Thiazolidinedione Analogs Research Articles

In Silico Molecular Dynamics and 3D‐QSAR Study on Thiazolidinedione Derivatives as Dual Inhibitors of DPP IV and PTP1B (DDPI's) for the Management of T2DM

AbstractSimultaneous inhibition of dipeptidyl peptidase IV and protein tyrosine phosphatase 1B as DDPI's emerged as a therapeutic intervention for the management of T2DM. In the present study, we have employed molecular dynamics simulation in conjugation with the field‐based 3D QSAR studies on a dataset having DDPI activities to identify the spatial fingerprints of target‐specific thiazolidinedione analogs. Separate contours were generated for both DPP IV and PTP1B showing respective pharmacophoric structural requirements for optimal inhibitory activity. These developed 3D QSAR models also showed good statistical measures (DPP IV: r2 = 0.9468; q2 = 0.7173, and PTP1B: r2 = 0.9718; q2 = 0.819) with the excellent predictive ability with PLS‐generated validation constraints. Comparative steric and electrostatic features were elucidated using respective contour maps for selective target‐specific favorable activity. Furthermore, molecular docking was used for elucidating the mode of binding as DDPI's to DPP IV and PTP1B, along with MD simulation (200 ns) analysis such as RMSD, RMSF, Rg, SASA, PCA, and FEL. These studies revealed that all the protein‐ligand docked complexes elicited an overall better stability as compared to reference ligand (vildagliptin or ertiprotafib) complexes. Molecular docking studies revealed that compound 24 (DPP IV: −150.667 kcal/mol; PTP1B: −142.792 kcal/mol) showed maximum affinity toward both the proteins DPP IV and PTP1B, as compared to their respective standard inhibitor, i.e., vildagliptin −99.9843 kcal/mol and ertiprotafib −125.399 kcal/mol, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study were employed for the optimization of drug candidates as DDPI's. Compound 24 showed most stable behavior in the binding pockets of both the enzymes, as compared to their respective standard inhibitors. This study will be helpful in designing novel DDPIs with appropriately substitute thiazolidinedione for the management of T2DM. The designed compound YSR‐14 exhibited the predicted IC50 values of 0.143 µM in DPP IV and 0.158 µM in PTP1B along with their excellent binding affinity against both targets.

Thiazolidinedione as a Promising Medicinal Scaffold for the Treatment of Type 2 Diabetes.

Thiazolidinediones, also known as glitazones, are considered as biologically active scaffold and a well-established class of anti-diabetic agents for the treatment of type 2 diabetes mellitus. Thiazolidinediones act by reducing insulin resistance through elevated peripheral glucose disposal and glucose production. These molecules activate peroxisome proliferated activated receptor (PPARγ), one of the sub-types of PPARs, and a diverse group of its hybrid have also shown numerous therapeutic activities along with antidiabetic activity. The objective of this review was to collect and summarize the research related to the medicinal potential, structure-activity relationship and safety aspects of thiazolidinedione analogues designed and investigated in type 2 diabetes during the last two decades. The mentioned objective was achieved by collecting and reviewing the research manuscripts, review articles, and patents from PubMed, Science Direct, Embase, google scholar and journals related to the topic from different publishers like Wiley, Springer, Elsevier, Taylor and Francis, Indian and International government patent sites etc. Results: The thiazolidinedione scaffold has been a focus of research in the design and synthesis of novel derivatives for the management of type 2 diabetes, specifically in the case of insulin resistance. The complications like fluid retention, idiosyncratic hepatotoxicity, weight gain and congestive heart failure in the case of trosiglitazone, and pioglitazone have restricted their use. The newer analogues have been synthesized by different research groups to attain better efficacy and less side effects. Thus, the potential of thiazolidinediones in terms of their chemical evolution, action on nuclear receptors, aldose reductase and free fatty acid receptor 1 is well established. The newer TZD analogues with better safety profiles and tolerability will soon be available in the market for common use without further delay.

