ArticleMedicinal chemistry (Shariqah (United Arab Emirates))2026
Inhibitors of Phosphatidylinositol-specific Phospholipase C wit h
Article in Medicinal chemistry (Shariqah (United Arab Emirates)), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPhosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, both of which play crucial roles in regulating biochemical processes. Despite the wellestablished link between elevated PI-PLC activity and pathophysiological conditions, no PI-PLC inhibitors are currently in clinical development. Moreover, existing inhibitors demonstrate only limited potency.
objectiveDue to the structural similarity with known inhibitors with a
methodsThe newly synthesized compounds were evaluated for their ability to inhibit PI-PLC activity in porcine platelet lysate and porcine brain homogenate, as well as their inhibitory potency against the recombinant isoenzymes PLCγ1 and PLCγ2. The assay measured the release of diacylglycerol from L-α- phosphatidylinositol using HPLC coupled with MS detection. Furthermore, the specificity of selected compounds was assessed by determining their inhibitory potency against other surface-active enzymes through HPLC-based assays.
resultsIt was found that DL-1-O-dodecylsulfonyl-myo-inositol-3,5-bisphosphate inhibits PI-PLC activity at micromolar concentrations. However, its maximum achievable inhibitory effect was limited to approximately 70%. Through structural modifications, inhibitors were developed that led to near complete inhibition of PIPLC activity. The study also revealed that the alleged PI-PLC inhibitor U73122, still frequently cited in the literature to demonstrate PI-PLC involvement in biochemical processes, is unsuitable for this purpose. Consistent with observations by others, its inhibitory activity in bionucleophile-containing cell or tissue preparations was found to be significantly lower than its activity against purified PI-PLC enzymes. Additionally, U73122 was shown to inhibit other enzymes, such as cytosolic phospholipase A
conclusionNew compounds exhibiting significant inhibitory activity against PI-PLC have been identified. The findings could prove valuable in the development of clinically applicable PI-PLC inhibitors, particularly for the treatment of cancer. Additionally, the
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