Synthesis and LTB4 receptor antagonist activities of the naturally occurring LTB4 receptor antagonist leucettamine A and related analogs

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Abstract
The isolation and structure determination of the naturally occurring LTB4 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 [H-3]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 [H-3]LTB4 binding to its receptors on intact human U-937 cells with a K(i) = 3.5 +/- 0. 8 muM 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 (K(i) = 2.4 +/- 0.2 muM).

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