Synthesis and biochemical evaluation of benzyl propargyl ethers as inhibitors of 5-lipoxygenase.
A series of benzyl propargyl ethers were synthesized and tested as inhibitors of 5-lipoxygenase, the key enzyme involved in leukotriene biosynthesis. Among these, optimum activity was displayed by 1-(2-heptynyloxymethyl) benzene 12 (IC50 1.2 microM). Addition of carboxyl group at the end of the alkyl side chain attached to the acetylenic group abolished the inhibition. Selective reduction of the acetylenic group to cis or trans double bond reduced the inhibitory potential, the cis isomer 24 showing more than 20-fold higher inhibition than the trans isomer 25. Introduction of sulphur in place of oxygen in the alkyl side chain attached to the (carboxyalkyl) benzyl group also reduced the inhibition. The IC50 value of 12, towards rabbit reticulocyte 15-LOX is > 50 fold higher than that of 5-LOX. These results indicate that compound 12 is a specific inhibitor of 5-LOX.
School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India.
N B
NB
Barhate
Madhava C
MC
Reddy
P Srinivas
PS
Reddy
R D
RD
Wakharkar
P
P
Reddanna
D000480:Alkynes / Q000737:chemistry*; D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry*; D001671:Biochemistry / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008956:Models, Chemical; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D013329:Structure-Activity Relationship
D000480:Alkynes; D004791:Enzyme Inhibitors; D004987:Ethers; D016859:Lipoxygenase Inhibitors; C531209:propargyl ether; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase