Design, synthesis and anti-inflammatory evaluation of PEGylated 4-methyl and 4,8-dimethylcoumarins.
Aberrant interaction between the leukocyte and the endothelial cell (EC) resulting from the deregulated expression of cell adhesion molecules (CAMs) on the endothelium results in uncontrolled inflammation leading to various inflammatory disorders. The existing drugs used to modulate the cytokine-induced expression of cell molecules have severe side effects. Therefore, there is an unmet therapeutic need to develop potent and safe drugs to treat inflammatory disorders. In the present study, novel PEGylated and non-PEGylated 4-methyl and 4,8-dimethylcoumarin derivatives were designed, synthesized and, evaluated for ICAM-1 inhibitory activity. The PEGylated coumarins were synthesized in two different ways. In the first approach, diesters of 4-methyl and 4,8-dimethylcoumarin were co-polymerized, separately with poly(ethylene glycol) using Candida antarctica lipase under solventless conditions. In the other approach, 4-methyl and 4,8-dimethylcoumarins were suitably converted to their bromo analogues and were tethered to already synthesized PEGylated polymers. Synthesized derivatives were evaluated for anti-inflammatory activities with respect to their ability to inhibit the TNF-alpha induced ICAM-1 (intercellular cell adhesion molecule-1) on human endothelial cells. It was found that PEGylated 4-methyl and 4,8-dimethylcoumarin derivatives were more effective than their non-PEGylated analogues to inhibit ICAM-1 expression. The present study opens new vista for PEGylated non-steroidal anti-inflammatory compounds and their further investigations.
Pandey
Mukesh K
MK
Institute of Nano-science and Engineering Technology, University of Massachusetts Lowell, One University Avenue Lowell, MA 01854, USA.
Balwani
Sakshi
S
Sharma
Pramod K
PK
Parmar
Virinder S
VS
Ghosh
Balaram
B
Watterson
Arthur C
AC
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D003374:Coumarins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D011092:Polyethylene Glycols