Polycystic ovary syndrome and obesity: a modern paradigm

Polycystic ovary syndrome is a heterogeneous endocrine disease that affects women of childbearing age. The pathogenesis of polycystic ovary syndrome has not been fully studied to date, its paradigm considers the genetic determinism of the manifestation of hormonal and metabolic disorders, which are considered to be criteria for the verification of the disease (hyperandrogenism, oligo/anovulation and/or polycystic ovarian transformation during ultrasound examination (ultrasound). This review discusses the main ways of interaction between hyperandrogenism, insulin resistance and obesity and their role in the pathogenesis of polycystic ovary syndrome, as well as possible methods of treatment for this category of patients. The review analyzes the role of hyperandrogenism and insulin resistance in the implementation of the genetic scenario of polycystic ovary syndrome and finds out the reasons why women with polycystic ovary syndrome often demonstrate the presence of a «metabolic trio» - hyperinsulinemia, insulin resistance and type 2 diabetes mellitus. It is noted that obesity is not included in the criteria for the diagnosis of polycystic ovary syndrome, but epidemiological data confirm the existence of a relationship between these diseases. Obesity, especially visceral, which is often found in women with polycystic ovary syndrome, enhances and worsens metabolic and reproductive outcomes with polycystic ovary syndrome, as well as increases insulin resistance and compensatory hyperinsulinemia, which, in turn, stimulates adipogenesis and suppresses lipolysis. Obesity increases the sensitivity of tech cells to luteinizing hormone stimulation and enhances functional hyperandrogenism of the ovaries, increasing the production of androgens by the ovaries. Excess body weight is associated with a large number of inflammatory adipokines, which, in turn, contribute to the growth of insulin resistance and adipogenesis. Obesity and insulin resistance exacerbate the symptoms of hyperandrogenism, forming a vicious circle that contributes to the development of polycystic ovary syndrome. These data allow us to conclude that bariatric surgery can become an alternative to drugs (metformin, thiazolidinedione analogs of glucagon-like peptide-1), which has shown positive results in the treatment of patients with polycystic ovary syndrome and obesity.

Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4.

Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group.

Design, synthesis and bioactivity evaluation of thiazolidinedione derivatives as partial agonists targeting PPARγ

Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor γ (PPARγ) agonist with many side effects. Herein, we developed a series of novel TZD analogues as partial agonists targeting PPARγ. The study of anti-hyperglycemic activity and anti-inflammatory activity enabled us to identify a novel compound, 4 g, which quickly recover the blood glucose of mice at the concentration of 100 mg/kg, and show similar anti-inflammatory activity to ibuprofen at the concentration of 20 mg/kg. The competitive binding assay confirmed direct binding of 4 g to the LBD of PPARγ with IC50 being 1790 nM, and dose-dependently increased the transcriptional activity of PPARγ. Besides, through computer-aided drug design software simulation docking, it was found that compound 4 g showed the best binding ability to target protein PPARγ. Furthermore, because of the introduction of benzene containing group at N3 position, the stability of H12 in the active pocket is reduced and the stability of H3 and β-fold is increased, showing the characteristics of some PPARγ agonists, based on the docking model analysis. Together, these results suggest that 4 g is a promising PPARγ agonist that deserves further investigation.

Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates

Separation of the preferred enantiomer from racemic mixtures, i.e. “chiral switching,” often improves efficacy and reduces toxicity. However, this strategy is not applicable for all chiral compounds—particularly for molecules with hydrogen-containing chiral centers, which can be prone to rapid stereoisomerization. Deuterium incorporation can stabilize such chiral centers while retaining the pharmacologic characteristics of the parent racemic mixture, thereby enabling their “chiral switching”, changing the drug from a racemate to a single enantiomer. We describe “deuterium-enabled chiral switching” (DECS) as a means of improving on the therapeutic promise of chemically unstable racemic drugs and demonstrate its utility with the isolation and characterization of stable preferred enantiomers of thalidomide and thiazolidinedione (TZD) analogs.

