Synthesis and LTB4 receptor antagonist activities of the naturally occurring LTB4 receptor antagonist Leucettamine A and related analogues.
The isolation and structure determination of the naturally occurring LTB4 receptor antagonist Leucettamine A (1) was recently reported. Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [3H]LTB4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1) is achieved by a convergent route which takes advantage of the elements of symmetry within the molecule. Syntheses of analogues of 1, which lacked the same degree of symmetry, are achieved by a different approach starting from alpha-amino acids. The natural product 1 inhibits [3H]LTB4 binding to its receptors on intact human U-937 cells with a Ki = 3.5 +/- 0.8 microM and is devoid of measurable agonist activity at the concentrations tested. 2-Amino imidazole analogues of 1 lacking the dioxolane groups were prepared. Generally these are significantly less potent than 1. However, one (26), designed on the basis of a putative structural overlay with LTB4, demonstrated potency comparable to that of the natural product (Ki = 2.4 +/- 0.2 microM).
Boehm
J C
JC
Department of Medicinal Chemistry, Smithkline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Gleason
J G
JG
Pendrak
I
I
Sarau
H M
HM
Schmidt
D B
DB
Foley
J J
JJ
Kingsbury
W D
WD
D002118:Calcium / Q000097:blood; D004149:Dioxoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004149:Dioxoles; D007093:Imidazoles; D018102:Receptors, Leukotriene B4; C080227:leucettamine A; D007975:Leukotriene B4; D002118:Calcium