Synthesis and biological evaluation of acyclic triaryl ( Z)-olefins possessing a 3,5-di- tert-butyl-4-hydroxyphenyl pharmacophore: Dual inhibitors of cyclooxygenases and lipoxygenases

Abstract

A new class of regioisomeric acyclic triaryl ( Z)-olefins possessing a 3,5-di- tert-butyl-4-hydroxyphenyl (DTBHP) 5-lipoxygenase (5-LOX) pharmacophore that is vicinal to a para-methanesulfonylphenyl cyclooxygenase-2 (COX-2) pharmacophore were designed for evaluation as selective COX-2 and/or 5-LOX inhibitors. The target compounds were synthesized via a highly stereoselective McMurry olefination cross-coupling reaction. This key synthetic step afforded a ( Z):( E) olefinic mixture with a predominance for the ( Z)-olefin stereoisomer. Structure–activity studies for the ( Z)-1-(3,5-di- tert-butyl-4-hydroxyphenyl)-2-(4-methanesulfonylphenyl)-1-phenylalk-1-ene regioisomers showed that COX-1 inhibition decreased, COX-2 inhibition increased, and the COX-2 selectivity index (SI) increased as the chain length of the alkyl substituent attached to the olefinic double bond was increased (Et → n-butyl → n-heptyl). In this group of compounds, inhibition of both 5-LOX and 15-LOX was dependent upon the length of the alkyl substituent with the hex-1-ene compound 9c having a n-butyl substituent exhibiting potent inhibition of both 5-LOX (IC 50 = 0.3 μM) and 15-LOX (IC 50 = 0.8 μM) relative to the inactive (IC 50 > 10 μM) Et and n-heptyl analogs. Compound 9c is of particular interest since it also exhibits a dual inhibitory activity against the COX (COX-1 IC 50 = 3.0 μM, and COX-2 IC 50 = 0.36 μM, COX-2 SI = 8.3) isozymes. A comparison of the relative inhibitory activities of the two groups of regioisomers investigated shows that the regioisomers in which the alkyl substituent is attached to the same olefinic carbon atom (C-2) as the para-methanesulfonylphenyl moiety generally exhibit a greater potency with respect to COX-2 inhibition. The 4-hydroxy substituent in the 3,5-di- tert-butyl-4-hydroxyphenyl moiety is essential for COX and LOX inhibition since 3,5-di- tert-butyl-4-acetoxyphenyl derivatives were inactive inhibitors. These structure–activity data indicate acyclic triaryl ( Z)-olefins constitute a suitable template for the design of dual COX-2/LOX inhibitors.