Cytotoxicity of thiazolidinedione-, oxazolidinedione- and pyrrolidinedione-ring containing compounds in HepG2 cells

Abstract

Liver damage occurred in some patients who took troglitazone (TGZ) for type II diabetes. The 2,4-thiazolidinedione (TZD) ring in TGZ's structure has been implicated in its hepatotoxicity. To further examine the potential role of a TZD ring in toxicity we used HepG2 cells to evaluate two series of compounds containing different cyclic imides. N-phenyl analogues comprised 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT); 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO) and N-(3,5-dichlorophenyl)succinimide (NDPS). Benzylic compounds, which closely resemble TGZ, included 5-(3,5-dichlorophenylmethyl)-2,4-thiazolidinedione (DCPMT); 5-(4-methoxyphenylmethyl)-2,4-thiazolidinedione (MPMT); 5-(4-methoxyphenylmethylene)-2,4-thiazolidinedione (MPMT-I); 5-(4-methoxyphenylmethyl)-2,4-oxazolidinedione (MPMO); 3-(4-methoxyphenylmethyl)succinimide (MPMS) and 3-(4-methoxyphenylmethylene)succinimide (MPMS-I). Cytotoxicity was assessed using the MTS assay after incubating the compounds (0-250 μM) with HepG2 cells for 24 h. Only certain TZD derivatives (TGZ, DCPT, DCPMT and MPMT-I) markedly decreased cell viability, whereas MPMT had low toxicity. In contrast, analogues without a TZD ring (DCPO, NDPS, MPMO, MPMS and MPMS-I) were not cytotoxic. These findings suggest that a TZD ring may be an important determinant of toxicity, although different structural features, chemical stability, cellular uptake or metabolism, etc., may also be involved. A simple clustering approach, using chemical fingerprints, assigns each compound to one of three classes (each containing one active compound and close homologues), and provides a framework for rationalizing the activity in terms of structure.

Microreactor Technology as a Tool for the Synthesis of a Glitazone Drug Intermediate

“…Therefore, the last solvent is disregarded hereinafter. Both ethanol and n ‐propanol proved to be suitable solvents, each with its own advantages and disadvantages: the former can be more easily acquired and handled, is cheaper, and less toxic, whereas the latter would allow for a reaction time six times shorter than that reported in the literature , . For these reasons both were used in the following experiments.…”

“…Mishra et al batch‐tested reaction times from 30 to 35 h in ethanol, while other authors proposed 24 h , but no systematic study has been performed on the effects of the reaction time on the synthesis of ( Z )‐5‐(4‐hydroxybenzylidene)thiazolidine‐2,4‐dione by condensation of TZD with p ‐hydroxybenzaldehyde. The solvent is another factor that can significantly influence the reaction kinetics and product yield ( Y P ), besides accounting for up to 80 % (w/w) of the materials used to produce drugs.…”

“…Fig. a shows that a reaction time of only 630 min (10.5 h) was sufficient to reach Y P,max , which represents a 56–70 % reduction of the reaction time currently used , .…”

Use of Piperidine and Pyrrolidine in Knoevenagel Condensation

“…Experimental procedure for the synthesis of 1a and 1b was adapted from where a 125 mL round-bottom flask was attached to a heating plate, with a condenser linked to the flask and a needle in which samples were taken [9]. To the flask was added 4 mmol of TZD, synthesized according to the procedure described in Pinheiro et al [10,11], 4 mmol of Xa or Xb and 60 mL of ethanol.…”

Two human Mitochondrial Pyruvate Carrier mutations reveal distinct mechanisms of molecular pathogenesis

“…However, TZD treatments are not without significant side effects. TZDs can cause fluid retention, bone loss, weight gain, hepatotoxicity, and congestive heart failure (138)(139)(140).…”