Validation of TZD Scaffold as Potential ARIs: Pharmacophore Modeling, Atom-based 3D QSAR and Docking Studies

Metabolic disorders associated with diabetic patients are a serious concern. Aldose reductase (ALR2) has been identified as first rate-limiting enzyme in the polyol pathway which catalyzes the reduction of glucose to sorbitol. It represents one of the validated targets to develop potential new chemical entities for the prevention and subsequent progression of microvascular diabetic complications. In order to further understand the intricate structural prerequisites of molecules to act as ALR2 inhibitors, ligand-based pharmacophore model, atombased 3D-QSAR and structure based drug design studies have been performed on a series of 2,4- thiazolidinedione derivatives with ALR2 inhibitory activity. In the present study, a validated six point pharmacophore model (AAADNR) with three hydrogen bond acceptor (A), one hydrogen bond donor (D), one negative ionic group (N) and one aromatic ring (R) was developed using PHASE module of Schrodinger suite with acceptable PLS statistics (survival score = 3.871, cross-validated correlation coefficient Q2 = 0.6902, correlation coefficient of multiple determination r2 = 0.9019, Pearson-R coefficient = 0.8354 and F distribution = 196.2). In silico predictive studies (pharmacophore modeling, atom-based 3D QSAR and docking combined with drug receptor binding free energetics and pharmacokinetic drug profile) highlighted some of the important structural features of thiazolidinedione analogs required for potential ALR2 inhibitory activity. The result of these studies may account to design a legitimate template for rational drug design of novel, potent and promising ALR2 inhibitors.

Binding mode exploration of LuxR-thiazolidinedione analogues, e-pharmacophore-based virtual screening in the designing of LuxR inhibitors and its biological evaluation

Master quorum sensing (QS) regulator LuxR of Vibrio harveyi is a unique member of the TetR protein superfamily. Recent studies have demonstrated the contribution of thiazolidinedione analogues in blocking QS by decreasing the DNA-binding ability of LuxR. However, the precise mechanism of thiazolidinedione analogues binding to LuxR is still unclear. In the present study, molecular docking combined with molecular dynamics (MD) simulations was performed to understand the mechanism of ligand binding to the protein. The binding pattern of thiazolidinedione analogues showed strong hydrogen bonding interactions with the amine group (NH) of polar amino acid residue Asn133 and carbonyl (C=O) interaction with negatively charged amino acid residue Gln137 in the binding site of LuxR. The stability of the protein–ligand complexes was confirmed by running 50 ns of MD simulations. Further, the four-featured pharmacophore hypothesis (AHHD) consists of one acceptor (A), two hydrophobic regions (HH) and one donor (D) group was used to screen compounds from ChemBridge database. The identified hit molecules were shown to have excellent pharmacokinetic properties under the acceptable range. Based on the computational studies, ChemBridge_5343641 was selected for in vitro assays. The 1-(4-chlorophenoxy)-3-[(4,6-dimethyl-2-pyrimidinyl)thio]-2-propanol (ChemBridge_5343641) showed significant reduction in bioluminescence in a dose-dependent manner. In addition, ChemBridge_5343641 inhibits biofilm formation and motility in V. harveyi. The result from the study suggests that ChemBridge_5343641 could serve as an anti-QS molecule.

SYNTHESIS AND EVALUATION OF NOVEL THIAZOLIDINEDIONE DERIVATIVES FOR ANTIDIABETIC ACTIVITY

The aim of study was to synthesize a new series of thiazolidinedione ’ s . Thiazolidinedione ’ s or glitziness forms a significant class of drugs which exhibit biolo gical activities ranging from antidiabetic, anti - inflammatory, antibacterial, antifungal, antiviral and anticancer . In the present study reported a systematic synthesis of thiazolidinedione analogues . A new series of 2 , 4 - thiazolidinedione based derivative s have been synthesized by the condensation of various substituted phenoxy benzene amines and 4 ’ - chlorosulphonyl 5 - benzylidene - 2 , 4 - thiazolidinedione . The structure of these compounds were established by IR and 1 H NMR . These new compounds ( F 1 – F 7 ) were ev aluated for their antidiabetic activity on albino rats . Most of the compounds showed significant antidiabetic activity when compared with the standard drug metformin .

