Fluorocurcumins as cyclooxygenase-2 inhibitor: molecular docking, pharmacokinetics and tissue distribution in mice.
OBJECTIVE
The purpose of the current study was to assess the effect of newly synthesized Curcumin analogs on COX-2 protein by molecular docking studies and by assessments of the effect of one such analog (CDF) on nuclear factor NF-kappaB and PGE(2). In addition, we have determined the pharmacokinetics and tissue distribution of CDF in mice compared to Curcumin.


METHODS
Molecular docking on COX-2 protein was assessed by standard computer modeling studies. PGE(2) assay in conditioned media was done utilizing high sensitivity immunoassay kit following manufacturer's instructions, while NF-kappaB was done by routine EMSA. Serum pharmacokinetics and tissue distribution studies were carried out using the validated high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods.


RESULTS
The molecular docking showed that fluorocurcumin analogs do not introduce any major steric changes compared to the parent Curcumin molecule, which was consistent with down-regulation of NF-kappaB and reduced PGE(2) levels in cells treated with CDF. Pharmacokinetic parameters revealed that CDF had better retention and bioavailability and that the concentration of CDF in the pancreas tissue was 10-fold higher compared to Curcumin.


CONCLUSIONS
Our observations clearly suggest that the bioavailability of CDF is much superior compared to Curcumin, suggesting that CDF would be clinically useful.
Padhye
Subhash
S
D.Y.Patil Institute of Pharmaceutical Sciences, Pune, 411018, India.
Banerjee
Sanjeev
S
Chavan
Deepak
D
Pandye
Shubhangini
S
Swamy
K Venkateswara
KV
Ali
Shadan
S
Li
Jing
J
Dou
Q Ping
QP
Sarkar
Fazlul H
FH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; D003474:Curcumin