism to combat the treatment of disease. It has been found that only few compounds are in clinical trial that produces anticancer activity so in this review we provide the SAR of the compounds in the direction to design most active compound that can produce anticancer activity through inhibition of multiple signaling pathways.

[2] [3] [4] [5] [6]

[7]

Acknowledgment The authors gratefully acknowledged to Indian Council of Medical Research (ICMR), New Delhi Grant No. 45/28/2013-PHA/ BMS for providing senior research fellowship assistance for research work, related to this topic and wish to thanks Guru Ghasidas Vishwavidyalaya (Central University), Chhatishgarh, India, for providing facilities and future platform for doing the research work.

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Thiazolidine-2,4-diones as multi-targeted scaffold in medicinal chemistry: Potential anticancer agents.

A variety of substituents on the thiazolidine-2,4-dione(TZD) nucleus have provided a wide spectrum of biological activities by the using of different ...
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