12(R)-methyl-leukotriene B3: a stable leukotriene B analogue toward the reductase metabolism.
Biological potencies of 12(R)-methyl-LTB3 [12(R)-Me-LTB3] and 12(S)-Me-LTB3 and their stability toward reductase metabolism are described. 12(R)- and 12(S)-Me-LTB3 of more than 95% chemical purity were synthesized highly stereoselectively via the palladium catalyzed coupling reaction of the vinylborane derived from the enzyme 1 and Sia2BH with the iodide 2 of R and S configuration. To assess biological activity of 12-Me-LTB3, cytosolic free calcium ([Ca2+]i) rise in rat PMNLs and binding affinity to the LTB4 receptors were compared with those of natural LTB4. The potency of 12(R)-Me-LTB3 was found to be almost equal to LTB4, while, by complete contrast, 12(S) isomer showed very low activity of 1/200-1/400. These results indicate that the C(12) hydroxyl group of R configuration is essential to elicit the biological activity and that [Ca2+]i rise elicited by 12-Me-LTB3 is mediated through interaction with the LTB4 receptors. Stability of 12(R)-Me-LTB3 toward the reductase metabolism was evaluated by using rat PMNLs. Thus, rat PMNLs were incubated at 37 degrees C with 12(R)-Me-LTB3 and LTB4, respectively. The amount of 12(R)-Me-LTB3 was almost unchanged up to 30 min under these conditions, though LTB4 was rapidly consumed in a time-dependent manner, thus strongly indicating that 12(R)-Me-LTB3 is not metabolized via the reductase pathway.
Shimazaki
T
T
Department of Biomolecular Engineering, Tokyo Institute of Technology, Japan.
Kawajiri
K
K
Kobayashi
Y
Y
Sato
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D007975:Leukotriene B4 / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology / Q000031:analogs & derivatives; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000378:metabolism; D018102:Receptors, Leukotriene B4; D013237:Stereoisomerism
D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C081156:12-methylleukotriene B3; D007975:Leukotriene B4; D010088:Oxidoreductases; C071224:leukotriene B4 reductase; D002118:Calcium