Design and synthesis of a novel 5-(aminomethylene)thiazolidine-2,4-dione derivatives as potent hepatitis-B virus polymerase inhibitors

<p>A series of novel thiazolidinedione analogues (TZD) were designed and synthesized potent inhibitors of HBV capsid assembly. The synthesis of thiazolidine-2,4-dione derivatives (4a–4o), starting from the condensation of 5-(ethoxymethylene)thiazolidine-2,4-dione (1) with various secondary amines (3) derived from biologically active compounds. The newly synthesized TZD analogues 4a-4o were characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and MS and evaluated for their anti-HBV activity. Most of the compounds inhibited the expression of viral antigens at low concentration. Six compounds, 4g, 4h, 4l, 4m, 4n, and 4o, demonstrated potent inhibition of HBV DNA replication at submicromolar range. Of these five initial hits, compound 4o was the most active when compared with lamivudine.</p><p> </p><p> </p>

Wound healing effects of new 15-hydroxyprostaglandin dehydrogenase inhibitors

Previously, we reported that the antidiabetic drug ciglitazone and its analogs were potent inhibitors of 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In continuing attempts to develop highly potent 15-PGDH inhibitors, a series of thiazolidinedione analogs were synthesized and tested. Compound 17 exhibited IC50 of 45nM. This compound also significantly increased levels of prostaglandin E2 (PGE2) in A549 cells by approximately eight-fold that in the control. Much experimental data suggests that PGE2 plays a role in the prevention of excessive scarring. However, it has a very short half-life in blood, its oxidization to 15-ketoprostaglandins is catalyzed by 15-PGDH. Therefore, 15-PGDH inhibitors may have utility for the therapeutic management of diseases requiring elevated PGE2 levels. Scratch wounds were analyzed in confluent monolayers of HaCaT cells. Cells exposed to compound 17 showed significantly improved wound healing with respect to a control.

In-silico design and study of novel piperazinyl β-carbolines as inhibitor of HIV-1 reverse transcriptase

Despite of all the extensive research work done on recently developed diaryl pyrimidine analogues, thiazolidinedione analogues and indolyl aryl sulfones as HIV-1 reverse transcriptase (RT) inhibitors, there still continues the never-ending problem of resistance. In the present study, we have designed novel β-carboline analogues as inhibitor of HIV-1 RT. Molecular docking studies were performed using Autodock v4.2 against both wild and mutant strains of HIV-1 RT. Among the designed analogues, compound 9H3NH4CN, 9H6CNP and 9H4CN showed significant binding free energy against wild strain (−10.99, −12.06, −11.33 kcal/mol) and against mutant strain (−15.27, −13.9, −15.81 kcal/mol) of HIV-1 RT, respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (−12.02, −8.55 kcal/mol) and against mutant strain (−10.81, −12.1 kcal/mol) of HIV-1 RT, respectively. The predicted inhibitory constant values (K i) of these compounds are against wild strain (8.8, 1.37, 4.92 nM) and against mutant strain (6.4, 64.43, 2.56 pM), respectively, as that of standard drugs efavirenz, rilpivirine against wild strain (1.6, 538.7 nM) and against mutant strain (11.8, 1.36 nM) of HIV-1 RT, respectively. In addition to this, molecular descriptors such as Lipinski drug likeness and ADMET properties were calculated using online servers like Molinspiration and admetSAR. These compounds can be further developed as next generation non-nucleoside reverse transcriptase inhibitors with promising anti HIV-1 activity with better pharmacokinetic profile.

