Abstract
Our laboratory has been credited for the discovery of a unique membrane bound enzyme termed Acetoxy Drug: Protein Transacetylase (TAase) catalyzing the transfer of acetyl group from polyphenolic peracetates (PA) to certain functional proteins resulting in the modulation of their catalytic activity. In this report, we have synthesized eight novel 4-methylcoumarins and demonstrated the comparisons of acetoxy derivatives of 4-methylcoumarin with their propoxy and butoxy derivatives for the modulation of some receptor proteins such as cytochrome P-450 (Cyt.P-450), NADPH cytochrome c reductase and cytosolic glutathione S-transferase (GST). The results clearly indicated that acetoxy derivatives have very high efficacy for the modulation of above mentioned functional proteins as compared to their other derivatives. We have also compared the acetoxy derivatives of 4-methylcoumarin with their acid substituted acetoxy derivatives and found that inclusion of carboxylic acid groups on the benzenoid rings of the coumarins system hardly affected TAase mediated catalytic activity.
Highlights
In our earlier publications [1, 2] evidences were given for the existence of a novel enzyme acetoxy drug: protein transacetylase (TAase) present in rat liver microsomes
The extent of inhibition of glutathione S-transferase (GST) by 7-acetoxy-4-methylcoumarin-6-carboxylic acid (10) is similar to that of the 7-acetoxy-4-methylcoumarin (8). These results clearly indicate that the addition of carboxylic group on the benzenoid ring hardly affect on TAase mediated catalytic activity
DAMC, 2 a model acetoxy drug was found to modulate the activities of enzyme proteins, such as cytochrome P-450 linked mixed function oxidases (MFO), NADPH cytochrome c reductase and cytosolic GST catalyzed by TAase [3, 4]
Summary
In our earlier publications [1, 2] evidences were given for the existence of a novel enzyme acetoxy drug: protein transacetylase (TAase) present in rat liver microsomes. Eight novel 4-methylcoumarins were synthesized and characterized by spectral data (UV, IR, 1H NMR and 13C NMR) to examine structure activity relationship (SAR) of acetoxy, propoxy and butoxy derivatives of 4methylcoumarin on liver microsomal Cyt. P-450 linked MFO, NADPH cytochrome creductase and cytosolic glutathione S-transferase (GST). Compound 12 had three characteristic absorptions at 1792, 1761, 1699 cm-1 for acetoxy, carboxylic and C-2 carbonyl groups respectively in its IR spectrum.
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