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 LTB 4 receptor antagonist Leucettamine A (1) was recently reported. 1 Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [ 3 H] LTB 4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1 , 2-amino-4,5-bis[[3,4-(methylenedioxy)phenyl]methyl]-1-methylimidazole) 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 α-amino acids. The natural product (1) inhibits [ 3 H]LTB 4 binding to its receptors on intact human U-937 cells with a K 1 =3.5 ± 0.8 μM 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 1-methyl-2-amino-4-[[4-(4-hydroxybutyl)phenyl]methyl]-5-(phenylmethyl)imidazole (26), designed on the basis of a putative structural overlay with LTB 4 , demonstrated potency comparable to that of the natural product(K 1 =2.4 ± 0.2 μM)