Mono-, di-, and triaryl substituted tetrahydropyrans as cyclooxygenase-2 and tumor growth inhibitors. Synthesis and biological evaluation.
Rationally designed tetrahydropyrans (THPs) carrying one, two, or three aryl rings and other substituents were synthesized by the allylation of beta-hydroxy ketones followed by iodocyclization. It has been observed that compounds with one aryl ring on THP are moderate inhibitors of cyclooxygenase-1 (COX-1) (IC(50) = 0.3 microM) and cyclooxygenase-2 (IC(50) = 0.17 microM) with poor selectivity index (SI = 2-3) for COX-2. The presence of two aryl rings enhanced their inhibitory activities for COX-2 (IC(50) = 0.9-5.5 nM). Selectivity for COX-2 over COX-1 also increased (SI = 50-1900), while triaryl substituted THPs, along with high inhibition (IC(50) = 0.57-4.0 nM), also exhibited excellent selectivity for COX-2 over COX-1 (SI = 3200-44000). Similar to the experimental results of increased COX-2 inhibition and selectivity with the increase in the size of the molecule, their docking in the active sites of COX-1 and COX-2 also showed same trend. Seven compounds from the category of di- and triaryl substituted THPs exhibited average GI(50) over all the human tumor cell lines in the range 1.6-3.2 microM and showed in vitro therapeutic indices of 8-17.
Singh
Palwinder
P
Department of Chemistry, Guru Nanak Dev University, Amritsar-143005, India. palwinder_singh_2000@yahoo.com
Bhardwaj
Atul
A
D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006131:Growth Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006841:Hydrocarbons, Aromatic; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D006131:Growth Inhibitors; D006841:Hydrocarbons, Aromatic; D011714:Pyrans