Comparative molecular docking studies of novel 3, 5-disubstituted thiazolidinedione analogs as HIV-1-RT inhibitors

Molecular docking studies were performed on 30 novel thiazolidinediones using Glide, FlexX and Scigress Explorer Ultra programs and the X-ray crystallographic structure of HIV-1 Reverse transcriptase (PDB code 1RT2) to study the binding mode of these analogs. The experimental conformation of the bound ligand TNK 651 was precisely reproduced by the docking procedures as demonstrated by low (<3.00 A) root mean square deviations. Results of this study indicated that most of the compounds dock into the active site of 1RT2 enzyme with good docking scores comparable to the bound compound TNK 651. The docking analysis of the best docked molecules 29 (Glide XP score −11.76) and 22 (FlexX score −20.77) showed significant interactions with active-site amino acid residues and formed H bond interactions with the key amino acid residues, while the molecule 1 in Scigress Explorer Ultra exhibited the highest score of −59.49.

Synthesis of a Novel Thiazolidinedione and Evaluation of Its Modulatory Effect on IFN-γ, IL-6, IL-17A, and IL-22 Production in PBMCs from Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is an autoimmune disease frequently characterized by chronic synovitis of multiple joints. The pathogenesis of RA is complex and involves many proinflammatory cytokines as Th17 related ones. PPARγ is a nuclear receptor activator that represses proinflammatory gene expression. Thus, this work aimed to synthetize a new thiazolidinedione (TZD) analogue based on a well-known anti-inflammatory and PPARγ agonist activity of this ring and evaluate its anti-inflammatory activity. After chemical structure confirmation, the compound named 5-(5-bromo-2-methoxy-benzylidene)-3-(2-nitro-benzyl)-thiazolidine-2,4-dione TM17 was submitted to cytokine releasing inhibition and PPARγ genetic modulation assays. The new compound showed no toxicity on human and murine cells, decreasing IL-6 secretion by murine splenocytes and reducing IL-17A, IL-22, and IFN-γ expression in peripheral blood mononuclear cells from patients with RA. TM17 was more efficient in modulating the mRNA expression of PPARγ than its well-used TZD agonist rosiglitazone. Surprisingly, TM17 was efficient on IL-17A and IFN-γ reduction, like the positive control methylprednisolone, and presented a better effect on IL-22 levels. In conclusion, PBMCs obtained from RA patients under TM17 treatment present a significant reduction in IL-17A, IL-22, and IFN-γ levels, but not IL-6 when compared with nontreated cells, as well as increase PPARγ mRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment.

Molecular docking studies of novel thiazolidinedione analogs as HIV-1-RT inhibitors

Molecular docking studies were performed on 280 novel thiazolidinediones by Glide, FlexX, and Scigress Explorer Ultra programs and the X-ray crystallographic structure of HIV-1 Reverse transcriptase (PDB code 1RT2) to study the binding mode of these analogs. The experimental conformation of the bound ligand TNK 651 was precisely reproduced by the docking procedures as demonstrated by low (<3.00 A) root mean square deviations. Results of this study indicated that most of the compounds dock into the active site of 1RT2 enzyme with good docking scores comparable to the bound compound TNK 651. The docking analysis of the highest active molecule 232 (Glide XP score −12.47) and 55 (FlexX score −29.71) shows significant interaction with active site amino acid residues and H-bond interactions with the key amino acid residues.

Synthesis and Biological Evaluation of Novel Thiazolidinedione Analogues as 15-Hydroxyprostaglandin Dehydrogenase Inhibitors

Novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors were synthesized. Compounds 2, 3, and 4 exhibited IC(50) of 25, 8, and 19 nM, respectively. They also significantly increased levels of PGE(2) in A549 cells. To assess the influence of 15-PGDH inhibitor on cochlear blood flow (CBF), 2 was applied intravenously to guinea pigs. It increased their CBFs. Scratch wounds were also analyzed in confluent monolayers of HaCaT cells. Cells exposed to 4 showed significantly improved wound healing with respect to a control.

Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors

Prostaglandins have a short life in vivo because they are metabolized rapidly by oxidation to 15-ketoprostaglandins catalyzed by a cytosolic enzyme known as NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, CT-8, a thiazolidinedione analogue, was found to be a potent inhibitor of 15-PGDH. Structure–activity analysis indicated that the N-methylation of thiazolidine-2,4-dione, CT-8, abolished the inhibitory activity, whereas the introduction of an ethyl hydroxyl group at amine in CT-8 still had a good inhibitory effect. Based on the structures of the thiazolidinediones analogues and inhibitory activity, a range of benzylidene thiazolidinedione derivatives were synthesized with different substituents on the phenyl ring and their inhibitory activity was evaluated. Replacement of the cyclohexylethyl group of CT-8 with the hetero five-member ring increased the inhibitory potency. However, replacement of the cyclohexylethyl group with a hetero six-member ring decreased the inhibitory potency significantly. It was found that compound 2 (5-(4-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) was the most potent inhibitor that was effective in the nanomolar range.

Antihyperglycemic effect of a new thiazolidinedione analogue and its role in ameliorating oxidative stress in alloxan-induced diabetic rats

Thiazolidinediones (TZDs) are a new class of antidiabetic drugs, having an insulin sensitizing effect in patients with type 2 diabetes. The contribution of oxidative stress from the standpoint of lipid and protein damage, alteration in endogenous antioxidant enzymes and effects of newly synthesized compounds, 5-[4-2-(6,7-Dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene]thiazolid- ine-2,4-dione, (C 1) in normal/alloxan-induced diabetic rats form the focus area of this study. Its effect was compared to two well-known TZDs, namely pioglitazone and rosiglitazone. It has been concluded from results that after thirty days of administration of C 1, Pg and Rg in alloxan-induced diabetic animal groups, the blood glucose level decreased, more remarkably in C 1 treated group. Also oxidative damage has been studied by estimating hepatic superoxide dismutase (SOD) activity, which was found to be increased ( p < 0.001 vs. control). An inverse change in SOD values between hepatic and pancreatic/kidney tissues were observed. Treatment with the test compounds lowered the activity of SOD in liver while increased its activity in kidney and pancreas. Similar normalizing effect of C 1 on liver, pancreatic and renal catalase (CAT)/ glutathione peroxidase (GPx) activities were pronounced in diabetic rats ( p < 0.001 vs. diabetic rats). Decreased reduced glutathione (GSH) content, found in diabetic animals, was significantly elevated to normal levels by C 1 treatment. The treatment with C 1 also decreased the levels of nitric oxide and increased the activities of glutathione-s-transferase and glutathione reductase, as compared to diabetic animals. Evidence of oxidative damage to lipids and proteins was shown through the quantification of protein carbonyl (in tissues) and malondialdehyde levels (both serum and tissues). It was observed that the protein/lipid damage in diabetic rats was improved by treatment with C 1. Total antioxidant activity (TAA) was found to be enhanced in C 1 treated rats ( p > 0.05 vs. group3, p < 0.001 vs. group2, p < 0.001 vs. group 4). These results suggest that the newly synthesized TZD derivative (C 1) has a potential to act as antihyperglycemic and antioxidant agent. In addition, for all parameters checked, it has better efficacy than rosiglitazone and is as effective as pioglitazone.

Beyond peroxisome proliferator-activated receptor γ signaling: the multi-facets of the antitumor effect of thiazolidinediones

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.

Process Development and Scale-Up of the Potential Thiazolidinedione Antidiabetic Candidate PNU-91325

An efficient six-step synthesis has been developed for the preparation of the thiazolidinedione analogue PNU-91325 (3) from the commercially available olefin 12. This process involves a novel epoxide ring opening with a deactivated phenol under phase-transfer conditions. Significant improvements were made in the oxidation of a secondary alcohol to the ketone and the 1,4-reduction of an enone from a previous process. Overall, this route allows for the preparation of PNU-91325 in 25% yield.